Journal articles: 'TP 7.5 UL 2008'

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Peterson, Julie A., Adam Kanack, Dhirendra Nayak, et al. "Prevalence and Clinical Significance of Low Avidity HPA-1a Antibodies in Women Exposed to HPA-1a During Pregnancy." Blood 120, no. 21 (2012): 266. http://dx.doi.org/10.1182/blood.v120.21.266.266.

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Abstract Abstract 266 Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal antibodies specific for fetal platelet antigens and is the most common cause of intracranial hemorrhage in full term infants. The antigen HPA-1a, carried on beta 3 integrin (GPIIIa), is the most common trigger for NAIT and the 2% of women who are HPA-1a-negative are at risk to produce such antibodies. Most HPA-1a antibodies causing NAIT can be easily detected but it is not rare for an HPA-1a negative mother who lacks detectable antibodies to give birth to an infant with thrombocytopenia. Several recent reports suggest that low avidity HPA-1a antibodies not detected by conventional serologic methods are responsible for some of these cases (Socher 2009, Bakchoul 2011). To examine this question, we retroactively analyzed a cohort of 3478 suspected NAIT cases referred for laboratory diagnosis. Among 677 HPA-1a-negative mothers, we identified 61 in whom HPA-1a-specific antibodies were not detected by conventional methods. Surface plasmon resonance (SPR) analysis enables ligand-receptor interaction to be studied in real time without washing the target. Using this approach, we studied reactions of IgG from the 61 archived serum samples against purified GPIIb/IIIa isolated from group O platelets and identified 18 samples that reacted preferentially with the HPA-1a-positive version of the integrin in comparison with HPA-1a-negative integrin. Information defining clinical status was obtained on 13 of these cases by follow-up communication. Seven cases had been referred because of neonatal thrombocytopenia. Platelet nadirs ranged from 8,000/ul to 141,000/ul (median 38,000/ul). Five of the 7 infants had bleeding and were given maternal platelet transfusions and/or IVIgG. Normal platelet counts were achieved after 4 to 70 days (median 7 days). One infant had a normal platelet count, however IVIgG had been given to its mother throughout pregnancy. The remaining 5 cases were referred in mid-pregnancy because an HPA-1a-negative sister previously gave birth to an infant with NAIT. Four of these infants had normal platelets at birth; one had mild TP (platelets 125,000/ul). Only 3 of 12 mothers typed for HLA were positive for HLA-DRB3*0101, a marker found in >95% of women who make “conventional” HPA-1a antibodies during pregnancy (p < 0.001). The ability of human antibodies to cause destruction of human platelets in vivo can be studied in the NOD/SCID mouse, which lacks xenoantibodies normally found in other species (Newman 2007). Serum from 4 mothers was available in quantities sufficient for mouse studies; three of the four maternal sera caused accelerated destruction of HPA-1a-positive, but not HPA-1a-negative platelets. These findings indicate that low-avidity HPA-1a antibodies not detectable by conventional serologic methods are made by a subset of women exposed to the HPA-1a antigen during pregnancy and that some, but not all of these antibodies are capable of causing NAIT, which is usually mild, but can be severe. Women negative for HLA-DRB3*0101 may be especially prone to produce antibodies of this type. Maternal-fetal incompatibility for platelet antigens other than HPA-1a is very common and many apparent NAIT cases not involving HPA-1a go unresolved. The possibility that low avidity antibodies specific for antigens other than HPA-1a are responsible for some of these cases deserves study. Disclosures: No relevant conflicts of interest to declare.

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von Drygalski, Annette, Brian Curtis, Dan Bougie, Scott Ahl, Kelty Baker, and Richard H. Aster. "Immune-Mediated Thrombocytopenia in Patients Treated with Vancomycin." Blood 106, no. 11 (2005): 1238. http://dx.doi.org/10.1182/blood.v106.11.1238.1238.

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Abstract Numerous drugs are known to cause immune thrombocytopenia (TP) mediated by antibodies (abs) that bind to platelets only when the sensitizing drug is present in soluble form. The widely used antibiotic, vancomycin, has been implicated as a cause of TP only in 8 case reports and little is known about antibodies possibly responsible for this complication. We characterized clinical and serologic aspects of TP occurring in 39 patients during treatment with vancomycin. In this group, TP developed after 1–27 days of treatment (median 6 days) and plt nadirs ranged from 1,000 to 60,000 plts/uL (median 14,000 plts/uL). Bleeding occurred in 14 patients and contributed to a fatal outcome in 3. TP persisted for 1–17 days after discontinuing vancomycin (median 7 days). Platelets eventually returned to baseline in all surviving patients. Serum obtained after the onset of TP was studied for vancomycin-dependent, platelet-reactive abs by flow cytometry and by solid phase ELISA using immobilized plt glycoproteins (GP) as targets. Vancomycin-dependent antibodies detected in patients and normal subjects IgG only IgM only IgG + IgM No antibody Total Patients with TP 21 (54%) 5 (13%) 13 (33%) (0)%) 39 Normal individuals 58 (21%) 4 (1%) 1 (0%) 210 (77%) 273 Results of flow cytometric studies are summarized above. All patients had IgG and/or IgM abs that reacted with normal plts in the presence, but not in the absence of vancomycin. The IgG mean fluorescence intensity (MFI) signal in the presence of drug was 1.6 to 32.0 times stronger (mean ratio 5.7) than that obtained in the absence of drug. Vancomycin-dependent IgG abs were also identified in 59 of 273 normal individuals but were much weaker than abs detected in patients (p = 0.004). IgM abs (mean ratio 5.7, range 1.6 – 34) were found in 18 of 39 patients (46%). Weaker IgM abs were found in only 5 of 273 normal subjects (1.8%) (p = 0.001). Two patient abs studied in ELISA reacted preferentially with GPIIb/IIIa. Studies to determine the frequency of abs in patients given vancomycin who do not develop TP are in progress. These findings provide evidence that TP in patients given vancomycin can be caused by drug-dependent abs specific for GPIIb/IIIa that are stimulated by vancomycin exposure. IgG and IgM abs in patients with TP are generally much stronger than drug-dependent, platelet-reactive immunoglobulins found in some normal subjects. The significance of the latter abs is presently unknown. Drug-dependent IgM abs are found almost exclusively in patients with vancomycin-associated TP and may be diagnostic. Patients treated with vancomycin often have life-threatening bacterial sepsis and may have various reasons for developing TP. Serologic testing for drug-dependent, platelet-reactive IgG and IgM abs may provide a means of identifying those in whom vancomycin should be discontinued.

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Drullinsky, P., M. N. Fornier, S. Sugarman, et al. "Dose-dense (DD) cyclophosphamide, methotrexate, and fluorouracil (CMF) at 14-day intervals: A pilot study of every 14- and 10–11-day dosing intervals for women with early-stage breast cancer." Journal of Clinical Oncology 27, no. 15_suppl (2009): 590. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.590.

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590 Background: CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2) is an option for adjuvant therapy for patients with low risk early stage breast cancer. DD regimens as predicted by mathematical models of cancer growth and treatment response are superior. We previously demonstrated the safety of DD EC (epirubicin/cyclophosphamide) followed by paclitaxel at 10–11 day (d) intervals. We investigated the feasibility of administering DD adjuvant CMF every 14 d and then every 10–11 d in a 2-stage phase II trial. Methods: An initial cohort (A) was treated q 14 d with PEG-filgrastim (Neulasta) support. A second cohort (B) was treated every 10–11 d with filgrastim/Neupogen x 5 d and then, based on feasibility, modified (cohort C) to use 7 d filgrastim. The primary end point was feasibility defined as having ANC > 1.5 x 103/uL on day 1 of planned treatment for all 8 cycles with no grade 3 or higher non-hematologic toxicity. All three cohorts were tested using a Simon's two-stage optimal design with type I and type II errors set at 10%. This design would effectively discriminate between true tolerability (as protocol-defined) rates of< 60% and> 80%. Cohort A: 38 pts with early stage breast cancer were accrued from 3/2008 though 6/2008. Cohort B: 7 pts were accrued from June 2008 through August 2008. Cohort C: Is still open with 16 pts accrued from August 2008 through December 5, 2008. Results: Median age 51: range 38 to 78. Cohort A: 29/38 pts completed 8 cycles of CMF. The regimen was considered feasible. 2 other pts completed 7 cycles and were withdrawn for depression and grade 2 transaminitis. The 7 other pts completed between 1 and 6 cycles of CMF were withdrawn as follows: 3 personal, 1 (grade 3) bone pain, 2 allergy unrelated to CMF, and 1 seizure. Cohort B: 7 pts were accrued. 6 out of 7 pts could not complete 8 cycles of chemotherapy secondary to neutropenia and 1 secondary to grade 3 ALT elevation. Cohort C: Accrual has not been completed. 16 pts are currently enrolled. Conclusions: Dose dense adjuvant CMF is feasible at 14 d intervals with PEG-filgrastim support. Adjuvant CMF every 10–11 days with filgrastim given for 5 days beginning day 2 is not feasible. Accrual is ongoing for CMF at 10–11 days with filgrastim x 7 days. Updated results will be available for Cohort C. [Table: see text]

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Seetharam, Mahesh, Olga K. Weinberg, Li Ren, et al. "AML Patients with Monosomal Karyotype Are Characterized by Absence of NPM1 and FLT3 Mutations and Worse Clinical Outcome." Blood 114, no. 22 (2009): 2638. http://dx.doi.org/10.1182/blood.v114.22.2638.2638.

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Abstract Abstract 2638 Poster Board II-614 Background: The importance of cytogenetics in prognosis of AML is now widely recognized and accepted in clinical practice. A recent study found that autosomal chromosomal monosomy predicted for an adverse outcome. The goal of this study is to characterize patients with monosomal karyotype by mutation status and clinical features. Methods: One-hundred forty consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2008 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. An abnormality was considered clonal when at least two metaphases had the same aberration, except for clonal monosomy, which required at least three metaphases. The karyotype analysis was based on 20 or more metaphases. All samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 77 males and 63 females with a median age of 58 (range 17-83). Cytogenetic risk-group stratification resulted in 14 patients with favorable, 88 with intermediate and 28 with unfavorable risk status. Loss of one or more autosomal chromosomes was present in 18 /130 patients (13.8%) with available cytogenetic studies. A single autosomal monosomy was found in 5 patients while 13 patients had two or more autosomal monosomies. The most common chromosomes lost in these 18 patients included 7 (55% of 18 cases), 5 (50%), 17 (33%), 21 (22%), 20 (22%), 22 (17%) and 18 (11%). Using the 2008 WHO criteria, there were 66 AML with myelodysplasia-related changes (AML-MRC), 55 AML not otherwise specified (AML-NOS), 14 AML with either t(8;21), inv(16) or t(15;17) and 5 therapy related AMLs. Overall, 35 patients (25% of all patients) had a NPM1 mutation (19 of which were FLT3 mutated), 33 had FLT3-ITD mutation (24%), 11 had FLT3-D835 (8%) and 11 had a CEBPA mutation (8%) (4 of which were FLT3 mutated). Patients with monosomal karyotype were significantly older (83 vs. 59 years, p=0.0125) and presented with lower WBC (34 vs. 66 K/uL, p=0.0006), lower platelets (41 vs. 64 K/uL, p=0.0111), and lower blasts (38% vs. 65%, p=0.0030) as compared to the rest of AML patients. In addition, patients with monosomal karyotype were more frequently diagnosed with AML-MRC (16/18 vs. 48/107, p=0.0034) and exhibited a decreased frequency of NPM1 mutation (0/18 vs. 28/107, p=0.0138) and FLT3-ITD mutation (0/18 vs. 29/107, p=0.0117). Clinical outcome data showed that patients with monosomal karyotype had a significantly worse OS, PFS and CR compared to the rest of AML patients (OS p=0.001, PFS p=0.002 and CR p=0.0262). Dividing patients by number of monosomies showed that patients with 2 or more monosomies had a significantly worse OS (p=0.0001) and PFS (p=0.0045) than patients without any monosomies. However, no difference in OS or PFS was seen when comparing patients with 1 monosomy to those with 2 or more monosomies. Within the AML-MRC group, monosomal karyotype correlated with lower WBC (17 vs. 37 K/uL, p=0.0005), lower platelets (21 vs. 35 K/uL, p=0.0095), lower blasts (19% vs. 36%, p=0.0015) and shorter OS (p=0.0322) and PFS (p=0.0084). Conclusion: AML patients with monosomal karyotype exhibit a significantly worse OS, PFS and lower CR as compared to other AML patients. Most of patients fall within the newly defined AML-MRC group and are characterized by significant absence of NPM1 and FLT3-ITD mutations. Disclosures: No relevant conflicts of interest to declare.

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Shastri, Aditi, Ira Braunschweig, Stefan Klaus Barta, et al. "Stimulation of Adrenergic Activity By Desipramine Enhances Hematopoietic Stem and Progenitor Cell Mobilization Along with G-CSF in Multiple Myeloma - a Pilot Study of Safety and Efficacy." Blood 126, no. 23 (2015): 3101. http://dx.doi.org/10.1182/blood.v126.23.3101.3101.

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Abstract Background: Hematopoietic stem cell release is regulated by the sympathetic nervous system through the β (3) adrenergic receptor [Mendez-Ferrer et al. Nature 2008]. Peripheral sympathetic nerve neurons express the G-CSF receptor and stimulation of peripheral sympathetic nerve neurons with G-CSF reduced norepinephrine (NE) reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability [Lucas et al Blood 2012]. Based on preclinical data, we investigated the NE reuptake inhibitor desipramine in HSC mobilization. Despite augmentation with Plerixafor (CXCR4 inhibitor), 20% of all patients fail to mobilize 6*10^6 CD34 cells/kg in myeloma and the collection rate with G-CSF alone is 51.1% [Diperiso et al Blood 2012]. The cost of upfront plerixafor is $9,081 per patient while desipramine costs $40. We undertook a feasibility study of adult patients with MM undergoing autologous transplantation (ASCT) to study safety and efficacy of mobilization with desipramine and G-CSF. Patients & Methods: From 2013- 2014, 10 patients between the ages of 18-70, eligible for ASCT were enrolled. Desipramine 100mg daily was administered for 7 days, starting 4 days prior to starting G-CSF (D-3) and continue along with G-CSF for a total of 7 days. CBC and CD34 counts were determined on Day+5. If CD34 counts were > 10/ul, stem cell collection was commenced and if < 10/ul, plerixafor was added as salvage therapy. The endpoints were safety and efficacy in mobilizing CD34 cells for ASCT in patients with multiple myeloma. This trial was registered at clinicaltrials.gov as NCT01899326. Results Six of ten patients enrolled completed the protocol and underwent stem cell transplantation. Reasons for not completing were 1. Lack of insurance coverage 2. Non-compliance with study treatment 3. Disease relapse prior to ASCT. Five patients did not have any grade 3 or 4 adverse events and 1 had disease-related Grade 4 hypercalcemia and Grade 2 AKI at the time of stem cell mobilization. No patients had significant treatment related adverse effects. All 6 patients who completed the protocol achieved the target collection of 5*10^6 CD34 cells/kg. Four patients achieved 6*10^6 CD34 cells/kg or more and the remaining 2 patients achieved 5.52 and 5.92 *10^6 CD34 cells/kg respectively. Among the 6 patients, 2 patients received salvage plerixafor. The median time to achieve WBC >1000/ul, ANC >500/ul and platelets>20k was 11.5, 11, 13.5 days Table 1. Age Ind. Regimne Disease status P PB CD34/ul CD34 collected *10^6 / kg Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine D1 D2 D3 D4 D2 D3 D4 ANC >0.5 Platelets> 20k G1,G2 G3,G4 1 62 Free λ VRD VGPR N 45.8 66.0 7.01 7.01 12 13 none none 2 50 Free λ VRD VGPR N 88.0 143.5 12.22 12.22 12 12 none none 3 58 IgA VCD VGPR N 38.0 67.7 31.6 4.22 2.75 6.97 13 17 none none 4 70 IgAκ VRD VGPR Y 2.40 40.2 16.6 4.31 1.61 5.92 12 14 none none 5 56 IgGκ VCD VGPR Y 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 6 70 IgGλ VD RD Relapse N 76.2 97.1 5.54 5.54 11 20 AKI hypercalcemia P-Plerixafor; V-Velcade; R-Lenalidomide; D-Dexamethasone; C-Cyclophosphamide Conclusions Overall G-CSF + Desipramine combination appears to be safe, well tolerated and shows signs of efficacy. G-CSF and desipramine was successful in 4/6 (66%) and all achieved the stem cell collection in 2 days or less. Desipramine, GCSF and Plerixafor was successful in all (6/6) patients to achieve a target of 5*10^6 CD34 cells/kg. The mean number of CD34 cells collected in the desipramine+ G-CSF mobilisers was 7.24*10^6 CD34 cells/kg which, based on historical data, is higher than what would be expected with G-CSF alone even though 3/4 of these patients had lenalidomide as induction therapy. Based on these results, a phase II clinical study evaluating the efficacy of G-CSF with desipramine with or without salvage plerixafor in multiple myeloma and lymphoma will be initiated. Disclosures Barta: Seattle Genetics: Research Funding.

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Morioka, Chie, Masahito Uemura, Tomomi Matsuyama, et al. "Decreased Activity of Plasma ADAMTS13 Parallels Enhanced Endotoxemia in Patients with Severe Acute Pancreatitis: Relationship to Multiorgan Failure." Blood 112, no. 11 (2008): 4541. http://dx.doi.org/10.1182/blood.v112.11.4541.4541.

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Abstract Background: Severe acute pancreatitis (SAP) frequently progresses to pancreatitis-associated multiorgan failure (MOF) with high mortality. Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and the formation of platelet thrombi, ultimately leading to MOF. We demonstrated that the imbalance between decreased ADAMTS13:AC and increased UL-VWFM could contribute to SAP pathogenesis through enhanced thrombogenesis, and serve as an early prognostic indicator for SAP patients (Scand J Gastroenterol, 2008, 26:1). Endotoxin has been considered to be the principle activator of the systemic inflammatory response syndrome, which predisposes patients for MOF and/or pancreatic necrosis, ultimately leading to SAP. We investigated the relationship of endotoxin to ADAMTS13:AC and its related parameters, and tried to explore their potential role on the development of MOF in patients with SAP. Methods: We sequentially determined plasma endotoxin concentration, ADAMTS13:AC and its related parameters in 13 SAP patients (APACHE-II score mean 6.6 ± 2.7), who were admitted into intensive care unit of our hospital between 2004 and 2006. Eleven patients were survivors and two were non-survivors whose APACHE II scores were 10 and 12 died of MOF, respectively. The degree of MOF was evaluated according to the SOFA score. Endotoxin concentration was determined by a chromogenic substrate assay (Toxicolor LS –M Set, Seikagaku Kogyo Co.) with kinetic analysis after pretreatment with detergent, Triton X-100, and heating at 70 °C for 10 min. Plasma ADAMTS13:AC was determined by a sensitive chromogenic ELISA (ADAMTS13-act-ELISA: Kainos Inc.). Plasma UL-VWFM was analyzed by a vertical SDS-1.0% agarose gel electrophoresis. Plasma VWF antigen (VWF:AG), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor -α (TNF-α) were measured by ELISA. Results: In normal healthy controls (n=20), plasma endotoxin concentration was 7.9±1.7 pg/ml (mean ± SD). The concentration in the SAP patients significantly increased at day 1 (means 65 pg/ml, p&lt;0.001) and at day 2 (88 pg/ml, p&lt;0.001) as compared to healthy controls. The values, thereafter, gradually decreased in 8 survivors (55 pg/ml at day 5, 53 pg/ml at day 7, 27 pg/ml at day 14), while in remaining 3 survivors needing necrosectomy, the concentration further increased (98 pg/ml at day 5, 178 pg/ml at day 7), and decreased to 20 pg/ml at day 14 at the recovery phase. In two non-survivors, the endotoxin levels increased from 37 pg/ml at day 1 to 462 pg/ml at day 2 in one needing necrosectomy, and showed 51 pg/ml at day 1 in another at the age of 91. Within 1 or 2 days after admission, the ADAMTS13:AC was lower in SAP patients (mean 29%, p&lt;0.001) than in healthy controls (99%), and gradually recovered in the 11 survivors but further decreased in the 2 non-survivors. On admission, VWF:Ag was higher (402%, p&lt;0.001) in SAP patients than controls (100%). VWF:Ag gradually decreased in the survivors, except in the 3 survivors needing a necrosectomy, but remained high in the non-survivors. UL-VWFM positive patients showed lower ADAMTS13:AC (25% vs. 42%, p&lt;0.05) and higher VWF:Ag ( 481% vs. 332%, p&lt;0.05), resulting in higher ratio of VWF:Ag to ADAMTS13:AC (25.2 vs. 9.1, p&lt;0.02), as compared to UL-VWFM negative ones. Patients with higher endotoxin concentration more than 50 pg/ml showed lower ADAMTS13:AC than those without (22% vs. 43%, p&lt;0.05). Plasma endotoxin concentration positively correlated with the ratio of VWF:Ag to ADAMTS13:AC (r=0.732, p&lt;0.005). The SOFA score correlated positively with plasma endotoxin concentration (r=0.604, p&lt;0.03), IL-8 (r=0.843, p&lt;0.001), and the ratio of VWF:Ag to ADAMTS13:AC (r=0.700, p&lt;0.01), and inversely with the ADAMTS13:AC (r= − 0.601, p&lt;0.03). Conclusion. The imbalance between decreased ADAMTS13:AC and increased UL-VWFM is closely related to enhanced endotoxemia, which may contribute to the development of SAP and subsequent MOF through enhanced thrombogenesis.

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Ohinata, Aki, Michael J. Wallace, Michael J. Overman, Jonathan Phillips, Robert A. Wolff, and Cathy Eng. "The role of partial splenic embolization (PSE) in the management of chemotherapy-induced thrombocytopenia." Journal of Clinical Oncology 30, no. 4_suppl (2012): 569. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.569.

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569 Background: Chemotherapy-induced splenomegaly is a relatively known treatment complication, where the clinical sequale of hypersplenism is persistent thrombocytopenia due to splenic sequestration. For cancer patients (pts) undergoing chemotherapy, thrombocytopenia may result in a dose delay or dose reduction, thus reducing dose intensity. The impact of refinement in technique with limited volume embolization (50-70%) of the spleen upon morbidity and mortality has not been well studied. Methods: A retrospective review of gastrointestinal cancer pts undergoing PSE for thrombocytopenia to facilitate the initiation or resumption of systemic chemotherapy between Jan. 2008 and March 2011 was completed. Pre- and post-PSE platelet (plt) counts within 30 days were evaluated for benefit of treatment. Objectives included the re-initiation of systemic therapy and post-PSE plt count >150 (< 30 days). Periprocedural laboratory values and adverse events were recorded. Results: PSE was performed in 79 pts. Median prior chemotherapy regimens = 2 (range 1-3). The median follow-up was 12M (range: 7-31). The mean plt count prior to PSE was 80 K/ UL (3-196). Post-PSE platelet count of > 150 was achieved in 52 (66%) pts with a mean peak plt count of 219 K/UL. Six (8%) pts underwent repeat PSE due to recurrent thrombocytopenia after initiation of systemic therapy. Re-initiation of chemotherapy was achieved in 59 (79%) pts. The median duration of chemotherapy following PSE was 8M (95% CI: 4.2-14.2); median overall survival was 33M (95% CI: 10-47). Post-procedure fever developed in 7 (9%) pts and pleural effusion, atelectasis, or consolidation was reported in 8 (10%) pts. Seventeen (21%) pts developed reversible grade 1 hyperbilirubinemia. Median length of hospital stay was 3 days (interquartile range 1-5 days). 60-day mortality rate was 9% (7 of 79). Conclusions: Partial splenic embolization (PSE) is a safe and effective method of managing thrombocytopenia secondary to chemotherapy-induced hypersplenism to facilitate re-initiation of systemic therapy in cancer patients. PSE may be considered as a potential option in patients with good performance status to facilitate further systemic chemotherapy.

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Medeiros, Larissa A., Samir K. Nabhan, Marco Antonio Bitencourt, et al. "Long-Term Clinical Outcome of Patients with Acquired Aplastic Anemia In Brazil Using Cyclosporine-A (CSA) and Prednisone (PRED): 20 Years Follow-up From a Single Institution." Blood 116, no. 21 (2010): 2234. http://dx.doi.org/10.1182/blood.v116.21.2234.2234.

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Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Beltran, Brady E., Erick Cotacallapa, and Jorge J. Castillo. "Survival and Clinicopathological Characteristics of EBV-Positive Diffuse Large B-Cell Lymphoma." Blood 120, no. 21 (2012): 1588. http://dx.doi.org/10.1182/blood.v120.21.1588.1588.

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Abstract Abstract 1588 Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients. Methods: Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001). Conclusions: Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS. Disclosures: No relevant conflicts of interest to declare.

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Awan, Farrukh, David Deremer, Elaine Mebel, Samith Thomas Kochuparambil, and Anand P. Jillella. "Utility of Plerixafor In Addition to Chemotherapy and G-CSF Mobilization Regimens." Blood 116, no. 21 (2010): 4443. http://dx.doi.org/10.1182/blood.v116.21.4443.4443.

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Abstract Abstract 4443 Introduction: Various chemotherapeutic agents particularly cyclophosphamide (CY) are utilized in combination with growth factors in an attempt to increase the number of stem cells available for collection in the peripheral blood. Plerixafor (P) is a reversible antagonist of CXCR4 and interrupts its interaction with SDF-1. This results in a rapid release of hematopoietic stem cells from the marrow to the circulation. Recent pivotal phase III trial data has established the efficacy of P in combination with G-CSF (G) in patients who had failed prior attempts at stem cell collection. However, there is limited data about the utility of plerixafor in patients who are being mobilized with chemotherapy and G. Method: In this single institution study of uniformly treated patients we describe our experience with the use of P as a salvage option in patients who fail to optimally mobilize CD34+ cells (>5 × 106 CD34+ cells/kg). Patients received CY (3-4 g/m2) followed by GCSF (10 mcg/kg) from day 1 to day 10. Thirteen patients (6 NHL, 4 MM, 2 Hodgkin lymphoma, 1 Ewings sarcoma) received salvage P from 2008–2010. Their outcomes were compared with 10 matched, historic controls mobilized with (CY n=8; CY + etoposide n=1; CY + topotecan n=1) plus G-CSF (10mcg/kg/d) identified from our institutional database. Data was collected on mobilization and transplant outcomes and analyzed utilizing SPSS version 13.0. Patients receiving P were closely matched to historic controls (CY+G). Result: Both groups were similar with regards to age, gender, disease type, prior therapies and performance status (p>0.05 for all). Patients in the P arm received a median of 2.5 doses (range 1–8). The mean CD34+ count was 21.5cells/ul in the P arm and 32.5 cells/ul in the CY+G arm (p=0.2). Similarly, no significant difference was observed in the average number of apheresis sessions in the P vs. CY+G arms (4.2 vs. 4.4, p=0.8) or the total number of CD34+ stem cells collected (4.0×106/kg vs. 3.9×106/kg, p=0.9). However, 7 out of the 13 patients who received P did have an increase of >10 CD34+ cells/ul in their peripheral blood. Utilizing a cut-off of 5×106 CD34+/kg, 3 (23%) patients in the P arm and 3 (30%) patients in the CY+G arm had a successful harvest. Three NHL patients required >4 doses of P, but all eventually collected >2 × 106 CD34+ cells/kg. Neutrophil and platelet engraftment dynamics were similar in both groups of patients. Median time to neutrophil engraftment was 10 days for both groups, p=0.8, and to platelet engraftment was 22 days vs. 20.5 days, p=0.1, respectively for P vs. CY+G. Conclusion: Our limited single-center retrospective case-controlled outcomes data, suggests that when compared with CY+G, the addition of P as a salvage agent does not significantly improve mobilization outcomes. Further evaluation is needed to combine P with CY+G in terms of optimal timing and potentially dosing of chemotherapy agents utilized. We suggest that the combination P+G would provide better potential outcomes such as improved collection and less hospitalization and reduce the use of chemo-mobilization prior to an Autologous Hematopoietic Stem Cell Transplant. Disclosures: No relevant conflicts of interest to declare.

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Benevolo, Giulia, Pietro Pioltelli, Michele Spina, et al. "Cerebrospinal Fluid Flow Cytometry Analysis in Newly Diagnosed Aggressive Non-Hodgkin Lymphomas at High Risk for Leptomeningeal Disease: Result of a Multicentric Prospective Italian Study." Blood 114, no. 22 (2009): 2919. http://dx.doi.org/10.1182/blood.v114.22.2919.2919.

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Abstract Abstract 2919 Poster Board II-895 Background: Flow cytometry (FCM) assessment of cerebrospinal fluid (CSF) has recently been known to increase the rate of positivity of occult leptomeningeal disease (LD) in comparison to conventional cytologic examination (CC). However it's still unknown its prognostic value. Patients and methods: The aim of this study was to compare CC vs FCM in a large cohort of patients with newly diagnosed aggressive NHL at high risk for LD (diffuse large B-cell lymphoma (DLBCL) IPI 2-3 and elevated LDH with at least two extranodal sites or with bone marrow, testis, paranasal sinuses, orbit or paravertebral involvement; Burkitt lymphoma (BL); blastoid variant of mantle cell lymphoma (B-MCL); B-cell precursor lymphoblastic lymphoma (B-LL); HIV+ aggressive lymphoma patients). All patients were required to have no evidence or signs of neurological disease. All patients received intrathecal standard prophylactic therapy with 12 mg of methothrexate except for BL that were given prophylaxis with 50 mg of liposomial aracytin for a total of 4 doses. CFS samples were analysed both with CC and FCM. The incidence of positive test for occult LD with FCM and CC was compared using the McNemar test for paired data. Results: Between August 2004 and June 2008, a total of 159 consecutive patients were enrolled in 11 Italian centres and underwent evaluation of CSF. Out of these, 128 patients (80%) were considered at high risk of occult LD. Clinical characteristics were: median age 53 years (IQR:43-62); DLBCL 96 patients (75%); BL 21 pts (16%); B-MCL 6 pts (5%); B-LL 5 pts (4%); 26 pts (20%) were HIV positive. FCM was able to detect a clonal population in 17 out of 128 patients (13%) whereas CC detected abnormal cells only among 7 pts (5%)(p= 0.0002). Therefore, 10 patients (8%) were discordant: FCM+/CC-. Among the 128 patients, there was no association between the CFS total protein, glucose level and the presence of positive analysis of FCM, whereas the difference between the number of WBC cells in CSF was significantly higher in patients with positive versus negative FCM with a median value of 12 cells/ul (IQR: 3.5;40) versus 1.0 cells/ul (IQR: 0.0;3.0) (p=0.0120). Univariate and multivariate analyses, using logistic models, showed that abnormal LDH (OR 3.98, 95%CI: 1-15.92)(p=0.05) and number of WBC cells in CSF ≥5 (OR 4.57, 95%CI:1.37-15.33)(p=0.014) were the only predictive factors of a positive test performed by FCM. From date of diagnosis, overall median follow up of survivors was 14 months (IQR:8-22). We observed 39 (30%) systemic progressions, 6 (5%) CNS progressions (in 5 cases an isolated CNS progression whereas 1 pts experienced a CNS along with systemic progression). Thirty-two (25%) patients died and causes of deaths were as follows: 27 progressive disease, 1 infection, 1 treatment related toxicity, 1 hepatitis, 2 unknown. PFS at 1 year was 71% (95%CI:62-78) in the whole group of patients. The progression risk was significantly higher in patients both FCM+/CC+ compared with patients both FCM-/CC- (1-yr PFS 43% vs 74%) (HR 3.8 95%CI:1.6-9.0) (p=0.003). An higher but not significant risk of progression was found in pts discordant (FCM+/CC-) with respect to patients both FCM-/CC- (1-yr PFS 65% vs 74%) (HR 1.61, 95%CI:0.63-4.11) (p=0.315). In the univariate and multivariate analyses performed with Cox models, we found that the presence of ECOG PS≥2 (HR 2.14, 95%CI: 1.14-4)(p=0.018) and level of protein in CSF >40/ul (HR 1.83 95%CI: 1.01-3.29)(p=0.045) were prognostic factor of PFS. Conclusion: FCM assessment of CSF increase the rate of positivity of occult LD compare with CC but it's clinical relevance is still to be clearly defined. Our preliminary data suggest that patients both FCM+/CC+ have an higher risk of progression compared with those both negative, whereas discordant cases may have an intermediate prognosis. Disclosures: No relevant conflicts of interest to declare.

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Pomares, Helena, Isabel Sánchez-Ortega, Esther Alonso, et al. "Validation of the Low Risk Prognostic Scoring System (LR-PSS) in Patients with VERY Low, Low and Intermediate Risk IPSS-R Myelodysplastic Syndrome. Results from a Single Center." Blood 126, no. 23 (2015): 2902. http://dx.doi.org/10.1182/blood.v126.23.2902.2902.

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Abstract Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the IPSS; however, this score system does not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) but a poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic impact according to OS and leukemia free survival of the LR-PSS when applied to a population MDS patients with very low, low and intermediate IPSS-R. Methods: A total of 789 consecutive patients diagnosed with MDS (01/1992-12/2014) at the Catalan Institute of Oncology of Barcelona were included in the study. 413 (52%) had available cytogenetics and therefore, IPSS-R was calculated. Overall, 371 (89%) patients were classified as very low, low and intermediate IPSS-R and included in the study. Results: 123 (30%) patients were classified as very low, 182 (44%) low and 66 (16%) intermediated IPSS-R risk MDS; median age 72 years (range 32-101) and 258 (69%) male. 1.4 % CRDU, 7.6 % RA, 41.6 % RCMD, 16.2 % RAEB‐1, 4.1 % RAEB‐2, 25.9 % CMML and 3.2 % MDS‐U with isolated 5q deletion according to the 2008 WHO classification. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.8 g/dL (5.5-17.1), 152 x109/L (1-1492) and 3 % (0-17), respectively and fifty-three (14.3 %) patients had unfavorable LR-PSS cytogenetics. For the whole population, median follow up was 6.6 years (range 6-7.7). At the time of last follow up, 48.2 % (179) had died and only 49 (13%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups three well-differentiated prognostic categories could be identified: 58 patients (15.6%) category 1, scores 0-2; 277 (74.6%) patients category 2, scores 3-4 and 36 (9.8%) patients category 3, scores 5-7 with significantly different overall survival and leukemia free survival. Median OS for categories 1 (9.4 years; 95% CI 6.7-12), 2 (6 years; 95% CI 5-7.1) and 3 (2.6 years; 95% CI 2.1-3) were significantly different (p<0.001; Figure 1). Moreover, the rate of progression to acute myeloid leukemia was 5% (3/58), 13% (37/277) and 25% (9/36) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, the LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early intervention. Further studies are warranted. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Fig 1. Kaplan-Meier survival for patients with very low-, low- and intermediate IPSS-R risk assigned to categories 1 to 3 by LR-PSS. Disclosures Sureda: Takeda: Consultancy, Speakers Bureau.

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Schroeder, Thomas, Christian Saure, Ingmar Bruns, et al. "Clinical Efficacy of Sorafenib in Patients with Acute Myeloid Leukemia (AML) and Activating FLT3-Mutations." Blood 114, no. 22 (2009): 2057. http://dx.doi.org/10.1182/blood.v114.22.2057.2057.

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Abstract Abstract 2057 Poster Board II-34 Introduction: Patients with acute myeloid leukemia (AML) and activating mutations in the Fms-like tyrosine-3 (FLT3) gene have an abysmal prognosis. Together with other groups we have recently demonstrated the clinical activity of the multikinase and FLT3 inhibitor sorafenib in patients with FLT3+ AML (Safaian et al., 2008; Zhang et al., 2008; Metzelder et al., 2009). We here present clinical results of 8 AML FLT3+ patients treated with sorafenib either prior or after allogeneic stem cell transplantation (allo-SCT) on an off-label basis. Patients, Treatment and Response Evaluation: Between February 2007 to August 2009 eight patients with AML (7 female, 1 male, median age: 47 years, range 23-63 years) were treated with sorafenib 800 mg daily (dose range 400-800 mg daily) for a median duration of 37 days (range 5-225 days). Six patients had an internal tandem duplication mutation (ITD), while 2 patients carried a tyrosine kinase domain (TKD) mutation. One patient received sorafenib at diagnosis before remission induction while all other patients had relapsed and/or refractory disease. Response and toxicity were evaluated regularly and defined according to established criteria. Results: Two of four patients who received sorafenib for refractory relapse after allo-SCT (median time to relapse 78 days, range 59-84 days) achieved complete remission (CR) (1 CR, 1 complete molecular remission (CMR) with disappearance of extramedullary chloromas) and survived 164 and 594 days, respectively. One of these patients died after another systemic relapse, while the other died as result of a CNS-chloroma being still in CMR in bone marrow (BM). In the 2 other patients sorafenib induced a hematological response (HR) and these patients survived 188 and 329 days before they died of progressive disease. Of the 4 patients treated prior allo-SCT, 2 had relapsed during consolidation after a previous CR, 1 had refractory disease and 1 was treated at diagnosis. Both patients with relapse showed response to sorafenib treatment thereby permitting allo-SCT. While one achieved HR, the other had regression of multiple isolated cutaneous relapse manifestations. Both patients are still alive at day +81 and day +16 in CMR and CR, respectively. The patient, who was primary refractory to double induction and high-dose cytarabine had a reduction of BM-blasts. She discontinued sorafenib because of neurotoxicity after 13 days. This patient reached a CR after allo-SCT, but died on day + 379 of another relapse. At the time of AML diagnosis the fourth patients had a WBC of 377.000/ul. Despite treatment with hydroxyurea, cytarabine and leukapheresis WBC could not be lowered <100.000/ul within 5 days and the patient developed pulmonary leukostasis syndrome. At this point of time FLT3 TKD mutation was detected and sorafenib was started promptly. Within the next 5 days WBC (peripheral blasts %) declined from 119.700/μl (98%) to 5.300/μl (28%) without tumor lysis syndrome facilitating induction therapy with cytarabine, daunorubicin and etoposide. Sorafenib therapy was continued in parallel and led to a CMR without increased toxicity. In general, sorafenib treatment was well tolerated. Besides neurotoxicity in one patient extrahematological side effects were almost limited to transient dermatological symptoms in two patients, which resolved after discontinuitation of sorafenib. Four Patients developed neutropenia grade IV and thrombopenia grade IV, which was not exclusively attributable to sorafenib, but also to the underlying AML. Conclusion: Our results add to the growing evidence that sorafenib is highly active in patients with FLT3+ AML. In view of the clinical course of our patients we suggest that sorafenib can achieve temporary disease control, but should be integrated into induction and consolidation regimens to achieve curative treatment. Recent data on synergistic effects between sorafenib and cytarabine and the CXCR4 inhibitor AMD3100 suggest these combinations for new clinical trials. Disclosures: Off Label Use: individual treatment approach of patients with refractory FLT3+ AML with multikinase inhibitor sorafenib, which is approved by EMEA + FDA for renal cell carcinoma.

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Strouse, John J., Joshua Field, Regina D. Crawford, and Sophie Lanzkron. "Antecedent Transfusion and Primary Hemorrhagic Stroke in Adults with Sickle Cell Disease." Blood 112, no. 11 (2008): 1437. http://dx.doi.org/10.1182/blood.v112.11.1437.1437.

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Abstract Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age &gt;18 years) with SCD from Johns Hopkins and Barnes- Jewish Hospitals and Duke University Medical Center from January 1989 to April 2008. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic hemorrhages and hemorrhagic conversion of ischemic strokes were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 19 cases (mean age 29 years, range 18 – 66, 42% male) and 18 controls (mean age 34 years, range 19 – 61, 39% male). Most cases (14/18) had sickle cell anemia (HbSS) and 22% had a prior overt stroke; controls had HbSS (9/17), HbSB0thalassemia (1), or HbSC (7) and 41% had a history of overt stroke. Cases presented with headache (89%) and seizure (37%) and less frequently hemiparesis (27%). Controls presented with hemiparesis (78%), headache (57%), and rarely seizure (11%). Twelve cases had IPH including those with extension to the ventricles (1), subarachnoid (2) or both (2); six had SAH including ventricular extension (1). Potential causes of hemorrhagic stroke included moyamoya (4), aneurysms (3), anticoagulation (1) and ateriovenous malformation (1). Four cases (21%) and no controls died during the initial hospitalization. More cases (82%) than controls (44%, P&lt;0.05) had elevated systolic blood pressure at the time of stroke. At steady-state, cases had lower hemoglobin (mean ± SEM 8.5 ± 0.6 g/dl vs. 9.7 ± 0.6 g/dl), lower blood pressures (systolic 121 ± 4 vs. 127 ± 6 mm Hg, diastolic 71 ± 4 vs. 72 ± 9 mm Hg) and higher platelet counts (399,231 ± 74,024/ul vs. 362,200/ul ± 39,927/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration at the time of stroke increased 1.3 g/dl (19%) from steady-state in cases and 0.01 g/dl (2%) in controls (p&lt;0.05). Seven cases had simple transfusions (between 1 and 11 days before their primary hemorrhagic stroke) in preparation for surgery (3), and for aplastic crisis (1), bacteremia (1), acute renal failure (1), or suspected acute chest syndrome (1). Only 1 control was transfused; and 1 with HbSS had a hemoglobin of 14.5 g/dl at the time of stroke (from excessive erythropoietin administration). In this group of adults with SCD, primary hemorrhagic stroke was associated with antecedent transfusion. Identifiable causes include moyamoya from obstructive cerebral vasculopathy, aneurysms and other vascular malformations, and rarely coagulopathy. Mortality was similar to that previously described. The association of recent transfusion and cerebral vasculopathy with hemorrhagic stroke suggests caution in the use of simple transfusion in adults with SCD and moyamoya or cerebral aneurysms. Table 1: Associations with Primary Hemorrhagic Stroke Variable Odds Ratio (95% CI) P-value Genotype (HbSS vs. other) 3 (0.6 – 17) NS Moyamoya 5 (0.4 – 260) NS Transfusion in the last 14 days 13 (1.3 – 630) &lt;0.02 NSAID in the last 14 days 2.9 (0.3 – 36) NS

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Blum, William, Rebecca B. Klisovic, Alison Walker, et al. "Epigenetic Targeting Via Transcriptional Inhibition of DNA Methyltransferase: a Phase I Study of Bortezomib in Combination with 5-Azacytidine in Adults with Relapsed or Refractory Acute Myeloid Leukemia (AML)." Blood 114, no. 22 (2009): 2065. http://dx.doi.org/10.1182/blood.v114.22.2065.2065.

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Abstract Abstract 2065 Poster Board II-42 Background: Hypomethylating agents have significant clinical activity in myelodysplastic syndromes (MDS) and AML. In AML, we recently demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via depletion of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which results in down-regulation of DNMT1 mRNA and enzyme, DNA hypomethylation and re-expression of otherwise hypermethylated target genes. Based on this preclinical work, we designed a phase I dose escalation study of 5-azacytidine (AZA) in combination with bortezomib in AML. Methods: Adults with relapsed or refractory AML by WHO criteria and preserved organ function with ECOG ≤2 were eligible. Previous decitabine or AZA was permitted. Patients received AZA at 75mg/m2 IV daily for days (d) 1-7. Bortezomib was gradually dose escalated–dose level 1 (DL 1): 0.7mg/m2 by IV push given immediately after AZA on d 2 and 5; DL 2: 0.7mg/m2 on d 2, 5, 9, and 12; DL 3: 1.0mg/m2 on d 2, 5, 9, and 12; and DL 4: 1.3mg/m2 on d 2, 5, 9, and 12. Cycles were repeated every 28 d, regardless of count recovery or response at least until 3 cycles were administered. Responses were graded by International Working Group criteria for AML (Cheson, JCO 2003). Bortezomib was discontinued after 3 cycles if no objective response of complete remission (CR), CR with incomplete count recovery (CRi), or partial remission (PR) was achieved, but AZA could be continued beyond this timepoint in the absence of disease progression. For responding patients, 12 or more cycles of therapy were permitted. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT. Six additional patients were treated at the recommended phase 2 dose (RP2D). Results: 23 patients were enrolled with a median age of 65 years (range, 42-81) and had received a median of 2 prior inductions (range, 1-5). Median presenting WBC was 3,700/uL (500-59,100/uL); median BM blast was 26% (2-93%). 14 patients were refractory to last therapy received, including 4 with primary refractory AML. 9 patients had relapsed disease; all but 2 of these had prior CR duration <1 year. Patients received a median of 2 cycles of study therapy (range, 1-12+ cycles). Dose escalation was halted once the target bortezomib dose was reached; the RP2D was AZA at 75mg/m2 d 1-7 plus bortezomib 1.3mg/m2 d, 2, 5, 9, 12. Though no toxicities were considered to be DLT in this study, infection and/or febrile neutropenia were universal. Death within 8 weeks occurred in 5 patients (22%) due to pneumonia (1), sepsis (1), or progressive disease (3). Two patients had discontinuation of bortezomib after 2 cycles due to Grade 3 neuropathy; only 1 patient received bortezomib beyond 3 cycles. In 3 patients without objective response (and with no progression), AZA alone was continued after 3 cycles of combination therapy; each reported a subjective improvement in fatigue without bortezomib. Overall, the objective response rate was 26% (6/23). Responses were as follows: 3- CR, 2- CRi, and 1-PR. One CRi patient (in cytogenetic remission also) who discontinued study treatment after 2 cycles due to unrelated trauma subsequently had complete count recovery, but a repeat marrow examination was not performed. Three patients went on to allogeneic transplantation due to response achieved. Response followed the typical pattern of azanucleoside activity, requiring more than one cycle of therapy; the median number of cycles to initial response was 2 (range, 1-5). 5/6 responders had response to combination therapy; one patient responded following 5 cycles of treatment, the last 2 cycles with AZA as a single agent. Conclusions: The combination of 5-azacytidine and bortezomib is well tolerated and active in this cohort of relapsed or refractory AML patients. Additional studies to further elucidate the role of proteasome inhibition as a mediator of hypomethylating activity in AML are warranted. Correlatives studies are ongoing. Disclosures: Blum: Celgene: Research Funding.

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Wang, Weiwei, Gabrielle Meyers, Haibo Li, Ying Wang, Lisong Shen, and Guang Fan. "Retrospect Reviews of PNH Tests with Long-Term Follow-up in a Single Institution." Blood 134, Supplement_1 (2019): 948. http://dx.doi.org/10.1182/blood-2019-124896.

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I ntroduction : Paroxysmal nocturnal hemoglobinuria (PNH) often presents as hemolysis and/or bone marrow failure. Flow cytometric testing can accurately detect PNH. However, the long term studies on PNH clone size and how it relates to clinical course are few. We sought to understand how PNH clone size correlates with clinical course over time and the impacts on clone size with different treatments. Here we report long term clone size monitoring and clinical data of 57 patients with PNH in a single intuition. Methods : High sensitivity PNH flow cytometry (0.01% limit of detection) was performed with FLAER-FITC, CD64-PE, CD14-ECD, CD15-PC5, CD24-AA7500, CD45-KO for neutrophils & monocytes; CD59-PE and CD235a-AA750 for RBCs. Retrospective analysis was done in the positive PNH cases from 2008-2019 at OHSU. Total 173 cases for 57 patients; including 27 females and 30 males, 52 adults and 5 pediatrics, with a mean age of 45 (range 9-78). We also reviewed results of serum LDH, bone marrow biopsies and molecular/cytogenetics of these patients. Among of these patients, 18 patients (11 females and 7 males, mean age 49.33, age range 29-73) with long term (at least over 4 years) follow-up have more than 3 PNH tests. Besides PNH clone on RBC and PMN, we also reviewed results of WBC count (x103/ul), Hb (g/dL), PLT (x103/ul) serum LDH (U/L), bone marrow biopsy reports and molecular/cytogenetics findings in these patients. Results: Among 57 patients, there are 30 aplastic anemia (AA) patients (53.63%), 7 AA patients progressing to PNH (AA&PNH, 12.28%), 5 myelodysplastic syndromes (MDS, 8.77%), 12 PNH patients (21.05%), 1 pancytopenia, 1 autoimmune disease, 1 thrombosis. The diagnosis of AA and MDS were confirmed by bone marrow biopsy and molecular/cytogenetics. Significantly higher levels of all PNH clones were observed in PNH and AA/ PNH, compared to AA (all P &lt;0.001) and MDS (all P&lt;0.05) shown in Figure A-D. LDH was higher in PNH and AA/PNH than AA and MDS groups (P&lt;0.001, Figure E). LDH demonstrated positive correlation with PNH clone size in RBC-type-III, neutrophils and monocytes (all P&lt;0.0001, R= 0.4447, 0.5469, 0.5711, respectively, Figure F). No correlation was observed between LDH and RBC-type-II. Long term (4-11 years ) follow up include 18 patients were divided into 4 groups: 5 AA treated with immunosuppressant only, 5 AA treated with immunosuppressants and/or eltrombopag, 5 classic PNH or AA that progressed to PNH treated with immunosuppressants and/or eculizumab, and 3 PNH with observation and supplements only. The study showed immunosuppression only has lowest PNH clone size for both RBC and WBC (Figure G-H). As for the Hb and WBC count, there were no statistics differences among 4 groups (Figure I-J). Decreased PLT was detected in eltrombopag group (Figure K). Significantly, increased LDH was observed in the observation/supplement group (Figure L). Interestingly, all these 3 patients without special treatment have high PNH clones and LDH from diagnosis to now over 10 years. Despite receiving basic supportive care, the patients' clinical courses have been stable with only supplementation of vitamin B12 and Folic Acid. Conclusions : Positive PNH test was most frequently seen in AA patients. AA has lower PNH clone size and LDH than those of PNH patients or AA progressed to PNH patients. For all patients, PNH population showed positive correlation with LDH. Our study suggest that it is necessary to follow PNH clone size, as this may impact the decision of when to start therapy with what agents. Figure Disclosures No relevant conflicts of interest to declare.

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Liu, Yang, Ali Tabarroki, Valeria Visconte, et al. "A Prognostic Scoring System for Unclassifiable MDS and MDS/MPN." Blood 120, no. 21 (2012): 1701. http://dx.doi.org/10.1182/blood.v120.21.1701.1701.

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Abstract Abstract 1701 Patients with features of MDS and MDS/MPN who do not fulfill diagnostic criteria for a specific subtype of MDS and MDS/MPN are categorized by the WHO 2008 diagnostic criteria as MDS-U and MDS/MPN-U. MDS includes RCUD, RCMD, RARS, RAEB-1, RAEB-2, MDS-U and 5q- syndrome while MDS/MPN includes CMML, JMML, atypical CML and MDS/MPN-U. The natural history of patients who belong to these disease subtypes are hetergeneous. Although included in currently accepted prognostic scoring schemes like the International Prognostic Scoring System (IPSS) in MDS, Revised IPSS, and MD Anderson prognostic scoring schemes, they represent a minority of patients in the cohort. Within MDS/MPN cases, the clinical heterogeneity of diseases that belong to this group has been recognized and has led to the development of the MD Anderson prognostic Scoring System for CMML. Similarly, a prognostic scoring system for JMML has also been devised to help in risk stratification and treatment decisions. However, there are no prognostic scoring systems for unclassified cases of MDS and MDS/MPN. Clinically, we observe stark differences in treatment responses and clinical outcomes between MDS/MPN-U and other MDS/MPN-subtypes, and MDS-U with other subtypes of MDS. In total, we studied 92 patients with unclassifiable cases seen at the Cleveland Clinic, including MDS/MPN-U (n=52 [57%]) and MDS-U (n=40 [43%]). Hematologic, bone marrow (BM), cytogenetic (metaphase cytogenetic [MC]/SNP-A) and survival data were collected. Survival comparisons were made by Kaplan-Meier analyses. Cox-proportional hazard ratio was used to determine factors predictive of outcomes. A p-value of ≤0.05 was considered statistically significant. In this cohort, median age at diagnosis was 69 years (20–88), 65% (60/92) were male, and 35% (32/92) were female. Median follow-up was 21 months. Median absolute neutrophil count (ANC) was 2.69k/uL (0–87), peripheral blood (PB) blasts 0% (0–70%), hemoglobin 9.6g/dL (5–15), and LDH 260 U/L (105–2113). SNP-A karyotyping was completed for 65 patients, and new cytogenetic mutations were detected in 72% (47/65): (gains [64%], losses [57%], UPDs [25%]). In 52% (49/92) of patients, we sequenced molecular mutations that typically confer poor prognosis in myeloid neoplasms, such as ASXL1, IDH1/2, EZH2, K/NRAS, CBL and TP53. This sequencing revealed a mutational frequency of 18% (9/49) in TET2, 14% (7/49) in ASXL1, 6% (3/49) in EZH2 exons 18–19, 2% (1/49) in CBL, 2% (1/49) in NRAS, and 4% (2/49) in TP53. No mutations were found in IDH1/2 and KRAS. In univariate analysis of clinciopathologic factors, the following factors were found to be associated with overall survival: ANC (≥8.5 vs <8.5k/uL) (p<.0001), presence of PB blasts (p<.0001), presence of immature myeloid cells (p<.0001), presence of BM blasts (>3% v. ≤3%) (p<.0001), age (≥65 vs <65) (p<.0003), LDH (≥550 vs <550U/L) (p<.0004), albumin (≤3.6 vs >3.6g/dL) (p<.0008), IPSS Risk Group (Int-2/high vs int-1 vs low) (p<.01), IPSS-R Risk Group (High/very high vs low vs very low) (p<.001), WBC (≥15 vs <15k/uL) (p<.001), Hgb (≤11.5 vs >11.5g/dL) (p<.003), % BM cellularity (>85 vs ≤85%) (p<.009), and number of cytopenias (3 vs 2 vs 1 vs 0) (p<.04). In multivariate analysis, age (HR=3.47 CI 1.85–6.51, p=.001), ANC (HR=2.27 CI 1.15–4.49, p=.02), Hgb (HR=2.11 CI 1.07–4.14, p.03), peripheral blasts (HR=2.27 CI 1.19–4.36,p=.01) and LDH (HR=2.40 CI 1.11–5.16, p=.03) were independent predictors of OS in unclassifiable cases of MDS and MDS/MPN. Consequently, a prognostic scoring system was developed to include these factors. A simple scoring assigned 2 points each to an ANC of ≥8.5k/uL, the presence of peripheral blood blasts, hemoglobin ≤ 11.5g/dL, LDH ≥ 550U/L; and 3 points for age ≥65. This results in three well-separated prognostic groups: (favorable [score:0–3], median OS=67.4 months; intermediate [score:4–6],median OS=28.9 months; and poor [score: ≥ 7], median OS=13.1 months, p<.0001). 34, 21, and 24 patients were placed in these three groups, respectively. In conclusion, clinic-pathologic factors like age, LDH levels, ANC count, Hgb levels and peripheral blood blasts are helpful in predicting survival outcomes in patients with unclassifiable cases of MDS and MDS/MPN disorders. This is the first scoring system devised specifically for patients with this disease subtype. Disclosures: No relevant conflicts of interest to declare.

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Arnan Sangerman, Montserrat, Helena Pomares, Esther Alonso, et al. "Validation of Low Risk Prognostic Scoring System (LR-PSS) in Patients with Lower Risk IPSS-R Myelodysplastic Syndrome. Results from a Single Center." Blood 134, Supplement_1 (2019): 4270. http://dx.doi.org/10.1182/blood-2019-127901.

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Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the International Prognostic Scoring System (IPSS) (Greenberg et al, Blood 1997) and IPSS-R (Greenberg et al, Blood 2012). Recently, next-generation sequencing genetics has been incorporated into management of MDS, however its use is limited in routine clinical practice. Current prognostic models do not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) and poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin <10g/dl, platelet count <50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic value of Low Risk Prognostic Scoring System(LR-PSS) in a population of lower risk MDS patients (very low, low and intermediate IPSS-R) analyzing as endpoints overall survival (OS) and leukemia free survival (LFS). Methods: A total of 890 consecutive patients with MDS (01/1992-7/2018) diagnosed at the Catalan Institute of Oncology in Barcelona were included in the study. 539 (60%) had available cytogenetics and therefore, IPSS-R could be assessed. 474 (88%) patients were classified as very low, low and intermediate IPSS-R and were included in the study. Results: 178 (37.6%) patients were classified as very low, 219 (46.2%) low and 77 (16.2%) intermediated IPSS-R risk MDS. Median age at diagnosis was 73 years (range 32-101). 332 (70%) were male. According to the 2008 WHO classification, 2.5% CRDU, 7.4% RA, 42.2% RCMD, 13.7% RAEB‐1, 3.6% RAEB‐2, 26.4% CMML and 4.2% MDS‐U with isolated 5q deletion. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.6 g/dL (5.5-17.1), 157 x109/L (1-1492) and 2 % (0-17), respectively. 84 (17.7%) patients had unfavorable LR-PSS cytogenetics at diagnosis. Median follow up time for survivors was 5.4 years (range 0.25-23.8). At the time of last follow up, 58.4 % (277) had died and 71 (15%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups, three well-differentiated prognostic categories could be identified: 103 patients (21.7%) category 1 (scores 0-2); 330 (69.6%) patients category 2 (scores 3-4) and 41 (8.7%) patients category 3 (scores 5-7) with significant different OS and LFS. Median OS for categories 1, 2 and were 7.1 years (95% CI 4.9-9.2), 5.7 years (95% CI 4.7-6.7) and 2.8 years (95% CI 2.1-3.6), p<0.001 (Figure 1), respectively. Rate of progression to acute myeloid leukemia was 10% (10/99), 15% (48/323) and 27% (11/411) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early treatment intervention. Disclosures Sureda: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy; Roche: Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau.

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Cesaro, Simone, Gloria Tridello, Andrea Giulio Zanazzo, Stefano Frenos, Chiara Messina, and Sandro Dallorso. "PEG-Filgrastim for Autologous Peripheral CD34+ STEM CELL Collection in Pediatric Oncological PATIENTS: A PHASE II STUDY." Blood 112, no. 11 (2008): 2312. http://dx.doi.org/10.1182/blood.v112.11.2312.2312.

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Abstract Pegfilgrastim (Peg-f) is the pegylated long-acting formulation of filgrastim that allows recovery from chemotherapy-induced neutropenia by single-shot administration. Data on adults show that Peg-f is safe and efficacy also in CD34+ peripheral blood stem cell collection. From May 2007 to July 2008, Peg-f was administered to 34 consecutive patients from 4 Italian pediatric centres at a dosage of 100 ug/kg (max 6 mg) for PBSC purposes. They were 21 male and 13 female, median age at diagnosis of 10 years (range 3–18), affected by solid tumour, 30 (Ewing, 9; Medulloblastoma, 5; Neuroblastoma, 5; brain tumours, 4; other, 7), acute lymphoblastic leukaemia or non-Hodgkin lymphoma, 4. The remission status at PBSC was: CR 8 (24%), VGPR 5 (15%), PR 19 (56%), SD or not known 2 (6%). The median weight was 35.5 kg (range 13.5–86) and the median number of planned infusion was 1, range 1–3. Different regimens of mobilizing chemotherapy were used, etoposide, cyclophosphamide and ifosphamide being the most frequent drugs administered. The median time to first PBSC was 10 days, range 6–15. The least threshold for CD34+ collection (20 cell/ul) was obtained in 28 of 34 patients (82%), the median value of CD34+ peak being 140 (range 20–1988). Successful PBSC was obtained in 27 patients (79%) because one very low weight child failed it for suboptimal vascular access. Sixteen of 27 patients (59%) achieved the target PBSC collection with 1 leukapheresis whilst 10 patients required a second leukapheresis. The median collection yield was 8 (range 1.9–116) and 2.45 (range 1–6) CD34+ x 106/kg) for the first and second leukapheresis, respectively. No Peg-f related adverse effects were reported. So far, 15 of 27 patients (56%) underwent a first autologous transplant whilst 4 and 1 underwent a second and third transplant, respectively. The median time from PBSC to first transplant was 64 days (range 10–154) and the median value of CD34+ x 106/kg infused was 7 (range 3–299). Different conditioning regimen were used, myeloablative doses of busulfan, thiothepa, melphalan, and etoposide being the drugs most frequently used. After a median f-up of 29 days from first transplant (range 16–176), all patients achieved a PMN count &gt; 0.5 x 109/l in a median time of 13 days (range 5–23) whilst 14 and 12 achieved a transfusion-unsupported PLT count &gt; 20 and &gt; 50 x 109/l in a median time of 13 (range 5–23) and 15 days (range 12–36), respectively. Prophylactic post-transplant G-CSF was used in 7 of 15 patients (47%) for a median time of 7 days (range 1–11). All 5 patients who performed a second or third transplant successfully engrafted for PMN and PLT. All 15 transplanted patients were alive at latest f-up. We conclude that Peg-f single-shot CD34+ mobilisation is safe and efficacy also in pediatric patients. Further prospective studies are needed to investigate the non-inferiority or superiority of Peg-f vs. filgrastim in PBSC.

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Natale, Annalisa, Stefano Pulini, Antonio Spadano, Anna Morelli, and Giuseppe Fioritoni. "Leuco-Thrombocytopenia Due to Splenomegaly in a Patient Affected by Retroperitoneal Fibrosis." Blood 112, no. 11 (2008): 4569. http://dx.doi.org/10.1182/blood.v112.11.4569.4569.

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Abstract Idiopathic retroperitoneal fibrosis (RPF) is a rare clinical entity characterized by the progressive proliferation of connective tissue in the retroperitoneum. The chronic inflammatory process can entrap the retroperitoneal structures, mainly the ureters and the great vessels. Although the causes are unknown, immunogenetic factors and immunopathologic/autoimmune mechanisms are probably involved. The pathogenesis appears to be related to IgG4 autoimmune mechanisms (“hyper-IgG4 disease”). Surgical treatments are frequently performed such as ureterolysis and aneurysm repair; steroids and immunosuppressive agents are also used. In January 2008 a 62-year-old Caucasian man was referred to our institution for mild leucopenia and progressive thrombocytopenia. In 1999 he had a diagnosis of RPF treated surigically and complicated by chronic renal failure. He did not undergo regular follow-ups during the following years. When he came to our attention his peripheral blood count showed: Hb 14.5 g/dl, WBC 3.800/uL (N 60%, L 28%, M 8%), Plt 79.000/uL, confirmed by numerous measurements. He did not present signs or symptoms of cutaneous or mucosal bleeding and he did not report any recurrence of infectious episodes. At physical examination the spleen was palpable at 5 cm from the ribs, neither liver enlargement nor superficial lymphoadenopathies were noted. A peripheral blood (PB) smear showed only anisocytosis of red blood cells. To exclude an underlying hematologic disorder a bone marrow (BM) aspiration and a BM trephine biopsy were performed, both demonstrating a regular representation of the three hematopoietic series without any pathologic patterns. Cytogenetic examination revealed normal karyotype and molecular biology analyses resulted negative for Bcr/Abl rearrangement and for mutation V617F of JAK2 gene. Routine laboratory tests including liver function, LDH, Beta2 microglobulin serum levels, autoimmune tests, PB mononuclear cell immunophenotyping, viral sierology resulted within normal range. Abdominal ultrasound showed about 95 cm2 homogeneous splenomegaly and revealed an hyperechogenic rounded mass measuring 5–6 cm that completely embraced the splenic hilum. Splenic vein at the source was not visible and splenic flow was not measurable because of the hilum compression. Splenic vein in the retropancreatic site was measurable only partially: it presented thin caliber with normal directed blood flow inside. The abdominal CT exam confirmed the presence of a 5.6×7 cm solid tissue mass embracing the pancreatic tail and the splenic vessels and it extended across the spleno-pancreatic ligament. Moreover, the mass also involved the upper part of the left adrenal gland expanding until peri-renal space. Radiologically the mass was considered as RPF. In this case the retroperitoneal fibrotic tissue compresses the splenic hilum reducing the blood flow through the spleen thus causing congestive splenomegaly. The increase size of the spleen is responsible for thrombocytopenia as well as for leucopenia. The mechanism underlying splenomegaly-related thrombocytopenia is an induction of a reversible pooling of up to 90 percent of total body platelets. Both platelet production and the survival of platelets within the spleen are normal. Pooling is the major factor responsible for thrombocytopenia in uncomplicated splenomegaly. In this patient no hematologic specific treatment is indicated since neither thrombocytopenia nor leucopenia have clinical relevance. The aim of the therapy should be to reduce the progression of the fibrotic tissue to prevent further organ-related damages.

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Rosenthal, Allison C., Amylou Constance Dueck, Katherine Gano, et al. "A Phase II Clinical Trial of Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone (R-CyBor-D) in Relapsed Low Grade and Mantle Cell Lymphoma." Blood 124, no. 21 (2014): 4410. http://dx.doi.org/10.1182/blood.v124.21.4410.4410.

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Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

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Mohan, Sanjay R., Paul Elson, Ramon V. Tiu, et al. "Duration of Antecedent Complete Blood Cell Count (CBC) Abnormalities Predicts Response and Survival Rates In De Novo and Secondary AML." Blood 116, no. 21 (2010): 1040. http://dx.doi.org/10.1182/blood.v116.21.1040.1040.

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Abstract Abstract 1040 Introduction: Secondary acute myeloid leukemia (sAML) is a heterogeneous disease classification comprising patients (pts) with a history of myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) and pts with prior exposure to chemotherapy or radiation. Though sAML pts typically have lower complete remission (CR) and worse overall survival (OS) rates with induction chemotherapy, it is unknown whether pts with antecedent CBC abnormalities but without formal hematologic diagnoses prior to AML display similar poor outcomes. Methods: We retrospectively evaluated all pts with newly diagnosed, pathologically-confirmed AML treated with cytarabine-based induction chemotherapy at a single institution between 1997 and 2008 to identify both those with known antecedent hematologic disorders and those with antecedent CBC abnormalities irrespective of preceding myeloid diagnosis. sAML was classified as AML from MDS, AML from MPN, and therapy-related AML (t-AML); these groups were compared to pts classified as de novo AML with antecedent CBC abnormalities using univariate and multivariate regression analyses and recursive partitioning to determine cut-points. A CBC abnormality was defined as persistent white blood cell count (WBC) <3.5 or >12 k/uL, hemoglobin <10 or >16 g/dL, or platelet count <100 or >500 k/uL. Results: Of 413 AML pts who received induction chemotherapy, 140 were identified with sAML or antecedent CBC abnormalities; 46 (33%) had t-AML, 41 (29%) had AML from MDS, 23 (16%) had AML from MPN, and 30 (21%) had de novo AML with an antecedent CBC abnormality. The median age at AML diagnosis was 62 years (range 24–77) and differed among groups (MDS 67 years, MPN 61, t-AML 80, and de novo 62, p=.003); 49% were male. Overall, the median time from identification of a CBC abnormality to AML diagnosis was 5 months (range 2–83). The time from preceding event to sAML differed among groups (MDS 7 months, MPN 50, t-AML 53, p<.001). Unfavorable risk cytogenetics were more frequent in MDS (44%) and MPN (42%) than in t-AML (26%) or de novo (27%, p=.008). Median presenting WBC differed among groups (MDS 4.0 k/uL, MPN 9.9, t-AML 6.9, de novo with antecedent CNC abnormalities 2.7, p=.02). Among pts with de novo AML with antecedent CBC abnormalities, 18 (60%) had abnormal WBCs, 13 (43%) had anemia, and 8 (27%) had thrombocytopenia; 7 (23%) had multilineage cytopenias. Univariable analysis of CR rates among sAML pts without an antecedent CBC abnormality identified age <60 (71% vs 50% in age ≥ 60, p=.02), unfavorable cytogenetics (28% vs 75% in intermediate or favorable, p<.0001), and AML precursor (34% in MDS, 61% in MPS, and 65% in t-AML, p=.002) as significant factors. t-AML also exhibited better OS compared to prior MDS (hazard ratio [HR] 2.40, 95% confidence interval [CI] 1.38–4.19, p=.002) or MPN (HR 1.84, 95% CI 0.95–3.56, p=.07). In multivariable analysis, unfavorable cytogenetics (p=.0001) and prior MDS or MPN (vs t-AML) (HR 1.83, 95% CI 1.04–4.05), p=.04) were prognostic for worse OS. However, when an antecedent CBC abnormality was identified (n=55), t-AML exhibited poorer OS compared to prior MDS (p=.04) and de novo AML with a CBC abnormality (HR 4.79, 95% CI 1.95–11.77, p=.001). Pts whose CBC abnormality was present for ≥10 months prior to AML diagnosis had poorer OS than those for whom it was present <10 months (HR 2.06, 95% CI 1.08–3.93, p=.03), controlling for factors such as age and cytogenetics. By recursive partition analysis, pts with prior MDS, prior MPN, or de novo AML with CBC abnormality of fewer than 10 months had significantly longer median OS (20.8 months) than those with a CBC abnormality of greater than 10 months or with t-AML regardless of duration of CBC abnormality (5.9 months, HR 3.27, 95% CI 1.73–6.20, p=.0003) (Figure 1), and also exhibited higher CR rate to induction chemotherapy (78% vs 39%, p=.005). Conclusions: The presence of an antecedent CBC abnormality of greater than 10 months in both de novo and sAML patients negatively impacts CR and OS following induction chemotherapy. These pts should be considered for alternative therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

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López-González, Guillermo, Charles F. LeMaistre, Carlos Bachier, et al. "Clinical and Cost Outcomes of Double Umbilical Cord Blood Versus Bone Marrow and Peripheral Blood Unrelated Hematopoietic Stem Cell Transplants." Blood 112, no. 11 (2008): 967. http://dx.doi.org/10.1182/blood.v112.11.967.967.

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Abstract Umbilical cord blood (UCB) is a viable source of hematopoietic stem cells (HSC) however, because of the increased risk of nonengraftment associated with low total nucleated cell counts (TNC) per kg, double UCB (DCB) transplants are used in larger patients (pts). Minimal data has been collected on cost analysis and clinical outcomes comparing DCB to peripheral blood (PB) and bone marrow (BM) unrelated donor (UD) transplants. Thus, we conducted a retrospective review of DCB transplants (n=30) from January 2004 through April 2008 compared to BM (n= 23, 30%) and PB (n = 54, 70%) UD transplants during the same time period. Median age was 21 yrs (range 13–66) for DCB recipients and 45 yrs (range 0.4–67) for UD pts. UD pts were HLA typed at A, B, C, DR, and DQ and matched with donors at 9(10) (21%) and 10(10) (79%) loci [all mismatches at class I alleles]. Pts were considered for DCB transplant if a suitable 10/10 or 9/10 donor could not be identified. DCB recipients had HLA matches of 6/6, 5/6/, 4/6 and 3/6 as follows: (cord 1/ cord 2): (0.0%/6.7%), (20.0%/30.0%), (76.7%/63.3%), (3.3%/0.0%) [HLA disparity between each UCB unit and recipient was not necessarily at the same loci]. The median TNC/kg in DCB pts was 2.03x107 (range 7.9x106 – 9.3x108). Full intensity preparative regimens (BuCY2 or TBI³ 1200 cGy based) were used in 43% of UD and 50% of DCB pts. Median day to ANC>500/ul for DCB and UD pts was 23 days (range 6–66) and 15 days (range 7–52), and platelet >20,000/ul was 52 days (range 7–130) and 19 days (range 9–63), respectively. Incidences of acute GVHD ≥2 and chronic GVHD in the UD and DCB pts were 61.0% and 51% vs. 53.3% and 45%, respectively. Median follow-up was 143 days (range 12–847) for the DCB group and 242 days (range 34–1506) for the UD pts. Estimated overall survival (OS) at 1 year was 61% (95% CI: 48% to 71%) for UD pts vs. 55% (95% CI: 34% to 72%) in DCB pts (p = NS). Estimated transplant related mortality (TRM) at 100 days for UD pt was 6.5% (95% CI: 2.8% to 14.9%) and 16.7% (95% CI: 7.3% to 35.5%) (p=0.09) in DCB pts. There were 48 total deaths; 14 (46.7%) in the DCB pts and 34 (44.2%) in the UD pts. In both the DCB and UD groups, disease relapse (21.4% and 23.5%) and infection (28.6% and 14.7%) caused the majority of deaths. All facility transplant related costs were reviewed from the transplant center thru the first year post transplant, excluding pretransplant workup and care not received at the transplant center. The total median costs for DCB transplants were significantly more than the UD costs at D30, D100 and 1yr post transplant by differences of $42,067, $50,806, and $52,297, respectively (p<0.05 for each time interval). The median length of stay for initial hospitalization at start of preparative regimen was 22 days (2–144) in the UD pts and 29 days (6–103) in the DCB pts, and 60% of total median costs occurred by D30 in the DCB group compared to 52% in the UD group. In conclusion, DCB provides a viable option for HSC with comparable clinical outcomes to UD transplants, however DCB transplants are more expensive primarily because of inpatient costs in the first 30 days.

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Amaru, Ricardo, Ariel Amaru, Hortensia Miguez, et al. "Successful Treatment of HU-Refractory Polycythemia Vera with Atorvastatin and Low Dose Hydroxyurea. Results from a Pilot Study in Bolivia." Blood 126, no. 23 (2015): 5621. http://dx.doi.org/10.1182/blood.v126.23.5621.5621.

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Abstract Background Polycythemia Vera (PV) is a clonal myeloproliferative neoplasm, characterized by the JAK2V617F mutation. The main goal of current therapies for PV is to prevent thrombotic events and delay transformation to Myelofibrosis (MF) or Acute Myeloid Leukemia (AML).Treatment for PV to keep an hematocrit (Hct) level <45 %, has been associated with a reduction in cardiovascular deaths and thrombotic events (Marchioli, R et al. NEJM 2013). Currently, low-risk PV patients (<60 years and no previous thrombotic events) are treated with aspirin and phlebotomy while high-risk patients require additional cytoreductive therapy, usually with Hydroxyurea (HU). Resistance to HU is associated with an increased risk of transformation and reduced survival. This is why for HU-refractory patients, second line treatments with interferon alpha, anagrelide or even ruxolitinib are recommended. In Latin America, because of high cost and drugs availability, this last group reflects difficulties to be treated. Because statins have been reported to modulate the erythroid clonogenic activity of normal BM erythroid colonies we performed a pilot study to investigate in vitro and in vivo the biologic and clinical activity of atorvastatin in PV patients Patients and Methods Ten high risk PV patients with a median age of 64.3 years (range 58-73) entered into this study. The diagnosis of PV was done according to the 2008 World Health Organization diagnostic criteria and patients were stratified according to an algorithm proposal provided by Griesshammer et al. (Ann Hematol, 2015). The definition of HU resistance (Barosi, G et al.: BJH 2009) was applicable to five patients (median age 63.9 years) failing to achieve a satisfactory hematologic response upon treatment with more than 2 g of HU, 100 mg of Aspirin and phlebotomies. The assessment of the JAK2V617F mutation was performed as previously described (Guerini et al.: Leukemia 2009). Colony assay, proliferation and apoptosis tests were performed with or without Simvastatin (3.5 uM), as previously described (Amaru, A, Experimental Hematology 2012), on cell lines (UKE1 and K562) and bone marrow mononuclear cells obtained from PV patients and healthy donors. Patients with HU refractory PV (n=5) and high risk PV with hypercholesterolemia (n=5) were eligible to receive Atorvastatin (20 mg/day) added on the top of the ongoing treatment with phlebotomies, Aspirin (100 mg/day) and cytoreductive HU therapy (500 mg/day). All treated patients were high altitude residents (> 3.600 m.a.s.l.) of La Paz (Bolivia) where the normal Hct level of healthy subjects is 48-57% for men and 44-54% for women. This pilot study was approved by the Review Board of the Hospital and the University of San Andres, La Paz. Results In a preliminary set of in vitro proliferation cell assays, simvastatin (3.5 uM), added for 5 days, induced a 33% inhibition of cell proliferation of UKE-1 (JAK2V617F mutated) as compared to 5 % of K562 (BCR/ABL positive). A comparable result was obtained in a 7-day clonogenic cell assay where the colony inhibition was 50 % for UKE-1 and 10 % for K562. On the basis of these results similar experiments were also performed using BM mononuclear cells derived from PV patients and healthy donors. In these experiments performed with the addition of simvastatin, it induced a 41% of inhibition in BFU-E colonies of PV patients and a 25% of inhibition in healthy donors. Furthermore, BFU-E colonies inhibited by simvastatin presented a decrease in hemoglobinization and the size of colonies. HU refractory PV patients and High-risk PV patients with hypercholesterolemia treated with the addition of Atorvastatin, Aspirin, cytoreductive HU and phlebotomies; after a follow-up of 2.6 years (1-7 years), induced a decrease of WBC from 16.500 to 9.270/ul, Hct 61.1 to 52.3% and PLT 457.900,000 to 324.7000/ul. The number of required phlebotomies is reduced in comparison to the required at starting treatment. None of the patients presented thrombotic or cardiopulmonary event. One patient died within two years of starting treatment, due to complications of diabetes mellitus. Conclusions In vitro and in vivo, statins showed some evidence of inhibitory activity of the hematopoiesis of PV patients. These preliminary results might indicate the opportunity to further investigate the potential clinical value of these molecules in the treatment of PV. Disclosures Off Label Use: Atorvastatin was used for its antiproliferative activity on myeloid progenitor cells shown by in vitro experiments.

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Nangia, Julie R., Jamile M. Shammo, Shilpa D. Tilwalli, et al. "Immune Ablation Using Cyclophosphamide without Stem Cell Rescue for Intractable Multiple Sclerosis and Its Variants." Blood 112, no. 11 (2008): 4903. http://dx.doi.org/10.1182/blood.v112.11.4903.4903.

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Abstract Background: Multiple sclerosis (MS) is the most common progressively disabling neurologic disease of young adults worldwide. MS is a cytotoxic T Cell mediated disease with autoimmune-driven destruction occurring most actively in the early stages. Immune suppression with high dose steroids, cyclophosphamide (CTX), cladribine, and mitoxantrone has demonstrated benefit in intractable, more progressive or frequently relapsing patients, both on clinical and MRI parameters. In particular, non-ablative doses of CTX appear to stabilize progressive MS for one year or longer and were most effective earlier in the course of the disease. In aggressive MS deletion of cytotoxic T cells through immune ablation may offer a more durable remission than standard immune suppression. Due to aldehyde dehydrogenase mediated resistance of CD34+ cells to CTX, hematopoietic reconstitution without hematopoietic stem cell rescue is possible and could eliminate the need for stem cell mobilization which has been associated with disease flare and potential re-infusion of T-cells. Objective: To assess the safety and efficacy of immunoablation using CTX without hematologic stem cell rescue for intractable relapsing progressive multiple sclerosis failing standard immune modulation or immune suppression. Patients and Methods: Eight patients (median age = 29, range 24–37, men = 2, women = 6) between January 2005 and July 2008 underwent immunoablation with high dose CTX (HD-CTX) at 50 mg per kg per day intravenously for four consecutive days. Adequate hydration and forced diuresis were implemented to prevent hemorrhagic cystitis. G-CSF was started 6 days after the last dose of chemotherapy at 5 mcg/kg per day until the absolute neutrophil count was &gt; 1000 per UL for two consecutive days. Red cell transfusions were administered to maintain hemoglobin of &gt; 8 gm/dl and platelet transfusions were given to patients with &lt; 10 Th/ul or to patients with active bleeding regardless of their platelet count. Clinical, laboratory, and MRI monitoring was scheduled at 3–6 month intervals over 24 months. Results: Eight patients have been treated with HD-CTX since 2005 and six of these patients have been monitored for more than 2 years. Hematologic complications included grade 4 neutropenia in all patients (duration 9–18 days), grade 4 thrombocytopenia in all patients (duration 3–13 days in 5 patients; 3 patients were discharged prior to platelet recovery), and grade 3 anemia in 6 patients (duration 1–9 days). All 8 patients required platelet transfusion (mean = 3.85 units, range 1–13 units) and 7 patients required PRBC transfusion (mean = 1.625 units, range 0–4 units). Non-hematologic grade 3 or 4 complications included grade 3 neutropenic fever in 7 patients, grade 3 hematuria in 2 patients and CTX-induced cardiotoxity with troponin elevation and infective endocarditis in 1 patient. 1 pt had a dystonic reaction to compazine. All patients have demonstrated improvements ranging from halting progression of MS clinically and radiologically to dramatic reductions of neurologic deficits, except in two patients whose disease reprogressed after 20 months of stability. One of these two patients demonstrated only subclinical disease activity on brain MRI without clinical correlates whereas the other experienced two milder clinical exacerbations. The latter has begun therapy with natalizumab, and the same has been recommended for the former. Given the refractory nature of these patients’ MS prior to therapy, the absence of further disease activity has been remarkable. Conclusions: Immunoablation with HD-CTX without stem cell rescue in patients with intractable MS represents a reasonable treatment option. These patients had significant improvements ranging from amelioration to stabilization of the disease course as well as reduction of disabilities. HD-CTX was tolerable with acceptable side effects and full hematologic recovery without the use of stem cell rescue. This is particularly important in patients with MS because of the associated disease flare and potential re-infusion of T-cells with stem cell mobilization. More data is needed and this clinical trial continues to accrue patients.

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Liebman, Howard, Laurie Hornor, Tse-Ling Fong, Casey O'Connell, and Ilene C. Weitz. "Romiplostim For Thrombocytopenia in Patients with Hepatitis C (HCV)-Associated Liver Disease: Preliminary Report Of An Ongoing Clinical Trial." Blood 122, no. 21 (2013): 3555. http://dx.doi.org/10.1182/blood.v122.21.3555.3555.

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Abstract Background Thrombocytopenia (Tp) is frequently observed in individuals with advanced cirrhotic liver disease. Patients with HCV may develop Tp even in the absence of significant liver disease. Decreased thrombopoietin production may also contribute to the Tp. The current management of HCV infection includes the use of the Peg-interferon α (IFN) and ribavirin (RIB), which can induce a sustained viral remission in 40 to 50% of treated patients. However, Peg-INF is a known inhibitor of megakaryocyte growth and maturation and can result in treatment related Tp. Therefore, patients presenting with platelet counts <70,000/mcl are frequently excluded from treatment or often fail treatment due to the development of critically low platelet counts. With this understanding, we initiated a clinical trial of the thrombopoietin receptor agonist, romiplostim, in HCV cirrhotic patients with Tp to determine if platelet count can be increased to >100,000/mcl to allow for HCV treatment with Peg-INF/RIB. Methods This is a two phase clinical trial of HCV infected patients with Child-Pugh class A liver disease. All patients were required to have platelet counts <70,000/µl and have liver biopsy confirmed early cirrhosis. Phase I is a double-blind placebo controlled trial of romiplostim given up to 8 weeks to raise platelets to >100,000/mcl before initiating Peg-INF treatment. There are separate 1 to 1 randomizations for patients with platelets 70 to 50,000/µl and patients with platelets<50,000/mcl. Initial treatment dose is 1 µg/kg with weekly progressive increases in dose. For patients who failed to obtain platelet counts >100,000/µl by week 8, blind is terminated and placebo patients can enter the romiplostim arm. Phase II is a dose escalation study of romiplostim during Peg-INF/Rib treatment up to week 24 of HCV treatment. If patients are viral load negative by week 24, romiplostim treatment is held to see if the patients can sustain a safe platelet count with continued HCV therapy. If not, romiplostim is continued until completion of HCV treatment. A protocol amendment allowed the addition of HCV protease inhibitors for genotype 1a patients. Results At the time of this report 21 patients (7F/14M; mean age 54.9 yrs, range 28-72yrs) have been enrolled in this trial; 13 with platelets 70 to 50,000/µl (Mean 62,000/µl; range 55 to 70,000µl) and 8 with platelet counts<50,000/µl (Mean 35,000/µl; range 25-46,000/µl). 17 patients have completed Phase I; 2 patients are ongoing, 1 patient withdrew at wk 5 with no platelet response (Blind remains) and one patient was withdrawn at wk 2 when review of the pre-randomization ultrasound found evidence of an old partial portal thrombosis. Five patients failed to obtain a platelet count of >100,000/ul by wk 8; all on placebo and were rolled over to romiplostim. The mean romiplostim dose for patients completing Phase I with platelets 70 to 50,000/µl was 2.2 mcg/kg and 3.1 mcg/kg for patients with platelets of<50,000/µl. During the 8 wk course of romiplostim there were no SAEs and no change in HCV viral load. Eleven patients have successfully completed Phase II with 24 wks of HCV treatment; with 4 patients on HCV treatment at wks 21, 20, 13 and 9. One patient was withdrawn at wk 14 due to intractable pancytopenia. 7/11 (64%) were HCV viral load negative at wk 24 and continued to completion of their HCV treatment. The mean romiplostim dose for the 11 patients completing Phase II with HCV treatment was 7µg/kg (3 to 10µg/kg). Three major SAEs occurred during Phase II. A 61 y.o. female developed pancytopenia at wk 14 unresponsive to growth factor support with a hypocellular bone marrow. She had a slow recovery of counts over several months. A 63 y.o. female developed portal vein thrombosis at wk 22 of HCV therapy. Her platelet count was 92,000/µl. She was treated with LMW heparin, continued HCV treatment with romiplostim off study and was viral load negative at wk 44 of treatment. A 50 y.o. female had a sudden death at home at wk 20 of HCV therapy. She has a platelet count of 32,000/µl on a clinic visit the day before her death and her romiplostim dose was 10µg/kg. No autopsy was performed. Conclusion In this interim analysis of ongoing clinical trial, romiplostim appears well tolerated and effective in increasing platelet counts in HCV cirrhotic patients and can maintain a safe platelet count in the majority of patients during HCV antiviral therapy with Peg-INF/RIB. This study was funded by a grant from AMGEN. Disclosures: Liebman: Amgen: Research Funding. Off Label Use: A clinical trial of romiplostim to treat hepatitis C-related thrombocytopenia performed under an FDA IND.

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Schiffman, Schiffman D., Jonathan Downie, Bradley Demarest, et al. "Novel Use of Molecular Inversion Probes to Interrogate Formalin-Fixed Paraffin-Embedded (FFPE) Samples of Childhood Leukemia." Blood 114, no. 22 (2009): 1589. http://dx.doi.org/10.1182/blood.v114.22.1589.1589.

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Abstract Abstract 1589 Poster Board I-615 Genome-wide, high-resolution analyses of copy number alterations (CNAs) now play an increasingly important role in identifying new genomic loci associated with leukemia biology and prognosis. The most powerful of these studies include large numbers of patients with associated clinical features and outcome data. Molecular Inversion Probes (MIPs) analyze genetic target sequences in parallel at the highest genomic resolution and can detect both gene copy number and allelic imbalance in clinical samples, and have been demonstrated to work on archived formalin-fixed paraffin-embedded (FFPE) samples as old as 20 years. In this pilot study, we report for the first time the successful interrogation of high-resolution CNAs in archived FFPE samples in childhood leukemia. We first extracted genomic DNA from FFPE bone marrow aspirate clots from 18 pediatric patients diagnosed with precursor B-cell acute lymphoblastic leukemia (pre-B ALL) diagnosed between 2006-2008 at Primary Children's Medical Center at University of Utah. DNA from paired remission samples was also extracted for each patient, again using archived FFPE bone marrow aspirate clots. Blast percentages on pre-B ALL marrow clots ranged from 39-99% (Mean 88%, Median 94%). Genomic DNA was isolated using RecoverAll” Total Nucleic Acid Isolation Kit for FFPE Tissues (Ambion®, Applied Biosystems). Clinical features and outcome data were readily available and abstracted from the medical record. The 18 patients in the FFPE cohort included: ages 2-21 years old (Median 5.5 years old), 7 females, presenting WBC 1-75 × 103/uL (Median 3.9), CNS negative disease (n=18), no reported cytogenetic abnormalities (n=8), t(12;21) [n=6], t(9;22) [n=1], and MLL rearrangement (n=1). 7 patients were designated “High Risk” by NCI-Rome Criteria and 1 patient relapsed. The MIP assay was run using the customized 330K Cancer Panel (Affymetrix®, Santa Clara, CA), which includes both cancer-specific SNPs and genome-wide coverage with a median probe distance of 4,207 basepairs (bp). Copy number was calculated by comparing leukemia samples to pooled normal control signal intensity for each probe. CNA calls were based on 5 consecutive probes with >90% call rate, standard deviation < 20%, and copy number ' 1.2 or ≥ 2.8. MIPs revealed remarkably high-quality CNA data for each of the 18 FFPE samples, including the cytogenetically “normal” patients. Both known and novel recurring CNA loci were identified in this cohort. Deletions included: 14q11.2 (n=11 [61%], 51569 bp, no known genes), 22q11.2 (n=10 [56%], 185944 bp, VPREB1), 14q32.33 (n=10 [56%], 631377 bp, no known genes), 7q34 (n=9 [50%], 292586 bp, PRSS1, TRY6, PRSS2), and 12p13.2 (n=6 [33%], 292586 bp, ETV6). Gains included: 10p15.2 (n=10 [56%], 26481 bp, PFKP), 10q26.3 (n=10 [56%], 69691 bp, MGMT), 10p11.21 (n=8 [44%], 922257 bp, FZD8, CCNY, GJD4), and 8p23.3 (n=7 [39%], 90307 bp, ARHGEF10). Interestingly, of 52 amplified segments recurring in 35% or greater of samples, all but one were located in chromosome 10, 14, 17, 18, or 21 suggesting genetic amplification hotspots. Additionally, 100% of IKZF1-deleted samples (n=2/2) compared to 37.5% of IKZF1-normal samples (n=6/16) had M3 marrows (>25% blasts) at Day 7. These same two IKZF1-deleted FFPE samples belonged to the patients with the two highest WBC values at presentation (75.3, 22.9 × 103/uL), in addition to containing two of the six highest bone marrow blast percentages at diagnosis. This is consistent with known findings that IKZF1 deletions are associated with high-risk ALL. In this pilot study of 18 patients, we have shown that archived FFPE bone marrow aspirate specimens (standard of care for all bone marrow procedures) can be used successfully for known and novel CNA analysis in childhood leukemia. We believe this is the first time that high-resolution, genome-wide CNA data from FFPE samples in any type of leukemia have been reported. This is an important development in CNA studies of hematological disease because now it is possible to investigate an unlimited number of archived FFPE childhood leukemia samples from around the world, or to explore rarer and more difficult to find specimens such as relapse or concordant identical twins. Disclosures No relevant conflicts of interest to declare.

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Bernaudin, Francoise, Suzanne Verlhac, Cécile Arnaud, et al. "Cerebral Vasculopathy Outcome in a Sickle Cell Anemia (SCA) Newborn Cohort Screened Early with Transcranial Doppler." Blood 112, no. 11 (2008): 2497. http://dx.doi.org/10.1182/blood.v112.11.2497.2497.

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Abstract Background: Stroke is the most severe complication in children with SCA and has been reported to concern 11% of patients by the age of 18 years. Transcranial Doppler detects patients at risk for stroke and transfusion program significantly reduces the risk of stroke in patients with abnormal TCD (Adams, NEJM 1998, 2005). However, the estimate of overt and silent strokes occurrence in a newborn SCA cohort explored early with TCD has not yet been reported. Methods: In our Créteil pediatric center, TCD was systematically performed annually since 1992 as soon as 12–18 months of age and patients were assessed by MRI/MRA every 2 years after the age of 5 years or earlier in case of abnormal TCD. Time-averaged mean of maximum velocities higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program (TP). A switch to hydroxyurea was proposed to patients with normalized velocities on TP (&lt; 170 cm/sec) and normal MRA, but TP was reinitiated if abnormal velocities recurred. Patients with “conditional velocities” (170–199 cm/sec) were assessed with TCD every three months. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF%; LDH levels; MCV; SpO2) were obtained after 12 months of age, before the first TCD, a minimum of 3 months away from a transfusion, one month from a painful episode, and always before intensive therapy. One patient refused initiation of TP for abnormal TCD and was excluded from the analysis. Results: This study included 217 SS/Sb0 children (114 M, 103 F), annually explored by TCD before age 5 (mean age at first TCD±SD: 2.2±1.1yr). They were followed for a total of 1627 patient-years. Eighty-two of 187 patients had alpha-Thal (44%); beta genotype, available in 157, was BaBa in 67 (43%), BeBe in 36 (23%), SeSe in 11 (7%) and “other” in 43 (27%); 21 of 182 (11.5%) had G6PD deficiency. TCD became “conditional” in 57 of 217 (26.3%) at the median age of 3.3 yr (range 1.2–8), and abnormal in 45 of 217 patients (20.7%) at the median age of 3.2 yr (range 1.3–8.3). Three patients had a stroke at the ages of 1.6, 4.2 and 4.4 yr: the first one had a first abnormal TCD at the age of 1.5 but had a stroke just before the TCD control at 1.6 yr; the second one had normal TCD on one side but unaivalable window on the other side and had a stroke before the first MRI/MRA; the third one had normal TCD just before the occurrence of an ACS and had a massive thrombotic stroke in intensive unit. The Kaplan-Meier (KM) estimate of stroke occurrence was 1.9% by the age of 18 yr. MRA, available in 126, was normal in 104 and showed stenoses in 22 (17.5%) at the median age of 4.8 yr (range 2.6–11.5). In stroke-free patients, MRI showed silent infarcts in 31 of 122 patients (25.4%) at the median age of 5.9 yr (range 3.5–15.3); 10 of the 31 had a history of abnormal TCD. KM estimate for abnormal TCD was 29.7% by the ages of 10 and 18 yr. KM was higher in case of G6PD deficiency: 52% vs. 26% (Log Rank, p=0.059), significantly lower in case of alpha-Thal: 16.3% vs. 36.9% (Log Rank p=0.005) and significantly dependent on the degree of hemolysis: LDH IU/l &lt;750:11.6%; 750–1209:27%; &gt;1209: 40.3% (Log-rank &lt; 0.026). KM estimate of stenoses on MRA was 23.6% by the age of 18 yr, was highly significantly higher in case of G6PD deficiency: 53.3% vs 15.8% (Log Rank p&lt;0.001), lower in case of alpha-Thal: 8.7% vs 29.9% (p=0.022), and significantly dependent on hemolysis: LDH IU/l &lt;750: 0%; 750–1209:13.9%; &gt;1209: 37.1% (Log Rank p=0.013). KM estimate of silent infarcts was significantly dependent on the presence of stenoses on MRA (Log Rank p=0.002), and on gender (male older than 8) (Log Rank p=0.038). Conclusion:This monocenter prospective study reports a significant decrease in the risk of stroke at 18 yr (KM 1.9% vs. 11–11.5%, previously published by Ohene-Frempong [Blood, 1998] and Quinn [Blood, 2004]) demonstrating the strong efficacy of systematic and early screening by TCD in association with TP to prevent stroke. It confirms our recent study that G6PD deficiency, absence of alpha-Thal and hemolysis significantly and independently increase the risk for abnormal velocities (Blood 2008 in press), which are themselves highly significantly predictive of stenosis occurrence. Morever, this study shows that the risk of silent infarcts remains high, even in patients with normal TCD, and is higher in males than in girls after the age of 8 years.

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Schroeder, Mark A., Michael P. Rettig, Sandra Lopez, et al. "Outcomes of Patients Receiving Allogeneic Peripheral Blood Stem Cell Products Mobilized with Intravenous Plerixafor." Blood 118, no. 21 (2011): 314. http://dx.doi.org/10.1182/blood.v118.21.314.314.

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Abstract Abstract 314 We have previously reported mobilization data of hematopoietic stem and progenitor cells (HSPCs) in donors treated with IV plerixafor in a phase I/II open label trial (Rettig et al. Blood 2010 116: a2261). Here we report the final outcomes of donors and recipients of the phase II portion of the trial evaluating the use of 0.32 mg/kg plerixafor IV as a single agent for stem cell mobilization. We hypothesized, based on preclinical studies in the mouse, that IV plerixafor would have more rapid and prolonged mobilization and increase stem cell yields so that failure to collect ≥2×106 CD34+ /Kg recipient weight in one apheresis would be reduced from 33% (seen with 240 ug SC plerixafor) to 11%. We also hypothesized based on our prior observations of increased plasmacytoid dendritic cells (pDCs) in plerixafor mobilized products (Rettig et al. Blood 2009 114: a32), that peripheral blood stem cell products would be enriched in pDCs which may lead to improved immunity in the recipient after transplant and reduced incidence of CMV. Methods. In this phase II open label trial donors were mobilized with 0.32 mg/Kg IV plerixafor (over 30 minutes), followed by a 20 L apheresis starting 4 hours after injection. The primary outcome was failure to collect ≥2×106 CD34+/Kg actual recipient weight on day 1. Secondary outcomes included donor toxicity, successful collection in 2 aphereses, pharmacodynamics of mobilization, engraftment, graft-versus-host disease (GvHD), treatment related mortality (TRM), incidence of CMV, relapse free survival, and overall survival. The study was powered to detect a difference in failure rate from 33% to 11%. Sibling donors were 18 – 70 years of age and 6/6 HLA matched with recipients. Recipients were 18 – 67 years of age with a hematologic malignancy (AML n=14, NHL n=9, CLL n=3, MDS n=3, ALL n=2, CML n=1, and HD n=1). 33 recipients were transplanted (5 reduced-intensity and 28 myeloablative conditioning). A total of 27 donor recipient pairs were initially enrolled and 7 additional pairs of subjects were enrolled to replace 6 donors who failed to collect goal apheresis volume (>17.5L) due to technical problems related to initial apheresis collections. Median follow up of recipients is 248 days (range 37–695 days). Results. The primary outcome of failure to reach ≥2×10e6 CD34+/Kg recipient weight was analyzed on a per protocol basis. CD34 HSPC mobilization kinetics were previously reported for the phase I cohorts (ASH 2010). 29 donors were evaluable for the primary outcome. 34% (10/29) failed to reach the day 1 collection goal of ≥2×106 CD34/Kg recipient weight. 10% (3/29) failed to reach goal after 2 apheresis procedures. Toxicity in donors was mild with the most common reported side effects being grade 1 GI toxicity of abdominal bloating (30%) and grade 1 bradycardia (30%). All recipients engrafted and there was no graft failure. The median time to neutrophil engraftment (ANC>500K/uL × 2 days) was 14 days, with 31/33 engrafting by day 21. The median time to platelet engraftment (Platelets>50K/uL × 2 days) was 25 days, with 23/33 engrafting by day 30. The incidence of grade II-IV acute GvHD was 7/33 (21%). The incidence of grade III-IV acute GvHD was 4/33 (12%). The cumulative incidence of chronic GvHD in those living beyond 100 days was 7/25 (28%) and 4/25 (16%) had severe disease. The incidence of CMV viermia >10,000 copies in at risk recipients (defined as serology positive in donor or recipient) was 3/20 (15%). The incidence of CMV disease was 1/20 (5%). Median overall survival was 258 days, with 43% one-year survival. Median relapse free survival was 238 days. The day 100 TRM was 1/33 (3%). Summary. IV administration of plerixafor was well tolerated by donors. However, based on our prior experience with subcutaneous dosing with 0.24mg/kg (Devine et al Blood, 2008) there was no improvement in the percent of normal donors who successfully collected ≥2×106 CD34+/Kg after a single IV infusion of 0.32 mg/Kg plerixafor (67% vs. 66% respectively). Failure to reach collection goal in one apheresis procedure remains high with single agent plerixafor regardless of route of administration. Incidence of CMV viremia was low and could possibly be related to increased plasmacytoid dendritic cells in the product. The incidence of aGvHD was lower than historical controls for G-CSF mobilized peripheral blood transplantation and deserves further evaluation in future prospective trials involving CXCR4 antagonists such as plerixafor. Disclosures: Schroeder: Genzyme: Research Funding. Rettig:Genzyme: Honoraria. Uy:Genzyme: Consultancy, Speakers Bureau. DiPersio:Genzyme: Honoraria.

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Polprasert, Chantana, Tomas Radivoyevitch, Naoko Hosono, et al. "Molecular Predictors of Response in Patients with Myeloid Neoplasms Treated with Lenalidomide." Blood 124, no. 21 (2014): 4665. http://dx.doi.org/10.1182/blood.v124.21.4665.4665.

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Abstract While patients with del(5q) MDS treated with Lenalidomide (LEN) have a response rate as high as 70%, the efficacy of this drug is lower in non-del(5q) cases. Aside from the presence of del(5q), up front identification of potentially responsive patients is difficult, particularly as the mechanistic underpinnings of LEN response have not been elucidated. Although expression signatures of responders were described in 2008, they have not yet been translated into an actionable diagnostic test. Analyses of molecular lesions including somatic mutations and chromosomal defects may predict response to LEN in MDS. We performed deep targeted DNA sequencing on 62 genes in 111 cases of myeloid neoplasms (MDS, MDS/MPN, and MPN) treated with Len for at least 3 months for whom fully annotated clinical outcomes were available. Clinical parameters, FISH, SNP array-based karyotyping and metaphase cytogenetics were also included in our analysis. We assessed response according to IWG 2006 criteria and performed analyses for responses at 3 or 6 months of therapy. Of 111 LEN-treated patients, 77% had lower-risk MDS (IPSS Low /Int-1) and 23% higher-risk disease (IPSS Int-2/High/sAML). Regimens included either LEN alone (52%), or in various combinations (29%) LEN+azacytidine, TLK+LEN (1.8%) or high-dose chemotherapy (7+3)+LEN (0.9%). Any hematologic improvement, cytogenetic response, and complete response (BM) were achieved in 58%, 19% and 18% at 3 months and 84%, 44% and 30% at 6 months, respectively. Responders had better survival, with HR=0.55 (0.32, 0.94; P=.03). The mean age did not differ between responders and non-responders. Using IPSS scoring criteria, there was no difference in proportion of patients with lower-risk disease among responders and non-responders (73% vs. 81%). When IPSS-revised (-R) score was applied, there also was no significant difference between responder and non-responders with very low risk (4% vs. 7%), low risk (30% vs. 41%), intermediate risk (22% vs. 15%), high risk (29% vs. 22%), and very high risk (14% vs.12%). Refractory patients showed significantly lower platelet counts compared to responders (117 vs. 215 K/uL; P=.01). Responders tended to have higher reticulocyte counts prior to therapy compared to non-responders (0.5 vs. 0.3 M/uL; P=.07) and had significantly higher MCVs compared to refractory cases (99 vs. 91fL; P<.01). Focusing on karyotype, there was no difference between responders and non-responders in the proportion of patients with +8, -7/del(7q), and those with normal cytogenetics. Del(20q) was marginally associated with treatment failure (6/8 failed; P=.07). In this highly selected cohort, among all del(5q) patients (N=38) 63% responded, compared to 53% in non-del(5q) (N=73), (P=.4). Among lower-risk del(5q) MDS (blast<5%) 75% (12/16) had a response vs. 50% (16/32) in lower-risk non-del(5q) MDS (P=.06). In del(5q) patients both interstitial and long del(5q) (including q11.1-q14.2 and/or q34-qter) showed similar response rates. TP53 mutations were found coinciding with del(5q) and marginally correlated with failure to respond to LEN (P=.07), but not precluded response. Using multiplex amplicon panels of 62 genes commonly mutated in MDS, we confirmed 143 somatic mutations in responders vs. 137 mutations in non-responders. Mutations in RUNX1 correlated with LEN responses (OR=3.62 [0.63-20.87]). Mutations in DDX41 correlated with LEN response (8/8 responded; P=.009, odds ratio OR=Infinity), while mutations in U2AF1 correlated with failure to respond to LEN (1/9 responded; P=.01, OR = .08 [0, 0.66]) as did mutations in IDH1/2 (1/8 responded; P=.02, OR = .1 [0, 0.81]). DDX41 pooled with DDX54 had an odds ratio of OR=5.66 [0.58, 54.85] and DNMT3A, TET2 and IDH2pooled yielded OR=.12 [0.04-0.38]. Bayesian Model Averaging (BMA) was then applied to these and other covariates. BMA fits all submodels of a full model and then forms a weighted average of them wherein the weight of each model is the probability that it is correct relative to all other models in the model space. This yielded the linear predictor S=0.76 - 1.91•DNMT3A.TET2.IDH2 - 2.15•U2AF1 + 0.77•DDX41.54 + 0.06•del5q - 0.61•del20q-0.14•TP53.cmplx + 0.39•RUNX1 + 0.05•KDM6A that awaits validation using an independent set of patient data. In conclusion, in addition to the presence of del(5q), the various molecular lesions including specific somatic mutations may help to better predict responses to LEN. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

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Takagi, Shinsuke, Kazuya Ishiwata, Masanori Tsuji, et al. "Voriconazole Is Safe and Effective as a Prophylactic Regimen of Invasive Fungal Infections for High Risk Patients after Reduced-Intensity Umbilical Cord Blood Transplantation." Blood 112, no. 11 (2008): 4355. http://dx.doi.org/10.1182/blood.v112.11.4355.4355.

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Abstract Invasive fungal infections (IFI) are significant complications after allogeneic hematopoietic stem cell transplantation. We previously reported that 3-year cumulative incidence of IFI was 10.2 % and median onset of IFI was day 20 post reduced-intensity umbilical cord blood transplantation (RI-CBT) under the prophylaxis by fluconazole or micafungin (Biol Bone Marrow Transplant2007;13:771). In recent years, voriconazole (VOR) has been employed in IFI prophylactic regimens during bone marrow or peripheral blood stem cell transplantation in several clinical trials and reports, but the safety and efficacy during umbilical cord blood transplantation is unclear. In order to address this issue, we prospectively administered VOR to 46 high risk recipients of RI-CBT for IFI prophylaxis, between August 2007 and May 2008. All of the patients had no prior episode of IFI and were treated in reverse isolation in laminar airflow-equipped rooms. The plasma trough concentration of VOR and serum galactomannan index was obtained once a week. Chest CT scan was performed for persistent fever under the administration of broad antibiotics. Proven and probable IFI were defined according to revised EORTC/MSG criteria. Median age was 58 years old (range, 21–82). Twenty-three were AML, 10 were non-Hodgkin lymphoma, 6 were aplastic anemia, 5 were ALL, 1 was CML, and 1 was multiple myeloma. All patients were at high risk of IFI, except one patient with lymphoma in CR; 22 had high risk underlying diseases, 17 had prior transplantation, and 6 were very severe aplastic anemia. All patients received fludarabine-based preparative regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus & mycophenolate mofetil in 30, tacrolimus alone in 15, and cyclosporine alone in 1. Additional immune suppressive therapy against pre-engfraftment immune reactions (Transplant2005;80:34) or GVHD were administered in 35 patients; 19 received corticosteroid (CS), 7 beclomethasone (BDP), 5 CS & BDP, 1 CS & BDP & infliximab, 1 CS & infliximab, 1 CS & BDP & etanercept, and 1 CS & methotrexate. Forty-two patients achieved neutrophil recovery &gt; 500/uL on day 21 post-transplant at medium (range, 11–38). The median length of VOR prophylaxis from transplantation was 85 days (range, 6–422) for patients who survived longer than 100 days. The total number of patient-days on VOR was 4241 days. There were no proven IFI. Two patients developed probable pulmonary aspergillosis during VOR administration (at day 71 and 75; 1-year cumulative incidence 4.3 %.) No breakthrough infections by candida or zygomycetes were detected. VOR was well tolerated, except in 2 patients who discontinued VOR due to abnormal liver test and severe visual disturbance. Two patients developed probable pulmonary aspergillosis after switching from VOR to other antifungals (at day 80 and 263 under the administration of micafungin and itraconazole, respectively). Thus, VOR can be safely administered, and have reduced the incidence of IFI, with no breakthrough infections by candida or zygomycetes, indicating possible superiority of incorporating this drug as an IFI prophylactic regimen in RI-CBT.

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Sendilnathan, Arun, Jaskirat Singh Randhawa, Changchun Xie, et al. "Low-Dose Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor As an Efficacious and Safe Peripheral Blood Stem Cell Mobilizing Regimen in Patients with Hematologic Malignancies." Blood 126, no. 23 (2015): 5438. http://dx.doi.org/10.1182/blood.v126.23.5438.5438.

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Abstract Introduction: Collection of adequate numbers of Hematopoietic Stem Cells (HSCs) is a prerequisite for proceeding to autologous bone marrow transplant. However, various studies have showed that approximately 5% to 40% of patients do not meet the minimum threshold of 2×106 CD34+ cells/kg that is associated with timely engraftment and better outcomes. There is little consensus over the optimal mobilization regimen for procurement of peripheral blood CD34 + stem cells (PBSCs). Studies comparing mobilization using high-dose cyclophosphamide(HD-CY) {5-7 g/m2} or intermediate dose cyclophosphamide (ID-CY) {3-4g/m2} plus G-CSF with low dose cyclophosphamide (LD-CY) {1-2g/m2) plus G-CSF have reported higher total PBSC yield with the former but at the cost of higher toxicity [Hiwase et al, Cytotherapy 2007]. Hence the significance of our study to evaluate the efficacy and safety of LD-CY plus G-CSF in the era of novel induction therapies, takes precedence in terms of optimal resource utilization. Methods: We retrospectively analyzed mobilization efficacy and need for supportive care in Myeloma and Lymphoma patients that received LD-CY (2g/m2) plus G-CSF (10µg/kg/day) as the preferred mobilization regimen. Patients treated with novel induction regimens only, with or without radiation were included. LD-CY was given on day 1 with MESNA. G-CSF was started Day +5 from LD-CY and continued until the completion of apheresis. We started to measure peripheral CD34+ (pCD34) when patient's white blood cell count recovered to >1000/µL. When the pCD34 count was ≥10/uL, apheresis was started. Results: Out of 21 patients analyzed, 14 (67%) were Myeloma, predominantly IgG subtype (71%) and 7(33%) Lymphoma predominantly Non-Hodgkins type (71%). Our study population comprised of 53% females, 81% Caucasians with median age of 59 years (30-66). 28.5% patients had radiation treatment in the past. Mean/Median lines of chemotherapy previously received were 2/1 (1-5).71% patients received Lenalidomide (57%) / Thalidomide (14%) based regimens for induction therapies. 52% patients had complete response at the time of chemo mobilization. Successful mobilization (defined as total CD34+ cells collected >2x106/kg) was significantly achieved in 95% patients with mean/ median collection of 12.4/11.5 x106 CD34+ cells/kg (20 out of 21 patients, One sample T- test with significance level, alpha =0.025 [one sided ]showed T statistic 5.36 with p-value <0.0001). First apheresis yielded at least 2 x10 6/kg CD34+ cells in 76 % patients with a mean/median of 5.8/3.8 x106/kg CD34+ cells. 66% of patients were found to be good mobilizers, defined as patients collecting ≥5 x106 CD34+ cells/kg in ≤2 days. 81% patients collected ≥5x106 CD34+ cells/kg and 57 % patients collected ≥10 x106 CD34+ cells/kg. Mean/Median Peak pCD34count was 97.7/60 cells/µL(2-488). Median number of aphereses was 2 (mean 2.6) with the mean and median time to apheresis being 11 days (9-15). None of the patients needed inpatient hospitalization or intravenous antibiotics during mobilization or had any complication related to immunosuppression. 14% and 19% of patients needed packed red blood cell and platelet transfusions respectively during the mobilization period. One Myeloma patient (4.8%) that failed mobilization had previously received five lines of chemotherapy including lenalidomide/thalidomide containing regimens and had stable disease at the time of mobilization. Interestingly, 61% of myeloma patients that successfully mobilized had received lenalidomide containing induction regimen (mean/median no. of cycles- 3.9/4[1-7]) Conclusion: Our analysis shows that LD-CY plus G-CSF is efficacious to mobilize sufficient number of stem cells (>2x106 CD34+ cells /kg) in Myeloma and Lymphoma patients treated with novel agents, including the challenging sub-group of lenalidomide treated myeloma patients, with no infectious complications or morbidity noted during the entire period of mobilization. Therefore, we believe LD-CY plus G-CSF may overcome the negative effects of prior lenalidomide exposure on PBSC mobilization [Mark et al, Biol Blood Marrow Transplant 2008] and is superior in terms of optimal resource utilization compared to novel plerixafor based regimens [Chaudhary et al, J Clin Apher 2013]. Prospective studies involving CY based regimens will help elucidate the optimal dose of chemo-mobilization. Disclosures No relevant conflicts of interest to declare.

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Andreeff, Michael, Zhihong Zeng, Mary A. Kelly, et al. "Mobilization and Elimination of FLT3-ITD+ Acute Myelogenous Leukemia (AML) Stem/Progenitor Cells by Plerixafor/G-CSF/Sorafenib: Results From a Phase I Trial in Relapsed/Refractory AML Patients." Blood 120, no. 21 (2012): 142. http://dx.doi.org/10.1182/blood.v120.21.142.142.

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Abstract Abstract 142 FLT3-ITD AML are associated with poor prognosis. Our group identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is also associated with overexpression of the chemokine receptor CXCR4. Utilizing preclinical in vitro and in vivo models we determined increased activity of S when combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report clinical and translational data testing this concept in patients with R/R FLT3-ITD AML. Clinical trial: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400–600mg) on d 1 – 28(one cycle). G/P was held when blasts exceeded 5×104/uL. Cell populations expressing CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were assessed at baseline and at multiple time points during treatment by flow cytometry of up to 10 parameters and by flow cytometric mass spec using CyTOF. Results: 13 patients have been treated so far; responses are as follows: 1 CR, 3 CRp, 6 PR and 4 failed (NR), for an overall response rate of 10/13 (77%); One patients achieved 2 CRp. Six/13 patients, including 3/6 responders and 3/4 NR were previously treated with and considered refractory to FLT3 inhibitors. Four patients had additional D835 mutations: 2 failed and 2 achieved PRs, none of the CR/p patients carried this mutation. Side effects included hyperleukocytosis in 3/10 pts.(who missed 1 to 5 doses of G/P), skin rash (5 pts.), hand foot syndrome (3 pts.) hypertension (7 patients), diarrhea (10 pts.), nausea (8 pts.), headache (6 pts.), muscle weakness (3 pts.) and anorexia (5 pts.). Analysis of cells mobilized in 22 treatment cycles revealed massive mobilization: a 29-fold increase in WBC, 41-fold in absolute blasts and 77-fold in granulocytes. Increases in the numbers of circulating stem/progenitor cells: CD34+: 231-fold, CD34+/38-: 90-, CD34+/38-/123+(LSC): 148-, CXCR4+: 139-, VLA-4+: 68- and CD44+: 82-fold. Increase in circulating LSC was positively correlated with baseline blasts and VLA4 levels, but not with baseline CXCR4. Serial FISH analyses confirmed the preferential mobilization of leukemic vs. non-leukemic cells and 10-color flow cytometry demonstrated altered levels of pERK and pAKT but not of pSTAT3 in mobilized cells. Surprisingly, CXCR4 levels in mobilized cells were increased. CyTOF analysis of up to 29 parameters documented mobilization of primitive LSC. Conclusions: The combination of G-CSF+Plerixafor appears superior in increasing the number of circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, 2012). Treatment resulted in 4/13 CR and CRp and 6/13 PRs, for an overall response rate of 77%. Mobilized stem/progenitor cells displayed altered MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical study of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment and the initial results are providing proof-of–concept and encouraging clinical responses. Disclosures: Off Label Use: Clofarabine in AML. Burger:Pharmacyclics: Consultancy, Research Funding. Kantarjian:Genzyme: Research Funding.

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Tanosaki, Ryuji, Kimikazu Yakushijin, Yoshitaka Asakura, et al. "Long-Term Outcome of ATL Patients Who Underwent Reduced-Intensity Stem Cell Transplantation (RIST): Suggested Potent Graft-Versus-ATL and HTLV-1 Effects." Blood 114, no. 22 (2009): 3370. http://dx.doi.org/10.1182/blood.v114.22.3370.3370.

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Abstract Abstract 3370 Poster Board III-258 Although the outcome of patients (pts) with adult T-cell leukemia-lymphoma (ATL) remains poor when they are treated with conventional chemotherapy, we previously showed in a multi-center prospective study that one-third of pts who underwent RIST from a related donor in CR or PR could survive without disease for more than 2 years (Tanosaki R et al., BBMT 2008). In this retrospective study, we reviewed our single-center experience with RIST for ATL pts, focusing on the outcome of those who underwent RIST in non-remission status or who relapsed after RIST. A total of 24 pts underwent RIST from a related donor between 2001 and 2008. The median age was 54 years (range, 44-65). Of the 14 males and 10 females, 19 were acute type and 5 were lymphoma type. Disease status at transplantation was 5 CR, 10 PR, 8 NC and 1 PD. Donors were siblings in 18 and children in 6, including 5 HTLV-1 healthy carriers. HLA in serology was 6/6 in 19 and 5/6 in 5. Stem cell sources were PBSC in 22 and BM in 2. Conditioning regimens were fludarabine (30 mg/m2 iv days -8 to -3) and busulfan (3.2 mg/kg iv days -6 and -5) with (n=8) or without (n=16) rabbit anti-T-lymphocyte globulin (ATG, Fresenius; 2.5 mg/kg iv days -2 and -1). All patients received cyclosporine alone for GVHD prophylaxis. Engraftment was rapid in all 24 pts (neutrophil>500/uL; median 12 days, range 10 -19), with no graft failure. There were 3 non-relapse mortalities; respiratory failure from bronchiolitis obliterans at 21 months (mos), interstitial pneumonitis at 47 mos, and pneumococcal sepsis at 38 mos. Notably, 10 of the 19 pts who were non-CR at RIST survived without disease progression to a median of 53 mos (range, 20 to 85). All of these pts were acute type, and had circulating ATL cells in the peripheral blood (PB) immediately before RIST (average 33% of WBC, range 5-73). Circulating ATL cells decreased to below 5% within 1 mo in 8 pts. A total of 12 pts relapsed within 16 mos; 7 (58%) within 3 mos, and 11 (92%) within 12 mos. Two patients who had relapsed after RIST showed a significant but transient response to the withdrawal of immunosuppression (CR 1, PR 1). Donor lymphocyte infusion was performed in 6 pts without significant benefits. Seven pts who relapsed at a single site, which was confirmed by CT scan or FDG-PET, were treated with local irradiation alone, and 3 whose HTLV-1 proviral load in PB had become negative at relapse survived to 48, 64 and 77 mos; 1 pt required 2 courses of irradiation because of immediate relapse at the margin of the preceding radiation field, and another pt underwent surgical resection of a residual mass since a biopsy revealed a viable lesion at the irradiated site. The 5-year overall and progression-free survival of all pts were 52% (95% CI, 38-66%) and 37% (95% CI, 22-52%), respectively, at a median follow-up of 59 mos (range, 12 to 85) in surviving pts. HTLV-1 proviral load in PB was examined using real-time PCR for tax in 208 samples from 21 evaluable pts, and it became negative at least once in 15 pts (71%), including 1 pt whose donor was an HTVL-1 carrier; proviral load remained negative in 7 pts at a median follow-up of 32 mos (range, 3 to 84). Since HTLV-1 tax is a promising target molecule for identifying the immunological mechanism, HLA-restricted tax-specific CTLs were examined in HLA-A2- and/or A24-positive pts using tax tetramers by taking blood samples periodically after informed consent was obtained from each pt. A total of 80 samples in 13 pts were analyzed. The number of tax tetramer-positive (tax+) cells did not change significantly up to at least 1 year after RIST, while the clinical responses and decrease/disappearance of HTLV-1 proviral load were observed within 3 mos in most cases. An increase in tax+ cells was observed after 1 year in 2 pts who had achieved CR. In conclusion, about half of the acute-type ATL pts with a significant involvement of ATL cells in PB at RIST could survive for a long time in our cohort. ATL pts who relapsed at a single site after RIST still have a chance to be cured with local treatment using irradiation alone or surgical resection with the aid of HTLV-1 proviral load as a marker for minimum residual disease. Since most ATL pts had already become resistant to chemotherapy and the intensity of conditioning was reduced, potent GV-ATL and GV-HTLV-1 effects might have played a key role in disease control. However, tax-specific CTL kinetics did not correlate with either clinical responses or the HTLV-1 proviral load, which suggested that other molecules may be immunologically targeted. Our results might contribute to the establishment of the cure-oriented treatment strategy for ATL pts. Disclosures: No relevant conflicts of interest to declare.

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Caddell, Ryan J., Hayder Saeed, Rebecca Nelson, et al. "Toxicity of a Modified Peg-Asparaginase-Based SMILE Regimen Is Comparable to L-Asparaginase-Based SMILE in a Non-Asian Population." Blood 134, Supplement_1 (2019): 5292. http://dx.doi.org/10.1182/blood-2019-128435.

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Abstract Background: Asparaginase may improve outcomes in chemotherapy resistant malignancy, especially of lymphoid origin. L-asparaginase (L-ASP) was introduced in 1992 and hence has been incorporated in multiple regimens. An effective regimen including steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) was developed by the NK-Cell Tumor Study Group as a unique chemotherapeutic regimen to combat chemo-resistant NK-cell neoplasms (Yamaguchi et al. 2008) and later shown to have efficacy in relapsed and refractory lymphoblastic lymphoma (Chang et al. 2014). The pegylated-asparaginase (PEG-ASP) is the only readily available commercial product as the other forms either have limited availability due to shortages (Erwinia asparaginase) or are no longer available in the United States (E-coli asparaginase). We present retrospective data incorporating PEG-ASP into a modified SMILE (mSMILE) regimen. To our knowledge, no prior comparison between the PEG-ASP and L-ASP based SMILE regimen is available in the literature. Methods: All adult patients treated with mSMILE for either extranodal NK/T-cell leukemia and lymphoma (ENKTL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell leukemia/lymphoma (ATLL), or peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) from 12/1/2009-6/30/2019 at Moffitt Cancer Center were included. PEG-ASP replaced L-ASP in SMILE regimen at a dose of 2500 units/m2/dose IV on Day 8 only (maximum dose of 3750 units). Cycles were repeated every 28 days until disease progression, excessive toxicity, or consolidation with hematopoietic cell transplantion (HCT). Patients received appropriate supportive care with peg-filgrastim or filgrastim (until absolute neutrophil count > 1000/ul x 3Days or >3,000/ul) as well as antimicrobial prophylaxis with acyclovir, ciprofloxacin, and fluconazole once methotrexate cleared and post-chemotherapy. Toxicity assessment was analyzed retrospectively and graded based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5. Toxicity profiles of PEG-ASP-based mSMILE in present study were compared to profiles of L-ASP-based SMILE in the recently published literature (Pokrovsky & Vinnikov Expert Rev Anticancer Ther, 2019). Results: A total of 13 patients were treated with mSMILE during the 10-year period (Table 1). Of these patients, the median age was 46 years (range, 19-69), caucasians (46%) and males (70%). Most of the patients were treated for ENKTL (46%). mSMILE was the first line therapy in 3 patients, while the median number of prior therapies was 1 (range 0-3). Toxicity assessment for mSMILE focused on PEG-ASP-induced toxicity as no patients had any hemorrhagic cystitis, neurotoxicity, or renal dysfunction that could be associated with ifosfamide, methotrexate, or etoposide. mSMILE was comparatively associated with more hematologic toxicity, likely related to inclusion of patients with lymphoblastic leukemia (table 2). Grade 3/4 hepatotoxicity rates are low, possibly owing to inclusion of carnitine prophylaxis (Schulte et al. 2018). Thrombosis was not observed. Hypertriglyceridemia was observed in 15% with no cases of pancreatitis. Hypersensitivity and neurotoxicity were not observed. Of the two patients who discontinued therapy due to toxicity, one was related to grade 3 hypofibrinogenemia and the other grade 4 bleeding. Mortality was attributable to disease progression in all cases, with 0% treatment related mortality. Efficacy is comparable, with ORR 54% (7/13), including 30% (4/13) successfully bridged to HCT. Conclusion: In a non-Asian population, modified SMILE regimen with PEG-ASP is a safe alternative to L-ASP-based SMILE regimen. There is increased hematological toxicity, which did not seem to affect chemotherapy delivery. Disclosures Chavez: Genentech: Speakers Bureau; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sokol:EUSA: Consultancy. Shah:AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria.

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McMasters, Richard, Brian K. Turpin, Michael J. Absalon, et al. "Genomic Characterization Of Histiocytic Lesions Following Pediatric T-Cell Acute Lymphoblastic Leukemia." Blood 122, no. 21 (2013): 4940. http://dx.doi.org/10.1182/blood.v122.21.4940.4940.

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Abstract Introduction The development of histiocytic lesions after acute lymphoblastic leukemia (ALL) is rare, occurring in 6 of 971 patients enrolled on BFM treatment regimens for T-ALL (Trebo 2005). Few cases of histiocytosis arising after a history of T-ALL have been characterized at the molecular level for genomic alterations. One case of fatal Langerhans cell histiocytosis (LCH) following treatment of T-ALL revealed activating mutations in NOTCH1; in contrast, no NOTCH1 mutations were identified in 24 other cases of LCH or Rosai-Dorfman disease without a previous history of T-ALL (Rodig 2008). In patients without prior leukemia, BRAF V600 mutations have been identified in a significant proportion of patients with LCH or Erdheim-Chester Disease but not in other histiocytoses (Haroche 2012). Methodology and Principal Findings Next generation focused exomic sequencing of 236 genes and 47 Introns was conducted on samples of histiocytic lesions from two patients with a previous history of T-ALL. Case 1 A 2 year-old male presented with marked adenopathy, mediastinal mass and white blood cell count 67,000 cells/uL with 30% blasts. The blasts expressed CD45, CD2, CD3 (surface/cyto), CD5, CD7, CD38, CD45 (bright), TCR gamma-delta, but were negative for CD4, CD8, and TdT. Karyotype was 46,XY,t(8;14)(q24;q11.2),der(12)t(12;20)(q11;q13.3),der(20)t(12;20)(q21;q13.3) with rearrangement of MYC (8q24) confirmed by FISH. He was treated for T-ALL per Children’s Oncology Group (COG) protocol AALL0434 and had 5% residual bone marrow blasts at day 29 of induction. MRD-negative remission was ultimately achieved with high-dose cytarabine and methotrexate followed by consolidation with nelarabine. He underwent matched unrelated cord blood transplant following conditioning with cyclophosphamide and total body irradiation with cranial boost, and engrafted at day +14. Surveillance bone marrow at day +110 revealed systemic juvenile xanthogranuloma (JXG) without T-ALL. PET/CT revealed FDG-uptake in the diffusely enlarged spleen and throughout the skeleton. Due to progressive cytopenias, therapy was initiated with vinblastine and prednisone as per LCHIII. However, refractory cytopenias exacerbated by splenic sequestration developed following induction, and he was then treated with thalidomide and splenectomy. The spleen weighed 404 grams (expected 40 grams) and was diffusely infiltrated with JXG. The cytopenias dramatically improved and he continued thalidomide for 2 months until PET scan demonstrated progression. Genomic analysis of the JXG lesion revealed NRAS G13D mutation, and FISH demonstrated MYC rearrangement identical to the initial T-ALL sample. Case 2 A 12-year-old male presented with WBC 142,700 cells/uL and CNS leukemia. Flow cytometry showed T-ALL with CD2, surface CD3, CD4, CD5, CD7, CD8, CD24 (subset), CD71, HLA-DR (subset) and TdT (partial). There was a clonal TCR gamma gene rearrangement and a biallelic CDKN2A (p16) deletion by FISH. He was enrolled on COG AALL0434 and had a rapid response with remission in both CNS and marrow at induction day 29. Following completion of high-dose methotrexate interim maintenance he developed hepatosplenomegaly, pancytopenia and elevated serum bilirubin, ferritin, and triglycerides. Bone marrow aspirate showed rare hemophagocytosis but no evidence of T-ALL. He was treated with dexamethasone and etoposide with no response. Follow-up bone marrow revealed brisk hemophagocytosis and a diffuse histiocytic neoplasm. Karyotype was 48,XY,+7,+11[2] /49,idem,+18[3] /46,XY[14]. PET/CT showed hepatosplenomegaly with FDG uptake in anterior mediastinum, hepatic nodules, spleen, and bone marrow. He was treated with Campath and then with intensive chemotherapy with fludarabine, cytarabine, and liposomal daunorubicin with no response and ultimately succumbed to disease. Genomic analysis of the clonal histiocytic infiltrate revealed KRAS G12C, BRAF G469V, NOTCH1 Q2440, and CCND2 G268R mutations, and FISH positive for biallelic CDKN2A (p16) deletion similar to original T-ALL. Conclusions Our extensive genomic characterization suggests a unique molecular pathogenesis for histiocytic disorders arising after T-cell ALL and identified RAS signaling pathway and NOTCH1 mutations. Furthermore, these findings strongly indicate a potential derivation or trans differentiation from the malignant leukemic stem cell clone. Disclosures: No relevant conflicts of interest to declare.

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Lin, Ying-Chu, Wu-Ching Uen, Sheng-Po Hao, Chen-Yu Hsiao, and Hung-Chih Lai. "Triple combination treatment with anti-EGFR monoclonal antibody, low-dose chemotherapy, and anti-PD1 immune check-point inhibitors for recurrent and/or metastatic head and neck squamous cell carcinoma: A single institute experience." Journal of Clinical Oncology 37, no. 15_suppl (2019): e17514-e17514. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17514.

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e17514 Background: The 1st line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M SCCHN) was EXTREME regimen established by Vermorken at al since 2008. Recently in ESMO 2018, Keynote-048 presented frontline pembrolizumab monotherapy or combined chemotherapy had a better overall survival than EXTREME regimen, though with poor PFS (3.2m-3.4m) and response rate (19-23%). But chemotherapy plus pembrolizumab showed a shorter duration of response than the pembrolizumab alone. Therefore, role of chemotherapy as a partner of IO is debated. We presented a retrospective report of triple combination treatment of cetuximab, low-dose chemotherapy and anti-PD1 check-point inhibitor for R/M SCCHN patients as a e-publication in ASCO 2018. This is a update report. Methods: We retrospectively reviewed charts of R/M SCCHN patients who started triple combination of cetuximab, low-dose chemotherapy and anti-PD1 therapy during the period of Feb. 2017 till Jan.31 2018. The contents of combinations, previous treatments, duration of combination treatments, best response, and adverse effects were recorded. Data cutoff is Jan.15 2019. Results: Total 15 patients reviewed. The mean age was 55.4 years (age range 32 – 71 years). Previous treatments included chemotherapy (80%), anti-EGFR (33.3%), anti-PD1 check-point inhibitor (53.3%). The median duration of follow up was 434 days (range 187–707 days). Complete response was observed in 3 patients (20%), partial response in 7 patients (46.7%), stable disease in 4 patients (26.6%) and disease progression in 1 (6.6%). Objective response rate(CR+PR) observed was 66.7%. Clinical benefit rate(CR+PR+SD) observed was 93.3% . Dose of Cetuximab was 250-500mg/m2 every 2-3 weeks. Combination of chemotherapy included PF, TP, or docetaxel monotherapy. Doses were Cisplatin 30-50mg/m2, 5-FU 600-1000mg/m2, or docetaxel 20-30mg/m2; all in every 2-3 weeks. Anti-PD1 immune check-point inhibitors included Nivolumab 1-3mg/kg or Pembrolizumab 1-2mg/kg, every 2-3 weeks. Six patients (40%) died: 2 due to progression of disease, 1 due to tumour bleeding, 2 due to pneumonia, and 1 due to fungemia. Conclusions: Our real-world report might suggest a possible role of ADCC effect of cetuximab and less-toxic chemotherapy as a partner of IO. Further prospective study of triple combination therapy with biomarker evaluation is recommended.

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Veliz, Marays, John Powers, Ling Zhang, et al. "Correlative Analysis of T Cell Subpopulations and CD20 Expression In a Phase II Study of Lenalidomide In Combination with Rituximab In Patients with Relapsed or Refractory CLL/SLL." Blood 116, no. 21 (2010): 4630. http://dx.doi.org/10.1182/blood.v116.21.4630.4630.

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Abstract Abstract 4630 Background: The prognosis of patient with relapsed or refractory CLL/SLL is dismal with an overall response rate (ORR) to salvage therapy for refractory patients of 10–30%, and limited survival benefit with current treatment approaches. Phase II studies of single agent lenalidomide in patients with relapsed or refractory CLL revealed an ORR of 32–58% (7-17% CR). Recent in vitro studies have shown that lenalidomide enhances the rituximab-induced killing of NHL cell lines and B-CLL cells by enhancing ADCC activity and restoring the defective T-cell and NK-cell mediated tumor cell cytotoxicity. Methods: Patients with relapsed or refractory CLL/SLL received oral lenalidomide via dose escalation as follows: 2.5 mg on days 1–7, 5 mg on days 8–14 and 10 mg on days 15–21 followed by 7 days of rest in 28-day cycle; for cycle 2 and beyond 20 mg was given on days 1–21 on a 28-day cycle. Rituximab was dosed at 375 mg/m2 IV weekly for 4 weeks starting on day 15 of cycle 1. Treatment was continued until disease progression or toxicity. Primary objectives were ORR (CR+PR) and safety and tolerability of the combination regimen. CT scans, and bone marrow biopsies were done every 2 months to assess for response (NCI-WG 2008). Peripheral blood and bone marrow aspirates were collected for correlative studies before lenalidomide was initiated, before rituximab was initiated (between days 13–15), after finishing treatment with rituximab and then every two months until disease progression. Flow cytometry was performed using the following antibodies CD3, CD4, CD5, CD8, CD19, CD20, CD23, CD40, CD45RA, CD62L, CD80, CD86, CD95, IL-17A and FoxP3. Panels were created for the analysis of T-cell memory/naïve populations, B-cell populations, regulatory T-cells and Th17 cells. Data was collected to a limit of 10,000 events of the population of interest. Data is presented as total number of cells/ul instead as percentage to avoid misinterpretation due to the dramatic reduction in the number of B cell lymphocytes after initiation of therapy. Subpopulation of T cells memory/naïve were compared with an age matched population of normal controls. Results: 18 patients with CLL/SLL were enrolled on study. Median number of prior chemotherapies was 3 (range 1–5). Median age was 63 years (range 42–80). High risk cytogenetic abnormalities (del11q (11%), del 17p/p53 (11%), complex (22%)) were observed in 44% of the patients. 95% of the patients had received prior fludarabine therapy and 50% were fludarabine refractory. Overall clinical benefit was seen in 92% of patients (42% PR, 50% SD) with a median duration of response of 18 months for patients who achieved a PR and 12 months for patients with SD. Although all responses were PR, the PR rate improved with continued therapy suggesting increased responses with a longer duration of treatment with lenalidomide. Most common adverse effects were neutropenia (50% grade 3–4), tumor flare (28% grade 1–2, 11% grade 3–4), fatigue (11% grade 1–2, 6% grade 3–4), venous thromboembolic disease (11% grade 3–4), acute renal insufficiency (11%), rituximab related infusion reactions (11%), flu-like symptoms (11%), infections (11%), and hypercalcemia (11%). Correlative studies showed that peripheral blood CD4 and CD8 effector memory subpopulations decreased after initiation of lenalidomide therapy with subsequent elevation after rituximab treatment on the CD4 effector memory compartment. The Th17 compartment was minimally decreased after initiation of lenalidomide while the levels of regulatory T cells (Tregs) appeared to decrease with lenalidomide therapy and increase slightly after rituximab. The expression of CD20 from bone marrow samples decreased as expected with rituximab therapy; however shortly after the discontinuation of rituximab CD20 expression was regained by the B cells compartment. Later time points will be presented at the meeting. Conclusions The combination of lenalidomide with rituximab is a promising with clinical activity in heavily pretreated patients with relapsed or refractory CLL. The combination appears tolerable with observed events consistent with the use of these two agents in other studies. The impact of lenalidomide on the T cell subpopulations in patients treated with rituximab remains unclear. A detailed analysis of the BM compartment at latter time points will be investigated. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Komrokji:Genentech: Research Funding.

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Oberley, Matthew J., Gerald Wertheim, Sunil S. Raikar, et al. "Clinical Outcomes in Pediatric Mixed Phenotype Acute Leukemia (MPAL) Differ Depending on Disease Classification Criteria; A Multi-Center Cohort Study." Blood 132, Supplement 1 (2018): 4080. http://dx.doi.org/10.1182/blood-2018-99-117377.

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Abstract INTRODUCTION: Mixed phenotype acute leukemia (MPAL) is a category of acute leukemia established in the World Health Organization (WHO) 2001 classification, significantly modified in WHO2008, and again refined in the most recent WHO2016 update. The current WHO2016 iteration conceptualizes MPAL as a stem cell disorder whereby most cases will manifest heterogeneity of lineage-specific antigen expression by multi-parameter flow cytometry. The WHO2016 definition also urges caution for cases otherwise consistent with B-cell acute lymphoblastic leukemia (B-ALL) that express myeloperoxidase (MPO) as the sole representation of myeloid lineage. These cases met the WHO2008 definition but may not meet the newer WHO2016 criteria. There is limited data on the clinical impact of these recent changes in the WHO classification for MPAL. METHODS: Six institutions identified cases diagnosed as MPAL between 2008 and 2016 according to WHO criteria. The diagnostic flow cytometry was then reanalyzed by two independent hematopathologists blinded to clinical outcomes. The cases were evaluated as to whether they met criteria for WHO2008 MPAL and/or WHO2016 MPAL. Cases of WHO2008 MPAL were further subdivided into those that otherwise met criteria for B-ALL (including non-lineage specific expression of ±CD13, ±CD15, ±CD33) but qualified as MPAL due to MPO expression (MPO+MPAL) and all remaining cases of MPAL that demonstrated additional myeloid lineage specificity as described by the WHO criteria (MLS+MPAL). Data for a distinct cohort of pediatric B-ALL without significant MPO expression diagnosed during the same study period was submitted from one participating site to serve as a reference cohort (n=258). Endpoints of interest to evaluate clinical outcomes according to the WHO classification were event-free and overall survival (EFS, OS). All statistical tests were two-sided with significance set at p<0.05. RESULTS: The cohort consisted of 112 cases submitted for central review; 94/112 met the strict criteria for WHO2008 MPAL. Of these, 21/94 cases also had sufficiently comprehensive testing performed at diagnosis to meet criteria for WHO2016 MPAL. Five-year EFS and OS for patients identified as WHO2016 MPAL (63±11% and 69±11%) was significantly worse than the remainder meeting only the WHO2008 criteria (69±7% and 87±5%, p=0.024 and p<0.001, respectively). Patterns of failure occurred earlier for the WHO2016 MPAL subset (Figure 1). For those diagnosed with WHO2008 MPAL, 67/94 (71%) cases were found to be MPO+MPAL, and the remaining 27 were consistent with MLS+MPAL. Favorable prognostic features (age<10 years, WBC <50 K/uL, favorable cytogenetics) were significantly less prevalent at diagnosis in MLS+MPAL and MPO+MPAL versus B-ALL. Five-year EFS and OS for patients with MPO+MPAL (68±7% and 87±5%) or MLS+MPAL (68±9% and 72±9%) were significantly worse when compared to B-ALL overall (84±3% and 93±2%, Wilcoxon p<0.001 for EFS and OS) (Figure 2). However, on multivariable analysis inclusive of prognostic features, OS differed significantly from B-ALL for MLS+MPAL but not for MPO+MPAL (p=0.016 and p=0.629, respectively). There was no association between percentage of MPO+ blasts and EFS or OS. CONCLUSIONS: Reported survival rates for MPAL continue to vary with changes to the WHO classification. The subset fulfilling WHO2016 criteria demonstrated significantly worse EFS and OS than the WHO2008 cohort; WHO2016-defined MPAL may better represent the concept of MPAL as a stem cell disorder. Applying WHO2016 versus WHO2008 criteria to diagnostic flow cytometry in this retrospective cohort resulted in fewer patients classified as MPAL. As a retrospective study, the antigen combinations necessary to fulfill newer WHO2016 criteria for blast heterogeneity were not tested in many cases; however, it remains likely that the updated WHO2016 criteria will reduce apparent disease prevalence. While cases of WHO2008 MPAL otherwise meeting criteria for B-ALL apart from MPO expression were less likely to have favorable prognostic features at diagnosis, survival on multivariable analysis was similar to B-ALL; it remains unclear how best to categorize this group of MPO+ acute leukemia. Better understanding of the biology of MPAL is therefore essential to appropriately classify these rare leukemias and to develop optimal therapy. Disclosures O'Gorman: Becton Dickinson: Consultancy.

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Goh, Hyun-Gyung, Dongho Kim, Soo-Young Choi, et al. "Monitoring of Dynamics of BCR-ABL Transcripts Over Time Using Digital PCR Assay In CP CML Patients After Achieving Complete Molecular Remission." Blood 116, no. 21 (2010): 1726. http://dx.doi.org/10.1182/blood.v116.21.1726.1726.

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Abstract Abstract 1726 With prolonged imatinib therapy, BCR-ABL transcript levels measured by RQ-PCR assay show a progressive reduction, and some patients achieve complete molecular remission (CMR), which is defined as sustained undetectable BCR-ABL using RQ-PCR assay with a sensitivity of at least 4.5-log below the standardized baseline. However, due to the sensitivity limit of the current RQ-PCR technology, PCR negativity should not be considered as cure as more than 106 leukemic cells can still remain in the absence of detectable BCR-ABL transcripts by RQ-PCR. Although the numbers of patients with undetectable BCR-ABL are increasing with prolonged imatinib therapy and also with advent of more potent novel tyrosine kinase inhibitors (TKIs) such as dasatinib, nilotinib and bosutinib, currently there is no methodology to further classify the patients in CMR. In this study, digital PCR (dPCR) assay was applied for measurement of BCR-ABL transcript levels in patients with CMR to assess if more sensitive detection methodology can be implemented for molecular monitoring in CML. Between May 2001 and Aug 2008, total 757 CML patients were treated with imatinib in St. Mary's Hospital of the Catholic University of Korea, and 192 chronic phase (CP) CML patients have been under imatinib therapy for more than 2 years. Among them, 36 patients achieved PCR negativity at least once during imatinib treatment, and serial PB samples collected from the patients who have maintained CMR for at least 3 years in RQ-PCR were screened by dPCR. In dPCR assay, each sample was partitioned into hundreds to tens of thousands of reaction chambers, and this sample partitioning enables detecting extremely low copy numbers that would normally be undetectable by conventional RQ-PCR platforms. Using the BioMark Real-Time PCR System (Fluidigm) and 12.765 Digital Array (Fluidigm) in dPCR assay, only 1 liquid-transfer step is required to automatically partition each of 12 samples into 765 reaction chambers of approximately 4.6 ul (6 nl × 765), and pre-amplification step was performed prior to dPCR assay to improve the sensitivity. Regarding the detection limit, whereas down to 10-5 of cell line dilutions and down to 10-4 of patient sample dilutions were detectable using conventional RQ-PCR, dPCR showed 2–3 log improvement in the detection sensitivity limit by detecting down to 10-7 of cell line dilutions and patient sample dilutions. In all the patient samples collected at the first time point of PCR negativity, positive BCR-ABL signals were detected in dPCR assay, and gradual decrease in the number of positive signals were observed in the serial samples collected on yearly basis after achieving CMR. PB samples collected from 5 healthy individuals were also screened to confirm the significance of positive results in dPCR, and no amplification was detected in all of 5 samples. This study shows that the patients in CMR who is currently categorized based on the data derived from conventional RQ-PCR assay could be classified further using more sensitive methodology such as dPCR assay. In the previous studies on imatinib discontinuation, the selection criteria of candidates was solely based on the duration of PCR negativity prior to discontinuation, and conventional RQ-PCR was employed to measure PCR negativity. The fact that the absolute number of residual leukemia clones could not be measured under the detection limits of conventional RQ-PCR might have resulted in relapse in more than half of the patients, and it reflects that firm conclusions cannot be drawn about if a patient could safely discontinue the therapy solely based on conventional RQ-PCR. It might be necessary to have more sensitive assays which will allow further classification of patients who could be candidates for imatinib discontinuation without relapse. This study shows the potential of highly sensitive PCR approach for molecular monitoring, and dPCR examined here can be extended to expand our understanding of molecular profiles in CML patients and to correlate to clinical significance. Detection and quantitation of low copy numbers may help to more precisely follow-up the course of disease and thereby to more accurately tailor personalized therapeutic choices. Disclosures: No relevant conflicts of interest to declare.

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Advani, Anjali S., Brenda Cooper, Paul Elson, et al. "A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML)." Blood 128, no. 22 (2016): 4065. http://dx.doi.org/10.1182/blood.v128.22.4065.4065.

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Abstract Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT > grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-< 10x upper limits of normal (ULN), 10-20 x ULN, and > 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (> 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, >1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Jagasia, Madan, Heidi Chen, Sheri Dixon, et al. "Pharmacoeconomics of Stem Cell Mobilization Using Cyclophosphamide and G-Csf." Blood 114, no. 22 (2009): 4526. http://dx.doi.org/10.1182/blood.v114.22.4526.4526.

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Abstract Abstract 4526 Introduction Autologous stem cell mobilization (SCM) is conventionally done using chemotherapy and G-CSF (G). Although safe and effective, patients (pts.) are exposed to risks of cytotoxic chemotherapy and myelosuppression. Plerixafor (P) and G mobilizes stem cells (SC) without any myelosuppression. Understanding the pharmacoeconomics (PE) of SCM is important so that the optimal approach can be used. Methods We studied PE of high dose cyclophosphamide (CY) and G SCM in 241 pts. (1/2004 to 3/2008) undergoing first autologous stem cell transplant and compared outcomes to projected costs using P+G. CY was dosed at 3 gm/m2 and G started the next day (10 mcg/kg) for 10 days with a planned first day of collection on day 11. Dose escalations were per institutional protocol. Pheresis was initiated if peripheral blood (PB) had >15 CD34+ cells/uL. PE analyses were done to compute total cost and included cost of CY, G, pheresis, product processing, and clinical events. Cost was based on Medicare part B physician, laboratory, and ancillary fee schedule and was calculated from review of random patient records. This approach removed the bias of inter-institutional cost variations. Ideal Outcome (IO) was defined as >2×106 CD34+ cells/kg collected on the planned day of collection in 1 or 2 apheresis without a preceding negative event that lead to additional evaluation in clinic or inpatient. Results 141 (61%) were males; 121 (50%) had myeloma (MM), 115 (48%) had lymphoma (L) and 5 had other diagnoses; 61 (25%) received radiation with prior therapy. Median WBC and neutrophil count prior to CY was 5.3 ×109 /L (range, 1.7 to 46), and 3.3 ×109/L (range, 0.95-31.37). 199 (82.6%) started pheresis on the planned first day of pheresis, 18 (7.9%) had a delay in start of pheresis (range, 1- 7 days) due to low PB CD34 count and 24 (9.9%) pts. did not proceed to pheresis due to low PB CD34+ cell count. The mean final SC dose was 10.22 ×106 CD34/kg (range, 0.45 - 60.18). Pts. with MM collected more than lymphoma (11.98 vs. 6.35, P<0.0001). 6 (2.8%) pts. collected <2 ×106 CD34/kg. Median number of pheresis was 1 (range, 0 - 4) with 41 (17%), and 10 (4.1%) requiring 2 and 3 pheresis, respectively. The target SC dose of >6×106 CD34/kg in MM pts. was collected in 1,2, or 3 pheresis in 84 (69.4%), 98 (80.9%), and 102 (84.2%), respectively. In L pts., the target SC dose of >2×106 CD34/kg was collected in 1, 2, or 3 pheresis in 68 (59%), 85 (73.9%) and 90 (74.3%), respectively. Clinical events included: febrile neutropenia (FN) clinic evaluation (7, 2.9%); FN admission (26, 10.8%); line infection (7, 2.9%); line change (8, 3.3%), gastrointestinal side effects (111, 46%), bone pain with evaluation in clinic (127, 52%) and admission for management of bone pain (9, 3.7%). Forty-three (18%) pts. were hospitalized for clinical events. IO was seen in 48 (20%) pts. 23% of MM and 15.7% of L pts. had an IO. Risk factors including prior radiation, WBC count and ANC prior to CY could not predict ability to collect SC or IO. Mean total cost of CY+G SCM was $10,732 (range, 6988-30827). IO was associated with a lower cost in overall group, (mean, $10,371 vs. $12,870, P=0.001), in MM pts. (mean, $10,511 vs. $12,152, P=0.026), and in L pts. (mean, $10,133 vs. $13,627, P=0.006). Assuming a similar distribution of IO in 100 pts. with MM and L, the projected per pt. cost of SCM would be $11,774 and $13,067 (mean, $12,421) with CY+G. Projected costs of SCM using P+G (based on published phase III data that used G dose of 10 mcg/kg without dose escalation and that the non-mobilizers had a maximum of 4 days of P) for 100 pts. with MM and L would be $12,852 and $8986 (mean, $10,919). These do not take into account costs associated with operational planning and predictability of the date of SCM with P+G, impact of the negative event on pts. quality of life with CY+G, effects of mobilization failure leading to other alternative clinical approaches including an allogeneic stem cell transplant (N=6). Conclusion Our study shows that SCM with CY+G is associated with a low incidence of IO. P+G can be justified as upfront method of SCM in pts. with MM and L from a PE perspective without any detrimental impact on SCM efficiency. As P+G is not associated with any negative clinical events related to myelosuppression, it should translate into a better quality of life for pts. SCM using P+G may allow for optimal utilization of resources which again will impact PE. These need to be validated and should be addressed in future studies of SCM. Disclosures: Jagasia: Genzyme: Research Funding.

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Oberley, Matthew J., Sunil S. Raikar, Jemily Malvar, et al. "Minimal Residual Disease Risk-Stratification in Pediatric Mixed Phenotype Acute Leukemia: Results of a Multi-Center Cohort Study." Blood 132, Supplement 1 (2018): 558. http://dx.doi.org/10.1182/blood-2018-99-113606.

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Abstract BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare form of leukemia in children. Current evidence supports the use of acute lymphoblastic leukemia (ALL)-directed regimens as initial therapy for MPAL; Children's Oncology Group (COG) ALL regimens are commonly used for pediatric ALL in the United States. Data for the predictive value of minimal residual disease (MRD) to risk-stratify therapy for pediatric MPAL is sparse overall and currently unknown in the context of COG ALL regimens. The primary objective for this study was to therefore examine the predictive value of MRD for event-free and overall survival (EFS, OS) in a centrally-reviewed, strictly-defined pediatric MPAL cohort treated according to COG ALL regimens. METHODS: A retrospective cohort of pediatric MPAL treated from 2008-2016 was assembled from six institutions in the United States. All sites submitted primary diagnostic flow cytometry for central review. Two independent hematopathologists blinded to clinical outcomes confirmed the diagnosis of MPAL according to the WHO2008 and/or WHO2016 classification and assigned a MPAL phenotype. MRD was assessed by multi-parameter flow cytometry ("negative" defined as <0.01%). Endpoints of interest included presenting features of MPAL, MRD levels at end of induction and consolidation (EOI, EOC), role of hematopoietic stem cell transplantation (HSCT) in complete remission (CR), EFS, and OS. Kaplan-Meier analyses were performed stratified by predictors of interest. Stepwise multivariable Cox proportional hazard models inclusive of MRD and candidate predictors were used to evaluate EFS and OS for patients with complete data. Analyses were repeated in the subset of patients with "neutral" cytogenetics (i.e. no favorable [double trisomy, ETV6-RUNX1] or adverse [hypodiploid, BCR-ABL1, KMT2Ar, Ph-like, iAMP21, FLT3-ITD] features). All tests were 2-sided with significance set at p <0.05. RESULTS: Of the 112 cases diagnosed by institutions as MPAL, 94 (84%) fulfilled strict WHO criteria. The majority of MPAL patients were B/Myeloid (89%), with a single blast population (87%), and without hyperleukocytosis (WBC≥50K/uL) or central nervous system involvement at presentation (Table 1). Within the cohort, 85/94 were treated with a COG ALL regimen with EOI MRD available (1/85 suffered an induction death prior to MRD assessment). ALL induction therapy resulted in a MRD-negative CR in 72% (61/85); three MRD-negative patients nonetheless converted to non-ALL therapy. Of those EOI MRD+ (≥0.01%), 12 of 14 who continued with COG ALL therapy achieved an EOC MRD-negative CR (i.e. 70/85 [82%] were MRD-negative by EOC). Induction failure (IF) occurred in 7% (6/85) and was defined as disease progression prior to EOI (n=2) or by EOI MRD ≥5% (n=4). The two patients with early disease progression were successfully "salvaged" with AML therapy (<21 days from initial diagnosis) and achieved a MRD-negative CR following one cycle. Patients achieving MRD-negative remissions at EOI and/or EOC with ALL chemotherapy had excellent EFS and OS (Figure 1). Multivariable analysis confirmed the predictive value of MRD at EOI (hazard ratio ±SE for EFS and OS = 3.77±1.67 and 3.54±2.09; p=0.032 and p=0.024 respectively). Only a few patients receiving ALL therapy proceeded to HSCT in CR1, all were alive at time of reporting. Use of HSCT was not associated with improved EFS or OS (p>0.50 for both); five-year EFS and OS for ALL chemotherapy without HSCT (n=73) were 78±6% and 90±4%, respectively. The presence of multiple blast populations of distinct lineages at diagnosis was similarly rare and was potentially associated with worse OS on multivariable analysis (p=0.024). No other candidate predictors were associated with EFS or OS. No difference in the predictive value of MRD was present when analyses were limited to patients with "neutral" cytogenetics. CONCLUSION: In a retrospective analysis of pediatric MPAL, the majority of patients treated with ALL chemotherapy achieved a MRD-negative CR by EOC (~week 12 of therapy); overall survival in this group was excellent. Further prospective validation of MRD is essential to refine risk-stratified therapy for pediatric MPAL. Optimal salvage for those who fail to achieve remission with ALL chemotherapy is unknown and requires further study. Disclosures O'Gorman: Becton Dickinson: Consultancy.

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Chaudhury, Ateefa, Rami S. Komrokji, Najla H. Al Ali, Ling Zhang, Pardis Vafaii, and Jeffrey E. Lancet. "Prognosis and Outcomes in MDS-MPN Unclassifiable: Single Institution Experience of a Rare Disorder." Blood 126, no. 23 (2015): 1698. http://dx.doi.org/10.1182/blood.v126.23.1698.1698.

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Abstract Introduction: The 2008 World Health Organization (WHO) classification has recognized a unique overlap category that has features of proliferation found in myeloproliferative neoplasms (MPN) and also dysplasia found in myelodysplastic syndrome (MDS). The least well characterized of the 4 MDS/MPN overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. Furthermore, given the rarity of this disorder, there is no validated risk stratification scoring system, although there are several commonly used prognostic models for MDS, including the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), and the M.D. Anderson Cancer Center model (MDAS). The objectives of this study were to evaluate the natural history of this very uncommon diagnosis and to determine which of the current scoring symptoms used for MDS best discriminates outcomes. Methods: The Moffitt Cancer Center database of over 3000 MDS patients was used to identify patients with MDS/MPN-U and to subsequently perform a comprehensive chart/pathology review. We then applied IPSS, IPSS-R, and the MDAS scores to each patient in order to compare differences in overall survival (OS) amongst different risk groups within each scoring system. Finally, we compared outcomes in the MDS/MPN-U group with a large number of matched MDS cases from within our database, using the MDAS. Descriptive statistical analyses were utilized. Chi square analysis and t- test were performed to compare categorical and continuous variables. Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. All data was analyzed using SPSS version 21.0 statistical software. Results: Forty three patients were identified with MDS/MPN-U and were pathologically confirmed to meet WHO criteria. Median age was 71 years (range 55 - 91) and the M:F = 26.17. Median baseline laboratory parameters: WBC 11.2 x 103/dL (range 0.9 - 84.8); Hb 9.7 g/dL (range 5.8-14.4); platelets 137 x 103/uL. Table 1 summarizes risk stratification per current validated MDS scoring systems. The majority of patients had lower risk disease by all the models. Forty of 42 (95%) patients evaluable for prognostic scoring were classified as low/Int-1 by IPSS. However, 11 out of the 40 pts (28%) classified as lower risk by IPSS were upgraded to Int-2 or high risk by MDAS. Twenty-two patients received hypomethylating agents (HMA) as first line treatment after supportive care. Per IWG 2006, 8 of 22, (36%) had complete response, partial remission, or hematologic improvement, 7 (32%) had stable disease, and 6 (27%) had progressive disease. The median OS for all MDS/MPN-U patients was 33 months (95% Confidence Interval 22 - 45). Within each MDS scoring system, statistically significant survival differences were detected between risk stages (table 1). The IPSS-R did not improve the IPSS prognostic value. Patients categorized as lower-risk (low/Int-1) by MDAS had superior survival compared to IPSS. Lastly, we compared outcomes between the 43 MDS/MPN-U patients and 1117 IPSS low/Int-1 matched controls within the MDS database. Median overall survival was inferior in MDS/MPN-U vs. MDS (33.4 mo vs. 57 mo, p = 0.005). In addition, using the MDAS, stage-by-stage, survival was significantly worse in the MDS/MPN-U group. Table 1. Risk Stratification Based on MDS Scoring Systems MDS/MPN-Un (%) Median Overall Survival (mo) P-value IPSS Low Int-1 Int-2 High 15 (35.7)25 (59.5)1 (2.4)1 (2.4) 33.433.312.86.0 < 0.001 IPSS-R Very Low Low Intermediate High Very High 6 (14.3)21 (50)10 (23.8)4 (9.5)1 (2.4) 18.2333.425.112.86.0 0.001 MDAS Low Int-1 Int-2 High 6 (14.3)20 (47.6)13 (31.0)3 (7.1) 52.433.425.16.0 < 0.001 Conclusions: MDS/MPN-U appears to have a variable disease course but with generally poor outcomes, even amongst lower-risk patients classified by MDS scoring systems, and despite a moderate rate of response to treatment. Matched comparisons indicate inferior outcomes compared with similarly staged MDS patients. The MDAS may offer increased discriminatory capacity for determining prognosis based on disease stage. Further work with a larger patient population and cross comparisons to other MDS/MPN diseases will assist further understanding of this rare disorder. Integration of somatic mutations data may compliment the clinical models. Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pharmacylics: Speakers Bureau; Incyte: Consultancy. Lancet:Kalo-Bios: Consultancy; Celgene: Consultancy, Research Funding; Pfizer: Research Funding; Amgen: Consultancy; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy.

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Advani, Anjali S., William Tse, Xuefei Jia, et al. "Long-Term Follow-up Results: A Phase 2 Trial of Imatinib Mesylate As Maintenance Therapy for Patients with Newly Diagnosed c-Kit Positive Acute Myeloid Leukemia (AML)." Blood 126, no. 23 (2015): 2536. http://dx.doi.org/10.1182/blood.v126.23.2536.2536.

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Abstract The c-kit (CD117) receptor is expressed on > 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels [defined as mean fluorescent intensity (MFI) > 20] correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/ refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in pts with newly diagnosed c-kit + AML improves progression-free survival (PFS) compared to historical controls. We previously presented our toxicity and correlative data at ASH 2012 (Abstract 3597). Here, we present our long term follow-up results. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0-2. Cytogenetics (CG) were classified per CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine and an anthracycline] or ADE [cytarabine, daunorubicin, etoposide]) and PRT (≥ 1 course for pts ≥ 60 yrs; ≥ 2 courses for pts < 60 yrs). CR was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by IHC on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/ MCN auto fluorescence using a CD45/orthogonal light scatter gate to isolate blasts and lymphocytes. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grade 2-4 non-hematologic toxicity and Grades 3-4 neutropenia and thrombocytopenia. PFS was measured from the CR date to the time of relapse or death. Primary endpoints: Based on historical data from the Cleveland Clinic and SWOG, the median PFS for all AML pts undergoing IT < 60 yrs of age is 13 mos and for pts ≥ 60 yrs of age is 8 mos. The goal of this study was to see a 30% improvement in PFS at these time points in the respective age groups (i.e. 65% PFS at 13 mos for pts < 60 yrs; 65% PFS at 8 mos for pts ≥ 60 yrs). Results: Of 32 pts enrolled, the median age was 54 yrs (range 19-81), median WBC at dx 22.13 K/ uL (1.55-98.44), median peripheral blood blasts at dx 23.6% (range 0-85), and 44% were male. CG risk included: 16% (5) good, 66% (21) intermediate, 16% (5) poor, 3% (1) miscellaneous. Of the pts with normal CG, 10 were NPM1+, FLT3 ITD negative; and 1 pt was FLT3 ITD+. The median c-kit+ blast % was 79.9, and median c-kit MFI 39.8 (range 6.5-120.1). Median AF1q expression was 9.59 (range 1.83-161.85) (> 9 is considered high and is associated with a poor prognosis; high AF1q is also associated with high c-kit expression). Eight-four percent of pts had moderate or high levels of drug resistance factors (GST1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. There was no correlation between MDR and c-kit MFI. Pts received IM for a median of 4.0 mos (range 0.1-12.2) and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent of pts experienced Grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. With a median follow-up time of 56.3 mos, the estimated median OS was 51.3 mos and estimated median relapse-free survival (RFS) 18.9 mos. The estimated PFS at 13 mos for pts < 60 yrs of age was 71 ± 10% (p=0.017, compared to the null hypothesis); and the estimated PFS at 8 mos for pts ≥ 60 yrs of age was 64 ± 15% (p=0.166, compared to the null hypothesis). Predictors of worse RFS included: age, WBC at dx, % peripheral blasts at dx, CG risk, and MDR expression. C-kit MFI and Af1q were not associated with RFS or OS. Conclusions: Use of IM maintenance therapy appeared to be associated with improved PFS compared to historical controls in pts < 60 yrs of age. In addition to a high c-kit MFI, these pts had other adverse characteristics (moderate to high levels of MDR. high AF1q). Though previous studies have demonstrated that c-kit MFI > 20.3 was an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months) in AML, use of IM maintenance therapy in this study appeared to mitigate this, supporting further investigation. Disclosures Off Label Use: imatinib in the treatment of AML. Rao:Boehringer-Ingelheim: Other: Advisory Board; amgen: Other: ad board; novartis: Other: ad board. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Griffiths:Alexion Pharmaceuticals: Honoraria; Astex: Research Funding; Celgene: Honoraria. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

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Lakkaraja, Madhavi, Michael Scordo, Audrey Mauguen, et al. "Rabbit Anti-Thymocyte Globulin Exposure (rATG) in CD34+ Selected Hematopoietic Cell Transplantation and Its Impact on Immune Reconstitution and Outcomes in Children and Adults." Blood 136, Supplement 1 (2020): 30–31. http://dx.doi.org/10.1182/blood-2020-136341.

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Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure. Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+&gt;50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, &lt;30 mg*d/L, 30-55 mg*d/L, and &gt;=55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses. Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L). A decreasing post-HCT AUC (optimum &lt;30 mg*d/L) was associated with higher probability of CD4+IR (p&lt; 0.0001, Figure 1a); lower NRM (p=0.03, Figure 1b) and improved OS (p=0.05, Figure 1c). Patients who attained CD4+IR earlier had lower rates of NRM (p&lt;0.0001, Figure 1d). On further assessing rATG exposure post allo-HCT by three cut -off levels (&lt;30mg*d/L, 30-55 mg*d/L and &gt;=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure &gt;=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of &lt;30 mg*d/L (HR: 4.11, CI: 1.52, 11.2, Figure 1f), and inferior OS (HR: 2.03, CI: 1.03,4.00, Figure 1g). In addition, post-HCT rATG exposure &gt;=55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure &lt;30mg*d/L group, 6 secondary rejections in the post-HCT ATG exposure of 30-55 mg*d/L group and 2 secondary rejections in the post-HCT ATG exposure &gt;=55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%). Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial. Figure 1 Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Curran:Celgene: Research Funding; Novartis: Consultancy, Research Funding; Mesoblast: Consultancy. Kernan:Amgen: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties: EBV-specific T-cell bank, Research Funding. Prockop:Mesoblast, Inc,: Consultancy, Honoraria, Research Funding; Atara: Research Funding; Jasper: Research Funding. Scaradavou:Excellthera: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boelens:Bluebird Bio: Consultancy; Advanced Clinical: Consultancy; Race Oncology: Consultancy; Bluerock: Consultancy; Omeros: Consultancy; Avrobio: Consultancy; Takeda: Consultancy.

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Hapidin, Winda Gunarti, Yuli Pujianti, and Erie Siti Syarah. "STEAM to R-SLAMET Modification: An Integrative Thematic Play Based Learning with R-SLAMETS Content in Early Child-hood Education." JPUD - Jurnal Pendidikan Usia Dini 14, no. 2 (2020): 262–74. http://dx.doi.org/10.21009/jpud.142.05.

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STEAM-based learning is a global issue in early-childhood education practice. STEAM content becomes an integrative thematic approach as the main pillar of learning in kindergarten. This study aims to develop a conceptual and practical approach in the implementation of children's education by applying a modification from STEAM Learning to R-SLAMET. The research used a qualitative case study method with data collection through focus group discussions (FGD), involving early-childhood educator's research participants (n = 35), interviews, observation, document analysis such as videos, photos and portfolios. The study found several ideal categories through the use of narrative data analysis techniques. The findings show that educators gain an understanding of the change in learning orientation from competency indicators to play-based learning. Developing thematic play activities into continuum playing scenarios. STEAM learning content modification (Science, Technology, Engineering, Art and Math) to R-SLAMETS content (Religion, Science, Literacy, Art, Math, Engineering, Technology and Social study) in daily class activity. Children activities with R-SLAMETS content can be developed based on an integrative learning flow that empowers loose part media with local materials learning resources. Keyword: STEAM to R-SLAMETS, Early Childhood Education, Integrative Thematic Learning References Ali, E., Kaitlyn M, C., Hussain, A., & Akhtar, Z. (2018). the Effects of Play-Based Learning on Early Childhood Education and Development. Journal of Evolution of Medical and Dental Sciences, 7(43), 4682–4685. https://doi.org/10.14260/jemds/2018/1044 Ata Aktürk, A., & Demircan, O. (2017). A Review of Studies on STEM and STEAM Education in Early Childhood. Journal of Kırşehir Education Faculty, 18(2), 757–776. Azizah, W. A., Sarwi, S., & Ellianawati, E. (2020). Implementation of Project -Based Learning Model (PjBL) Using STREAM-Based Approach in Elementary Schools. Journal of Primary Education, 9(3), 238–247. https://doi.org/10.15294/jpe.v9i3.39950 Badmus, O. (2018). Evolution of STEM, STEAM and STREAM Education in Africa: The Implication of the Knowledge Gap. In Contemporary Issues in Science, Technology, Engineering, Arts and Mathematics Teacher Education in Nigeria. Björklund, C., & Ahlskog-Björkman, E. (2017). Approaches to teaching in thematic work: early childhood teachers’ integration of mathematics and art. International Journal of Early Years Education, 25(2), 98–111. https://doi.org/10.1080/09669760.2017.1287061 Broadhead, P. (2003). Early Years Play and Learning. In Early Years Play and Learning. https://doi.org/10.4324/9780203465257 Canning, N. (2010). The influence of the outdoor environment: Den-making in three different contexts. 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Policy Brief, 1–10. Doyle, K. (2019). The languages and literacies of the STEAM content areas. Literacy Learning: The Middle Years, 27(1), 38–50. http://proxy.libraries.smu.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=eue&AN=133954204&site=ehost-live&scope=site Edwards, S. (2017). Play-based learning and intentional teaching: Forever different? Australasian Journal of Early Childhood, 42(2), 4–11. https://doi.org/10.23965/ajec.42.2.01 Faas, S., Wu, S.-C., & Geiger, S. (2017). The Importance of Play in Early Childhood Education: A Critical Perspective on Current Policies and Practices in Germany and Hong Kong. Global Education Review, 4(2), 75–91. Fesseha, E., & Pyle, A. (2016). Conceptualising play-based learning from kindergarten teachers’ perspectives. International Journal of Early Years Education, 24(3), 361–377. https://doi.org/10.1080/09669760.2016.1174105 Finch, C. R., Frantz, N. R., Mooney, M., & Aneke, N. O. (1997). Designing the Thematic Curriculum: An All Aspects Approach MDS-956. 97. Gess, A. H. (2019). STEAM Education. STEAM Education, November, 2011–2014. https://doi.org/10.1007/978-3-030-04003-1 Gronlund, G. (n.d.). “ Addressing Standards through Play-Based Learning in Preschool and Kindergarten .” Gronlund, G. (2015). Planning for Play-Based Curriculum Based on Individualized Goals to Help Each Child Thrive in Preschool and Kindergarten Gaye Gronlund. Gull, C., Bogunovich, J., Goldstein, S. L., & Rosengarten, T. (2019). Definitions of Loose Parts in Early Childhood Outdoor Classrooms: A Scoping Review. The International Journal of Early Childhood Education, 6(3), 37–52. Hapidin, Pujianti, Y., Hartati, S., Nurani, Y., & Dhieni, N. (2020). The continuous professional development for early childhood teachers through lesson study in implementing play based curriculum (case study in Jakarta, Indonesia). International Journal of Innovation, Creativity and Change, 12(10), 17–25. Hennessey, P. (2016). Full – Day Kindergarten Play-Based Learning : Promoting a Common Understanding. Education and Early Childhood Development, April, 1–76. gov.nl.ca/edu Henriksen, D. (2017). Creating STEAM with Design Thinking: Beyond STEM and Arts Integration. Steam, 3(1), 1–11. https://doi.org/10.5642/steam.20170301.11 Inglese, P., Barbera, G., La Mantia, T., On, P., Presentation, T., Reid, R., Vasa, S. F., Maag, J. W., Wright, G., Irsyadi, F. Y. Al, Nugroho, Y. S., Cutter-Mackenzie, A., Edwards, S., Moore, D., Boyd, W., Miller, E., Almon, J., Cramer, S. C., Wilkes-Gillan, S., … Halperin, J. M. (2014). Young Children’s Play and Environmental Education in Early Childhood Education. PLoS ONE, 2(3), 9–25. https://doi.org/10.1586/ern.12.106 Jacman, H. (2012). Early Education Curriculum. Pedagogical Development Unit, FEBRUARY 2011, 163. https://www.eursc.eu/Syllabuses/2011-01-D-15-en-4.pdf Jay, J. A., & Knaus, M. (2018). Embedding play-based learning into junior primary (Year 1 and 2) Curriculum in WA. Australian Journal of Teacher Education, 43(1), 112–126. https://doi.org/10.14221/ajte.2018v43n1.7 Kennedy, A., & Barblett, L. (2010). Supporting the Early Years Learning Framework. Research in Practise Series, 17(3), 1–12. Keung, C. P. C., & Cheung, A. C. K. (2019). Towards Holistic Supporting of Play-Based Learning Implementation in Kindergartens: A Mixed Method Study. Early Childhood Education Journal, 47(5), 627–640. https://doi.org/10.1007/s10643-019-00956-2 Keung, C. P. C., & Fung, C. K. H. (2020). Exploring kindergarten teachers’ pedagogical content knowledge in the development of play-based learning. Journal of Education for Teaching, 46(2), 244–247. https://doi.org/10.1080/02607476.2020.1724656 Krogh, S., & Morehouse, P. (2014). The Early Childhood Curriculum : Inquiry Learning Through Integration. Liao, C. (2016). From Interdisciplinary to Transdisciplinary: An Arts-Integrated Approach to STEAM Education. Art Education, 69(6), 44–49. https://doi.org/10.1080/00043125.2016.1224873 Lillard, A. S., Lerner, M. D., Hopkins, E. J., Dore, R. A., Smith, E. D., & Palmquist, C. M. (2013). The impact of pretend play on children’s development: A review of the evidence. Psychological Bulletin, 139(1), 1–34. https://doi.org/10.1037/a0029321 Maxwell, L. E., Mitchell, M. R., & Evans, G. W. (2008). Effects of Play Equipment and Loose Parts on Preschool Children’s Outdoor Play Behavior: An Observational Study and Design Intervention. Children, Youth and Environments, 18(2), 37–63. McLaughlin, T., & Cherrington, S. (2018). Creating a rich curriculum through intentional teaching. Early Childhood Folio, 22(1), 33. https://doi.org/10.18296/ecf.0050 Mengmeng, Z., Xiantong, Y., & Xinghua, W. (2019). Construction of STEAM Curriculum Model and Case Design in Kindergarten. American Journal of Educational Research, 7(7), 485–490. https://doi.org/10.12691/education-7-7-8 Milara, I. S., Pitkänen, K., Laru, J., Iwata, M., Orduña, M. C., & Riekki, J. (2020). STEAM in Oulu: Scaffolding the development of a Community of Practice for local educators around STEAM and digital fabrication. International Journal of Child-Computer Interaction, 26, 100197. https://doi.org/10.1016/j.ijcci.2020.100197 Moomaw, S. (2012). STEM Begins in the Early Years. School Science and Mathematics, 112(2), 57–58. https://doi.org/10.1111/j.1949-8594.2011.00119.x Peng, Q. (2017). Study on Three Positions Framing Kindergarten Play-Based Curriculum in China: Through Analyses of the Attitudes of Teachers to Early Linguistic Education. Studies in English Language Teaching, 5(3), 543. https://doi.org/10.22158/selt.v5n3p543 Pyle, A., & Bigelow, A. (2015). Play in Kindergarten: An Interview and Observational Study in Three Canadian Classrooms. Early Childhood Education Journal, 43(5), 385–393. https://doi.org/10.1007/s10643-014-0666-1 Pyle, A., & Danniels, E. (2017). A Continuum of Play-Based Learning: The Role of the Teacher in Play-Based Pedagogy and the Fear of Hijacking Play. Early Education and Development, 28(3), 274–289. https://doi.org/10.1080/10409289.2016.1220771 Quigley, C. F., Herro, D., & Jamil, F. M. (2017). Developing a Conceptual Model of STEAM Teaching Practices. School Science and Mathematics, 117(1–2), 1–12. https://doi.org/10.1111/ssm.12201 Ridgers, N. D., Knowles, Z. R., & Sayers, J. (2012). Encouraging play in the natural environment: A child-focused case study of Forest School. Children’s Geographies, 10(1), 49–65. https://doi.org/10.1080/14733285.2011.638176 Ridwan, A., Rahmawati, Y., & Hadinugrahaningsih, T. (2017). Steam Integration in Chemistry Learning for Developing 21st Century Skills. MIER Journail of Educational Studies, Trends & Practices, 7(2), 184–194. Rolling, J. H. (2016). 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Toporek, Sean M., and Anthony P. Keinath. "First Report of Colletotrichum scovillei Causing Anthracnose Fruit Rot on Pepper in South Carolina, United States." Plant Disease, November 23, 2020. http://dx.doi.org/10.1094/pdis-08-20-1656-pdn.

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Anthracnose fruit rot caused by various Colletotrichum spp. is a serious disease for pepper (Capsicum annuum) growers, resulting in extensive fruit loss (Harp et al. 2008). Samples of five pepper fruits were obtained from two commercial farms in Lexington and Pickens counties, South Carolina, in August and September 2019, respectively. All fruits had two or more soft, sunken lesions covered with salmon-colored spore masses. Pieces of diseased tissue cut from the margins of lesions were surface disinfested in 0.6% sodium hypochlorite, rinsed in sterile deionized water, blotted dry, and placed on one-quarter-strength potato dextrose agar (PDA/4) amended with 100 mg chloramphenicol, 100 mg streptomycin sulfate, and 60.5 mg mefenoxam (0.25 ml Ridomil Gold EC) per liter. Two isolates of Colletotrichum sp. per fruit were preserved on dried filter paper and stored at 10º C. One additional isolate of Colletotrichum sp. had been collected from a jalapeño pepper fruit on a farm in Charleston County, South Carolina, in 1997. Colony morphology of three isolates, one per county, on Spezieller Nährstoffarmer Agar (SNA) was pale grey with a faint orange tint. All isolates readily produced conidia on SNA with an average length of 16.4 μm (std. dev. = 1.8 μm) and a width of 2.2 μm (std. dev. = 0.2 μm). Conidia were hyaline, smooth, straight, aseptate, cylindrical to fusiform with one or both ends slightly acute or round, matching the description of C. scovillei (Damm et al. 2012). The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-tubulin (TUB2) genes from three isolates were amplified and sequenced with the primer pairs GDF1/GDR1 and T1/Bt2b, respectively. Species within the C. acutatum clade can be readily distinguished with GAPDH or TUB2 (Cannon et al. 2012). The GAPDH and TUB2 sequences for all three isolates were 100% similar to each other and strain CBS 126529 (GAPDH accession number JQ948597; TUB2 accession number JQ949918) of C. scovillei (Damm et al. 2012). GAPDH and TUB2 sequences for each isolate were deposited in GenBank under the accessions MT826948–MT826950 and MT826951-MT826953, respectively. A pathogenicity test was conducted on jalapeño pepper fruits by placing a 10-ul droplet of a 5 x 105 conidial suspension of each isolate onto a wound made with a sterile toothpick. Control peppers were mock inoculated with 10 ul sterile distilled water. A humid chamber was prepared by placing moist paper towels on the bottom of a sealed crisper box. Inoculated peppers were placed on upside-down 60 ml plastic condiment cups. Three replicate boxes each containing all four treatments were prepared. The experiment was repeated once. After 7 days in the humid chamber at 26ºC, disease did not develop on control fruits, whereas soft, sunken lesions covered with salmon-colored spores developed on inoculated fruits. Lesions were measured and C. scovillei was re-isolated onto amended PDA/4 as previously described. Lesion length averaged 15.6 mm (std dev. = 4.1 mm) by 11.5 mm (std dev. = 2.0 mm). Colletotrichum sp. resembling the original isolate were recovered from all inoculated fruit, but not from non-inoculated fruit. C. scovillei has been reported in Brazil in South America and in China, Indonesia, Japan, Malaysia, South Korea, Taiwan, and Thailand in Asia (Farr and Rossman 2020). This is the first report of C. scovillei as the casual organism of anthracnose fruit rot on pepper in South Carolina and the United States.

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Thi Viet Huong, Do. "Study of the Chemical Components and Bioactivities of Rhodomyrtus Tomentosa Extracts." VNU Journal of Science: Natural Sciences and Technology 35, no. 1 (2019). http://dx.doi.org/10.25073/2588-1140/vnunst.4838.

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Rhodomyrtus tomentosa is a flowering plant belonging to the family Myrtaceae. In this study, sample was leaves of Rhodomyrtus tomentosa. Three compounds were isolated from n-hexan extract (RTH), their structures were identified by proton and carbon 13 NMR spectral dât and compared with spectral data in the literature: rhodomyrtosone, combretol and loliolide. Determination of total flavonoids (TF) and phenolic (TP) compounds were shown that ethylacetate extract has the higher value for both TF and TP (25.32 mg BHT/g; 60.01 mg GAE/g) compared n-hexan extract.  Keywords Rhodomyrtus tomentosa, rhodomyrtosone, combretol, loliolide, total flavonoids content, total phenolic content References [1] Csurhes S., Hankamer C. Ceylon Hill Cherry (DownyRose Myrtle): Rhodomyrtus tomentosa. Brisbane, Queensland, Australia: Biosecurity Queensland, 2016 . [2] Do T. L. Medicine Plants and Remedies of Vietnam. Hanoi: Thoi Dai publisher, 434, 2004.[3] Arya V. A review on anti tuberculosis plants. Int. J. PharmaTech. Res., vol 3(2), 872-880, 2011.[4] Ong H, Nordiana M. Malay ethno‑medico botany in Machang, Kelantan, Malaysia. Fitoterapia, vol. 70(5), 502‑13, 1999.[5] Wei F. Manufacture of Oral Liquid Containing Traditional Chinese Medicine Extract for Treating Gynecopathy (Guangxi Huahong Pharmaceutical Co., Ltd., People’s Republic of China; Shanghai Fosun Pharmaceutical (Group) Co., Ltd.), Faming Zhuanli Shenqing Gongkai Shuomingshu. People’s Republic of China Patent CN1846715, 2006. [6] Chuakul W. Medicinal plants in the Khok Pho district, Pattani province (Thailand). Thai J. Phytopharm, vol. 12, 23‑45, 2005. [7] Geetha K. M., Sridhar, C., Murugan V. Antioxidant and Gastroprotective activities of Rhodomyrtus tomentosa (Ait.) Hassk. International Journal of PharmTech Research, vol 2(1), 283-291, 2010.[8] Jeong D., Yang W. S., Yang Y., Nam G., Kim J. H., Yoon D. H., Noh H. J., Lee S., Kim T. W., Sung G., Cho, J. Y. In vitro and in vivo anti-inflammatory effect of Rhodomyrtus tomentosa methanol extract. Journal of Ethnopharmacology, vol. 146, 205-213, 2013. [9] Lavanya G., Voravuthikunchai S. P., Towatana N. H. Acetone extract from Rhodomyrtus tomentosa: A potenr natural antioxidant. Evidence Based Complementary and Alternative Medicine, vol. 10, 1155-5, 2012.[10] Lai T. N. H., André C., Rogez H., Mignolet E., Nguyen T. B. T., Larondelle, Y. Nutritional composition and antioxidant properties of the simfruit (Rhodomyrtus tomentosa). Journal of Food Chemistry, vol. 168, 410-426, 2014.[11] Lai, T. N. H., Herent, M., Quentin-Leclerq J., Nguyen T.B. T., Rogez H., Larondelle Y., André C. M. Piceatannol, a potent bioactive stilbene, as major phenolic component in Rhodomyrtus tomentosa. Journal of Food Chemistry, vol. 138, 1421-1430, 2012.[12] Cui C., Zhang S., You L., Ren J., Luo W., Chen W., Zhao, M. Antioxidant capacity of anthocyanins from Rhodomyrtus tomentosa (Ait.) and identification of the major anthocyanins. Journal of Food Chemistry, vol. 139, 1-8, 2013.[13] Lim T. Rhodomyrtus tomentosa. Edible medicinal and non medicinal plants. New York: Springer, 732‑7, 2012.[14] Wu X., Beecher G.R., Holden J.M., Haytowitz D.B., Gebhardt S.E., Prior R.L. Lipophilic and hydrophilic antioxidant capacities of common foods in the United States. J Agric Food Chem, vol. 52(12), 4026‑37, 2004.[15] Limsuwan S., Hesseling‑Meinders A., Voravuthikunchai S.P., Van Dijl J.M., Kayser O. Potential antibiotic and anti‑infective effects of rhodomyrtone from Rhodomyrtus tomentosa (Aiton) Hassk. on Streptococcus pyogenes as revealed by proteomics. Phytomedicine, vol18(11), 934‑40, 2011.[16] Marinova D., Ribarova F., Altanassova. Total phenolics and total flavonoids in Bulgarian fruits and vegetables. Journal of The University of Chemical Technology and Metallurgy, vol 40, 255-260, 2005.[17] Dachriyanus, Salni, Sargent M.V., Skelton B. W., Soediro I., Sutisna M., White A. H., Yulinah E. Rhodomyrtone, an antibiotic from Rhodomyrtus tomentosa. Aust. J. Chem, Vol. 55, 229-232, 2002.[18] Dachriyanus, Fahmi R., Sargent M.V., Skelton B. W., White A. H., Yulinah E. 5-Hydroxy-3,3’,4’,5’,7-pentamethoxyflavone (combretol). Acta Cryst.,, Vol. E60, 86-88, 2004.[19] Hoges R. and Porte A.L. The structure of loliolide: A terpene from Lolium perenne. Tetrahedron, Vol. 20, 1463-1467, 1964.[20] Kimura J., Maki N. New loliolide derivatives from the brown alga Undaria pinnatifida. J. Nat. Prod., Vol 65, 57-58, 2002. [21] https://www.psychologytoday.com/us/articles/200307/flavonoids-antioxidants-help-the-mind.[22] https://www.nutraingredients.com/Article/2008/10/10/Flavonoids-heart-health-benefits-in-the-blood-vessels-Study

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Lee, M., C. Gill, A. Serauto Canache, et al. "P678Pericardiocentesis in thrombocytopenic cancer patients." European Heart Journal 40, Supplement_1 (2019). http://dx.doi.org/10.1093/eurheartj/ehz747.0284.

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Abstract Background Pericardial effusion is a known complication in cancer patients, resulting in chest pain, cardiac tamponade, and cardiogenic shock. Although technological advances allow for early detection, treatment options are limited for those also suffering from thrombocytopenia. Purpose Our study aims to evaluate survivorship of thrombocytopenic cancer patients who underwent pericardiocentesis. Methods From 2008 to 2019, we assessed overall mortality and follow-up post-pericardiocentesis in cancer patients with concurrent thrombocytopenia (<150,000 cells/microliter) at our cancer center. Thrombocytopenia grading was determined on the procedure day via serology platelet cell count with the following thresholds: Grade 1 (<50x103 cells/mL), Grade 2 (51–100x103 cells/mL), and Grade 3 (101–149x103 cells/mL). Results In 137 patients, we identified 65 (47%) patients with Grade 1, 30 (22%) with Grade 2, and 42 (31%) with Grade 3 thrombocytopenia. The calculated platelet count average was 66x103 cells/mL, median was 59x103 cells/mL, and range was 6 to 147x103 cells/mL. Of note, 7 (5%) patients had platelets <10x103 cells/mL. One patient developed a hematoma at the percutaneous site of pericardial drain, no other complications were noted. Kaplan Meier survival analysis by log-rank (mantel-cox) showed statistical significance (p=0.025). Comparatively, the cumulative survival of patients at 30 days was 63% in Grade 1, 67% in Grade 2, and 83% in Grade 3 patients. At one year, it was 26% in Grade 1, 37% in Grade 2, and 48% in Grade 3 patients. Conclusion Pericardiocentesis offers rapid symptomatic relief and can be life-saving in cardiac tamponade. In cancer patients, the development of pericardial effusions and thrombocytopenia increases due to the underlying malignancy and cancer therapeutics. Although thrombocytopenia is thought to increase peri-procedural risks, in this cohort there was only one minor complication and this occurred in Grade 2 thrombocytopenia. For thrombocytopenic cancer patients suffering from large pericardial effusions, high pre-operative risk scores often exclude them from receiving surgical pericardial windows. Although mortality was higher in severe thrombocytopenia, this is likely due to the competing risk of more severe cancer; there were no complications with Grade 1 thrombocytopenia. Especially noteworthy, no complications in those with platelets <10,000 cells/uL. Our study shows that in this population of patients, pericardiocentesis is a feasible intervention with low complication rate to help improve quality of life and potentially life-saving treatment.

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Journal articles on the topic 'TP 7.5 UL 2008'

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