Journal articles: 'G 60 UL 2009'

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Lane, Steven W., Julie Crawford, Melita Kenealy, et al. "Pegfilgrastim Compared to Granulocyte Colony Stimulating Factor (G-CSF) with Hyper-CVAD Chemotherapy Regimen for Aggressive Lymphoid Malignancy." Blood 106, no. 11 (2005): 4274. http://dx.doi.org/10.1182/blood.v106.11.4274.4274.

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Abstract Aim Pegfilgrastim (Neulasta®) has proven efficacy as supportive therapy in a variety of chemotherapy regimens, but has not been studied in dose intensive, rapidly cycling regimens such as hyper-CVAD. We examined whether pegfilgrastim leads to similar kinetics of neutrophil recovery as daily G-CSF. Methods Using retrospective analysis, patients receiving pegfilgrastim were matched with controls (G-CSF) for cycle of chemotherapy, prior chemotherapy, dose of cytarabine received, age (<60 or >60), diagnosis (ALL or NHL) and bone marrow involvement. The primary endpoint was duration of grade IV neutropenia (ANC <500/ul). Secondary endpoints included time to neutrophil recovery, incidence of febrile neutropenia, positive blood cultures and delay in subsequent chemotherapy. Results Between 01/1999 – 06/2005 we identified 124 pegfilgrastim supported cycles in 43 patients. Cases were successfully matched to 124 G-CSF supported cycles from 38 controls. There were no significant differences between cases and controls with regards to prior chemotherapy, age, sex, cytarabine dose, diagnosis or bone marrow involvement. The median duration of grade IV neutropenia was 4 days in both groups (p =0.55). Pegfilgrastim (95% CI) G-CSF controls (95% CI) P value Grade IV neutropenia - All cycles 4 days (0–11) 4 days (0–10) 0.55 - A cycles 2 days (0–7) 2 days (0–6) 0.65 - B cycles 6 days (2–12) 6 days (0–10) 0.70 Time to ANC >500/ul 13 days (10–19) 14 days (8–18) 0.75 Time to ANC >2000/ul 14 days (11–29) 14.5 days (9–22) 0.27 Febrile Neutropenia 29% 38% 0.16 Positive Blood Cultures 11% 12% 0.85 Delay in next cycle 44% 47% 0.75 Conclusions A single dose of pegfilgrastim is as effective as daily G-CSF for supporting the hyper-CVAD chemotherapy regimen.

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Karduss, Amado J., Eduardo Leon, Lina Buitrago, et al. "Irradiation of Cellular Blood Components with Cobalt 60 Is Very Efficient and Safe in the Prevention of Transfusion Associated Graft Versus Host Disease (TA-GVHD) in the Allogeneic Transplant Setting." Blood 108, no. 11 (2006): 4138. http://dx.doi.org/10.1182/blood.v108.11.4138.4138.

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Abstract For the prevention of TA-GHVH in patients who received a allogeneic stem cell transplant is mandatory the gamma irradiation of the all cellular blood components. This irradiation is usually done with Cesium 137 and with a special blood bank irradiators. However these devices are expensive; because that, in developing countries, is frequent the utilization of Cobalt 60 and the same device that is used in the radiotherapy department, instead of blood bank irradiators. We present our experience with this technique. From Dec 2002 to Dec 2005 thirty patients received a allogeneic stem cell transplant and 28 were analysed. The stem cells source was: peripheral blood 25, unrelated cord blood 2, and bone marrow 1. The irradiation of the blood was performed with Cobalt 60–1.24 Mev- (theratron 780 C); the irradiation field was calculated for covering all of the bag surface and a dose of 3.5 Gy was administered to the mild plane of the bag. 158 blood concentrates were transfused, 68 red cell (X:2.5 per patient), and 90 platelets (3.2 per patient). The pre transfusion median hemoglobin and platelet levels were 7.63 g/dl and 12.000/ul; after transfusion was a median increase of 2.3 gm/dl (0.6–4.7) in hemoglobin and 18.000/ul (0–140.000) in platelets. There was no any case of TA-GVHD. Four patients developed pos transplant aGVHD, in all of the cases the disease began 50 days or more after the last transfusion, there were no pancytopenia and the aGVHD was resolved completely with the treatment. Conclusion In receptors of allogeneic stem cell transplant the gamma irradiation of blood components with Cobalt 60 and with the same device which is used for patients radiotherapy is 100% effective and safe in the prevention of TA-GVHD. This is a good alternative in centers without blood bank irradiator

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Shah, Harsh, Seongho Kim, Paramveer Singh, et al. "Post-ASCT Outcomes in Multiple Myeloma Patients Who Underwent ASCT with G-CSF+Plerixafor Versus G-CSF Mobilized Graft." Blood 132, Supplement 1 (2018): 3350. http://dx.doi.org/10.1182/blood-2018-99-113713.

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Abstract BACKGROUND: Impact of Plerixafor (P) mobilized stem cells on immune reconstitution of autologous stem cell transplant (ASCT) patients has not been established. Early lymphocyte recovery (Absolute lymphocyte count of > 1 K/uL at day 30 after transplant) has been established to predict outcomes in multiple myeloma (MM) patients. The purpose of this study was to evaluate lymphocyte recovery in MM patients who underwent ASCT with stem cells mobilized with G-CSF vs G-CSF+P. Secondary objective was to evaluate the survival outcomes. METHODS: This is a retrospective analysis of MM patients who underwent first ASCT between 2008 and 2016 with either G-CSF or G-CSF+P mobilization at Karmanos Cancer Institute in Detroit, Michigan. Plerixafor was used per institutional guidelines when the peripheral CD-34+ve cell-count was < 20/ uL on day 5 of G-CSF mobilization. 610 total patients were identified. Mobilization agents used were G-CSF alone (n= 469) or G-CSF+P (n= 141). All patients underwent transplant after Melphalan (M) conditioning and dose of M was at treating physician's discretion (140 vs 200 mg/m2). The primary endpoint was the Absolute Lymphocyte Count at day 30 (ALC30). Secondary endpoints were PFS and OS Univariable and multivariable Cox proportional hazards regression models were fit to assess associations between ten pre chosen predictors( age, race, stage at diagnosis, doublet vs. triplet therapy, lines of treatment, disease status, mobilization agents, melphalan dose, ALC at day 30, post- transplant maintenance) and survival benefit (PFS and OS). RESULTS: Median age of patients was older in G-CSF+P group (62 vs 60 years, p=. 006) and they were more likely to receive triplet therapy (82 vs 72%, p=. 015) for induction compared to G-CSF group (Table 1). Patients in G-CSF group were more likely to receive greater than one line of treatment before transplant (p=. 006). Disease status at transplant was similar between the two groups. G-CSF patients received higher dose of M (at 200mg/ m2) more frequently (69 vs. 58%, p = 0.010) and median cell dose infused was higher in G-CSF group (3.19 vs 2.88 x106 CD 34+ve-cells/Kg, p= 0.001). Primary endpoint, ALC30, was 1.3 K/uL(.1-4.5) and 1.2 K/uL(.1-5.1) for G-CSF and G-CSF+P, respectively (p=. 608). Median day to neutrophil recovery were similar in both groups (ANC of 500 at Day 12). Post-transplant maintenance use was similar between the two groups. The median PFS was 2.46 years (95% CI, 2.14 to 3.15) and 2.77 years (95% CI, 1.99 to 3.27) for G-CSF and G-CSF+P, respectively (HR: 1.128; 95% CI, (.843-1.509); p=. 417) (Figure 1). The median OS was 6.09 years (95% CI, 4.55 to NR) and 3.73 years (95% CI, 3.20 to NR) for G-CSF and G-CSF+P, respectively (HR: 1.638; 95% CI, (1.118-2.399); p=. 011) (Figure 2) .In MVA, higher stage at diagnosis, less than PR before ASCT, and no post-transplant maintenance therapy were associated with worse PFS and OS. More lines of treatment adversely impacted PFS. Use of G-CSF+P for mobilization and Melphalan dose ≤ 200-mg/ m2 adversely impacted OS. ALC30 did not impact PFS or OS in MVA. There were no significant differences in causes of death among the 2 groups. CONCLUSIONS: In this large, retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery. Higher Melphalan dose resulted in improved OS in the MVA. There was an overall survival difference favoring the G-CSF group, however, differences in baseline characteristics not accounted for in the MVA may be responsible for this observation. A Prospective study comparing these mobilization regimens including patients with similar baseline characteristics is necessary to confirm this finding. Disclosures Deol: Kite Pharmaceuticals: Consultancy; Novartis: Consultancy.

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Ramadas, Poornima, Jennifer Leibovitch, and Teresa Gentile. "Hemophagocytic Lymphohistiocytosis: A Single Institution Experience." Blood 134, Supplement_1 (2019): 4877. http://dx.doi.org/10.1182/blood-2019-127517.

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Background: Hemophagocytic lymphohistiocytosis [HLH], is a rare life-threatening syndrome of excessive immune activation. It can be primary due to genetic predisposition or secondary due to infections, immune disorders or malignancies. With nonspecific clinical presentation, a high index of suspicion is required to make the diagnosis. Prompt treatment of underlying etiology and HLH specific therapy is warranted to prevent adverse clinical outcome. Methods: After IRB approval, we conducted a retrospective chart review of adult patients (pts) ≥ 18 years diagnosed with HLH between January 1st, 2010 and June 30th, 2019. We recorded age at diagnosis, gender, cause of HLH, symptoms, laboratory testing, bone marrow pathology, imaging, treatment and outcome. Results: We found a total of 15 patients in the time interval. Pt age ranged from 22 to 64 years with a median of 46 years. 60% were females and 40% were males. 14 pts had secondary HLH and one pt tested positive for HLH gene mutations. Etiology of HLH was malignancy in 6 (40%), infection in 5 (33%), rheumatological disease in 3 (20%) and cause was unclear in one pt but suspected to be an infection. One pt had prior allogenic stem cell transplant and one pt developed HLH even after completion of treatment for lymphoma. On presentation, 14 (93%) had fever, 6 (40%) had respiratory symptoms, 6 (40%) had neurological symptoms, 2 (13%) had a skin rash, 2 (13%) had bleeding manifestations and 3 (20%) required pressor support. Hemoglobin ranged from 5.5 to 13.3 g/dL on presentation, with median of 10.1 g/dL and 14 (93%) had Hb <9 g/dL. Absolute neutrophil count ranged from 0.3 to 16.94 x 103/uL with median of 2.87x103/uL and decreased to < 1000x103/uL in 11 (73%) and < 500x103/uL in 7 (46%). Platelet counts on presentation ranged from 18 to 244x103/uL with median of 82x103/uL and decreased to <100x103/uL in 14 (93%) and <20x103/uL in 8 (53%). 14 (93%) had bicytopenia. Initial ferritin levels ranged from 1,552 to 2,62,080 ng/ml with median of 5,515 ng/ml and increased to >10,000 ng/ml in 10 (66%) and highest level was 4,57,970 ng/ml. All 15 pts had some degree of hepatic dysfunction and one pt had acute kidney injury. Triglyceride levels were >265 mg/dL in 6 (40%). 10 (66%) had laboratory evidence of disseminated intravascular coagulation (DIC), one pt had clinical DIC. Blood cultures were negative in everyone, except 2 pts who developed infection during the hospital course, one with Candida krusei and the other with methicillin sensitive staphylococcus aureus. Bone marrow biopsy was performed in 14 (93%) and all of them demonstrated hemophagocytosis. 3 (20%) underwent lumbar puncture and 2 had elevated CSF protein. 11 (73%) had immunological testing and all of them had elevated soluble IL-2 receptor alpha (sCD25 or sIL-2R). Of the 3 pts who had HLH genetic testing, one had HLH associated mutations. Organomegaly was noted in 11 (73.3%) (4 had hepatosplenomegaly, 6 had splenomegaly, one had hepatomegaly). 6 (40%) had lung infiltrates. MRI brain was done in 5 (33%) and 2 had patchy hyperintensities. 11 (73.3%) were treated with HLH-94 protocol with etoposide and dexamethasone. One pt had matched unrelated donor Allogenic stem cell transplant. 13 (86.6%) had initial recovery. At the time of data cut off, 10 (66%) were alive. Of the 3 pts who initially recovered, one pt died of relapsed lymphoma, one died of HLH relapse and one developed Clostridium difficile infection with bowel perforation. [Refer to Table 1]. Conclusion: Even though literature suggests that malignancy associated HLH has a worse prognosis, our small series did not suggest that. We also noted that HLH associated with rheumatological diseases leads to a superior outcome if the underlying disease is adequately treated. The most significant finding in our series was a patient with diffuse large B cell lymphoma who was diagnosed to have primary HLH with HLH associated mutations. Typically, primary HLH presents in the first few years of life. This patient case points to the fact that patients with primary HLH can have a late presentation and can also be associated with immunological disorders with a predisposition to malignancy. This finding suggests that all patients diagnosed with HLH should have genetic testing done for HLH associated mutations, as this will impact treatment decisions and these patients will benefit from more intense treatment which may include an allogenic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

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Piccin, Andrea, Michael Steurer, Manfred Mitterer, et al. "Blood Cells Dynamic and Thrombo-Haemorragic Events in Low Risk Essential Thrombocytosis Patients. A North Italian and Austrian Study." Blood 120, no. 21 (2012): 2839. http://dx.doi.org/10.1182/blood.v120.21.2839.2839.

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Abstract Abstract 2839 Patients affected by low-risk essenthial thrombocythosis (ET) may develope thrombotic/haemorragic events at a lower rate compared to high-risk ET patients. So far, it has not be possible to identify useful markers to predict which of these patients are more likely to have an event. Previous authors [Carobbio A et al, Blood 2007] have shown that leukocytosis at diagnosis is associated with a high hazard risk (HR) of developing a thrombotic event, while high platelets count is not. Subsequently other authors [Gangant N et al, Cancer 2009] have contradicted this findings and instead shown that in low-risk ET, the increase in leukocyte count over time correlates with thrombotic events [Passamonti F et al ISTH 2009]. For these reasons we decided to evaluate risk parameters in a dynamic manner with the aim of identifying those patients who are more likely to have an event and might benefit from preventive treatment. We performed a large multicentre retrospective study that included several North Italian Haemathology centres and a large Austrian university hospital. Patient data was analysed using random effect linear regression model and a dedicated Cox model with dynamic proportional risk. We studied 136 patients with low risk ET. Out of those, 45 had a thrombotic/haemorragic event and 91 never had an event (events included: stroke, TIA, IMA, PE, PAD, epystaxis and gastrointestinal bleeding). Overall, the median age was 42 years (IQR 20; range 18–60), the median Hb was 14.0 g/dL (IQR 2.3; range 4.4–18), the median WBC was 8.1 ×103/Â μL (IQR 3.3; range 3.3–23.8), the median PLT was 701 ×103/ÂL (IQR 404; range 206–1806). Gender was M 33% (n=45), F 67% (n=91); smokers were 24% (n=18/N=74); hypercholesterolemia was 18% (n=17/N=92). The FBCs of both groups were recorded from the date of diagnosis (entry time) and up to 3 years of follow up or to the development of a thrombotic/haemorragic event (exit time). A total number of 1294 FBCs were provided by the group with event and compared to a total of 4487 FBCs from the group without event. The follow-up Hb values showed a decreasing linear pattern linear from baseline values. The PLT-count showed a trend similar to Hb over the period of follow-up in both the group without events and in the group with events. The WBC showed a decrease during follow-up in the group with events and an increase in the group without events. Surprisingly, the risk of developing an adverse event after 60 months of follow-up was reduced by 20% for each increase of 1 g/dL Hb (p =0.007), was increased by 8% for each WBC increase of 1 103/uL (p =0.026) and was decreased by 6% for each PLT increase of 100 × 103 /uL (p =0.434). No differences were seen between venous or arterious thrombotic events (Log rank test, p=0.842). In conclusion, this study confirms that baseline FBCs values are not predictive of events within the ET low risk group. The emerging new finding is that the risk of developing an event is higher when Hb is reduced. This strongly suggests a protective role of Hb in the low-risk ET group. Previous studies have shown that red cells might store and generate nitric oxide (NO), a key endothelial modulator [Kim-Shapiro DB et al 2006]. The presence of NO would keep PLT in resting state, would reduce endothelial cell adhesion and in turn reduce thrombosis rate. However this needs to be confirmed. Disclosures: Steurer: Amgen: Consultancy, Honoraria. Pizzolo:Hoffmann-La Roche: Consultancy, Honoraria.

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Rahman, Effie, Sarvari Venkata Yellapragada, Martha P. Mims, Kirtan Nautiyal, Manuel Molina, and Gustavo A. Rivero. "Cigarette Smoking Is Associated with Adverse Outcome in Low Risk MDS Patients." Blood 124, no. 21 (2014): 5628. http://dx.doi.org/10.1182/blood.v124.21.5628.5628.

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Abstract Background: Low-risk myelodysplastic syndrome (LR-MDS) is a heterogeneous group of diseases characterized by dysplastic ineffective hematopoeisis and risk for acute myelogenous leukemia (AML). Despite improved risk classification, LR-MDS subgroups exhibit outcome heterogeneity. Non-hemopoeitic comorbidities highlight interaction of organ dysfunction and adverse outcomes. Previous studies have identified association between smoking and development of MDS (Du Y. Leuk Res. 2010). Among others, smoking induces DNA double strand breaks (Huang et al, 2012) and gene methylation modification leading to impaired environmental chemicals detoxification. In this study, we analyze the clinical impact of smoking and intensity of exposure on LR-MDS outcome. Methods: With prior IRB approval, 90 LR-MDS patients from the Michael E. DeBakey VA Medical Center cancer registry were analyzed between 2000-2012. Smoked pack-years (PY) was recorded according to accepted definition. PY estimate derived from Framingham heart study (Mannan H et al., Heart International. 2010) was used to evaluate smoking dose-dependent correlation with survival in: (1) non-smoker [NS], (2) <20, (3) >20-39, and (4) >40 PY. Univariate and multi-variable analysis evaluated the impact of potential confounding variables such as degree of cytopenia at disease initiation, blast count, karyotype, and R-IPSS score. Results: 69 (76%) and 22 (24%) pts were smokers and NS. Median age was 71 years (y) (range, 55-84) and 73 y (60-87), for smokers and NS, P=0.38. 22 (24%), 35 (38%) and 34 (37%) of pt were very low, low, and intermediate risk R-IPSS. Median hemoglobin, ANC, and platelet levels among smokers and NS were 9.4 g/dL vs 8.8 g/dL (P=0.18), 2.7 K/uL vs 3.2 K/uL (P=0.13) and 118 K/uL vs 158 K/uL (P=0.11). Median absolute R-IPSS score for smokers and NS were 0.5 (range, 0-1.5) and 0.25 (range, 0-2), P=0.40. OS in smokers vs NS was 728 vs 1877 days (d), P=0.04, 95% CI= 1.015 to 2.923 (Fig. 1). 65/71 (92%) pt contributed to analysis of cumulative effect of smoking on OS. Given the lack of significant survival difference among pt with >20-39 and >40 PY, 3 distinct subgroups were identified showing a median OS of 2117, 1020 and 717 d, for NS, <20 and >20 PY, respectively, P=0.01 (Fig. 2). Univariate and multivariate analysis revealed no impact of blast count, depth of cytopenias, karyotype, and R-IPSS on observed outcomes. Conclusions: Our study suggests a mechanistic link between smoking and adverse outcome in LR-MDS. Higher cumulative smoking exposure is potentially associated with worse OS. Larger studies involving LR-MDS pt with smoking history are necessary to confirm this association. Further research is needed to clarify underpinning mechanisms resulting in unfavorable smoking-induced LR-MDS phenotype. This could facilitate implementation of MDS directed therapy in subgroups with more aggressive outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Yusuf, Rushdia Z., Steve McAfee, Bimalangshu R. Dey, Beow Yeap, Thomas R. Spitzer, and Karen K. Ballen. "Successful Autologous Stem Cell Transplantation in Patients with Non-Hodgkin’s Lymphoma over the Age of 70 Years." Blood 106, no. 11 (2005): 5290. http://dx.doi.org/10.1182/blood.v106.11.5290.5290.

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Abstract Autologous stem cell transplantation (SCT) is a potentially curative procedure for patients with relapsed lymphoma (NHL). Over 60% of the cases arise in adults over 60 years of age. We retrospectively analyzed the outcomes of patients >60 years old who received high dose busulfan (Bu) and cyclophosphamide (Cy) and autologous SCT for NHL. Stem cells were mobilized with G-CSF with or without chemotherapy. Patients received a dose-adjusted regimen of Bu 0.8 mg/kg IV (n=17) or 1mg/kg po (n=9) q 6 hours x 14 doses starting on Day -7 and Cy 60 mg/kg IV q day on days -3 and -2. In overweight patients, IV Bu doses were calculated based on ideal body weight and oral Bu doses and Cy doses were calculated on an adjusted body weight. All patients were treated as inpatients and received our usual supportive care including transfusion support, pneumocystis prophylaxis, antiviral prophylaxis, growth factor support and broad-spectrum antibiotic coverage for febrile neutropenia. 26 consecutive patients > 60 with relapsed NHL underwent autologous SCT at Massachusetts General Hospital between 1995 and February 2005. The median age of the population was 66 (range 60–78) years. 17 (65%) of the 26 patients were females. 15 patients had large cell lymphoma, 2 immunoblastic lymphoma, 3 follicular lymphoma, and 6 mixed small cleaved cell and large cell. All patients had recurrent disease; 7 patients were in a CR and 19 patients in a PR at the time of transplant. The median time from diagnosis to transplant was 32 months. All patients engrafted. The median time to absolute neutrophil count > 500/uL was 10 days (range 9–11) days. The median time to platelet count > 50,000/uL unsupported was 15 (range 12–39) days. The 100-day transplant related mortality was 0%. Patients experienced the following serious toxicities: interstitial lung disease (n=1), seizures in a patient with CNS lymphoma (n=1), venoocclusive disease which resolved (n=2), and transient atrial fibrillation (n=3). With a median follow-up of 22 months (range 4 months–9.5 years), the two year overall survival is 63% and two year progression-free survival is 42%. Six patients above the age of 70 years have been transplanted. 100-day transplant related mortality was 0%. With a median follow up of 25 months, all 6 patients are alive and 3 of 6 are progression free. In conclusion, 1) Bu/Cy is a well-tolerated conditioning regimen for patients with NHL above the age of 60 years, including selected patients over the age of 70; 2) Age alone should therefore not be used as an exclusion criterion for autologous SCT.

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Ballen, Karen K., Elizabeth J. Shpall, David Avigan, et al. "Parathyroid Hormone May Improve Autologous Stem Cell Mobilization Via the Stem Cell Niche." Blood 106, no. 11 (2005): 1968. http://dx.doi.org/10.1182/blood.v106.11.1968.1968.

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Abstract Autologous stem cell transplantation is curative for many patients with hematologic malignancies. Approximately 20% of patients do not have an adequate stem cell mobilization. Recently, work from our laboratories has shown that parathyroid hormone (PTH) increases osteoblast number and expansion of the stem cell compartment in mice. In murine models, the addition of PTH caused an increase in the absolute number of stem cells. Daily PTH injection caused an increase in the absolute number of murine stem cells and improved survival in transplant recipients of limiting numbers of stem cells. (Nature425: 841, 2003). This observation suggested that PTH might be able to increase stem cell numbers in humans. PTH is an FDA approved drug used for treatment of osteoporosis. In this Phase I study, patients who have collected less than 2 million CD34+ cells/kg after 1 or 2 stem cell mobilization attempts received 14 days of sc PTH, in escalating dose cohorts of 40 mcg, 60 mcg, 80 mcg, and 100 mcg per day, with G-CSF 10mcg/kg/day for the last four days. Patients with >5 CD34+/uL on Day +14 proceeded to stem cell apheresis and autologous stem cell transplant. 14 patients have enrolled on this study, now enrolling at the highest dose cohort, and 12 patients have completed treatment for this analysis with 3 patients per dose cohort. The median age was 57 years (range 24–71 years), and 9 (75%) patients are female. In 10 patients (83%) one attempt at stem cell mobilization failed with either growth factor alone or growth factor plus chemotherapy; in the other 2 patients (17%) two attempts at mobilization failed to attain adequate cells. The diagnoses were as follows: non Hodgkin’s lymphoma (7 patients, 58%), Hodgkin’s disease (5 patients, 42%). There were no dose limiting toxicities defined as calcium > 11.5, ionized calcium > 1.5, phosphate <1.0, or systolic blood pressure less than 80mm Hg. 3 patients had a self-limited fever, one patient had an unexplained eosinophilia, and 1 patient required an admission with fever, rigors, and headache. 6 of 12 patients (50%) achieved the target peripheral CD34 level of 5/uL, of whom 4 underwent stem cell apheresis. The median CD34 cells/uL on Day +14 was 4.3 (range 0–18.8). 2 patients who achieved the target peripheral CD34 level of 5/uL did not complete collections, 1 due to access problems, and 1 due to physician preference. The 4 patients who continued with the study collected a median CD34+ dose/kg of 2.2 x 106 (range 0.9–2.7) from stem cell apheresis with a median of 2 collections (range 1–4). These 4 patients proceeded to autologous stem cell transplant, with median days to neutrophil and platelet engraftments of 11 (range 10–12) and 14 (range 12–19), respectively. In conclusion, 1) PTH is well tolerated in this population, even at a dose of 100 mcg; 2) PTH plus G-CSF may be effective in patients that fail primary or secondary stem cell mobilization attempts; 3) PTH plus G-CSF should be tested in a larger Phase II study to improve donor stem cell yield. Future directions may also include the use of parathyroid hormone to improve engraftment efficiency in settings of low stem cell dose such as adult cord blood transplantation.

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Monge, Jorge, Kari Flicker, Danielle Guarneri, et al. "Comparison of Early Versus Delayed Filgrastim (G-CSF) Administration Following Autologous Stem Cell Transplantation in Patients with Multiple Myeloma - Real-World Data from a Single-Center Institution." Blood 134, Supplement_1 (2019): 5644. http://dx.doi.org/10.1182/blood-2019-130914.

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Background: Autologous stem cell transplantation (ASCT) performed early in the disease course or at first relapse leads to improved progression-free and overall survival in transplant-eligible patients with multiple myeloma (MM). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF), when used after ASCT has been shown to accelerate time to neutrophil engraftment (TNE), and in some studies, it has been associated with reduced length of hospitalization, infectious complications, and antibiotic use. Strategies that reserve G-CSF administration to when neutrophil recovery is delayed, have attempted to show that there is no difference in infectious complications, length of hospitalization or TNE when compared to early administration of G-CSF on the day after stem cell infusion (DOT). However, the optimal timing for administering G-CSF has not yet been determined in patients with MM undergoing ASCT. Methods: This is a retrospective, single-center analysis of patients with MM undergoing ASCT from mobilized peripheral blood stem cells. Patients enrolled in a clinical trial of high-dose lenalidomide and melphalan as conditioning therapy which mandated the administration of filgrastim from day +1 after DOT (Lenalidomide Plus Melphalan as a Preparative Regimen for Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma, NCT01054196) were assigned to the early strategy group (ES). Patients receiving filgrastim as per our institutional guideline (starting on day +12 if ANC < 1000 cells/uL, or at the physician's discretion) were included in the delayed strategy group (DS). Patients were excluded from the analysis if their conditioning regimen included a different agent other than melphalan or lenalidomide. DOT was defined as the day of stem cell infusion. Date of neutrophil engraftment was defined as the first of three consecutive days with an ANC ≥ 500 cells/uL. TNE was calculated as the time from DOT to the date neutrophil engraftment. Total duration of neutropenia was defined as the time from onset of neutropenia (ANC < 500 cells/uL) to date of neutrophil engraftment. Length of hospitalization was defined as the time from DOT to the day of discharge. Results: We identified 59 patients in the ES group and 39 patients in the DS group from 08-16-2010 to 05-22-2019, for a total of 98 included in this analysis. Median age was 60 and 65 years in the ES and DS groups, respectively. Patients received a comparable dose of CD34+ cells, 5.05x106/kg in the ES group vs 4.66x106/kg in the DS group (p = 0.48). The ES group started filgrastim administration earlier (day +1 vs +9, p < 0.001) and received a greater median number of doses (10 vs 4, p < 0.001) as compared to patients in the DS group. Median time to neutrophil engraftment was shorter in the ES group compared to the DS group (10 vs 12 days, p < 0.001), as was the total duration of neutropenia (5 vs 6 days, p < 0.001). Documented infections were just as likely in both groups, 37% in the ES group and 39% in the DS group (p = 1). Length of hospitalization was shorter in the ES group as compared to the DS group (15 vs 17 days, p = 0.01). Discussion: Filgrastim use guided by an ES decreased the time to neutrophil engraftment, the duration of neutropenia and the length of hospitalization compared to a DS. Further analyses to identify predictive factors associated with a reduction in infectious complications and length of stay are underway, with the aim of developing a risk-adapted strategy for the use of filgrastim in patients with MM undergoing ASCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

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Dumitriu, Bogdan, Danielle M. Townsley, Christina Chen, Rodrigo T. Calado, Phillip Scheinberg, and Neal S. Young. "Telomere Elongation and Hematologic Improvement in Humans Treated with Androgens: A Prospective Clinical Trial of Danazol in Telomeropathies." Blood 124, no. 21 (2014): 258. http://dx.doi.org/10.1182/blood.v124.21.258.258.

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Abstract Telomeres, the terminal complex of hexameric repeats and shelterin protein of linear chromosomes, shorten with every mitosis. Telomere attrition is accelerated in patients with mutations in telomerase complex genes (Calado and Young, NEJM 2009) and with replicative stress, as in chronic bone marrow failure. Historically, male hormones were effective in some patients with aplastic anemia (AA), and case reports and retrospective observations have suggested hematologic improvement in patients with telomeropathies treated with male hormones. Exposure of normal lymphocytes and CD34+ cells to androgens increased telomerase activity in vitro, and in cells from individuals carrying loss-of-function TERT mutations to normal levels (Calado et al. Blood 2009). We have conducted a phase I/II single-center trial (www.clinicaltrials.gov NCT01441037) assessing the safety and the effect of male hormones on telomere attrition in patients with telomere disease. Entry criteria included age-adjusted mean telomere content ≤1%ile, ± identified mutations in telomerase complex genes, and low blood counts (hemoglobin <9.5g/dL, platelets <30,000/uL, or neutrophils <1,000/uL) and/or pulmonary fibrosis. Danazol, 800 mg/day, was administered for 2 years. Primary protocol objectives were safety and activity of danazol in slowing telomere attrition. Secondary endpoints were hematologic response at 3 and 6 months (increase in hemoglobin >1.5 g/dL or platelets >20,000/uL or neutrophils >500/uL). Twenty seven patients were enrolled, accrual commencing August 2011. Most patients had moderate (n=20) or severe (n=4) AA, one had myelodysplasia, and two pulmonary fibrosis. Median age was 41 years (range 17-66); 15 patients were females. There was only one severe adverse event possibly related to drug. Frequent reported symptoms were muscle cramping with dehydration and exacerbation of headaches. Changes in serum lipid profiles were observed in all patients, with increased serum LDL and decreased HDL. Severe elevation in liver enzymes was not observed. One death occurred on study, not treatment related (pneumonia in a pulmonary fibrosis case). Mean telomere content of leukocytes at enrollment was compared with mean telomere content at 6, 12, and 24 months on drug as well as available samples before starting danazol. Telomere attrition prior to protocol entry, determined by q-pcr, was estimated at loss of 227 bp/year (95% CI, 58-368bp; p=0.009). Androgen administration appeared to elongate telomeres: the average increase in telomere length at 6 months was 205 bp (95% CI, 82-329 bp; p=0.002), at 12 months 441 bp (95% CI, 263-620 bp; p=0.0001), and at 24 months 347 bp (95% CI, 87-607 bp; p=0.01). A similar trend of increase in mean telomere content with danazol was confirmed in flow-sorted lymphocytes. Hematologic response rate, as defined by protocol, was 67% at 3 months and 60% at 6 months. Nine of eleven patients who required RBCs became transfusion-independent; two of them also became platelet transfusion independent. Liver cirrhosis was present in 6 patients at enrollment; worsening of liver disease in one occurred with continued alcohol abuse. To date 8 patients have completed two years of danazol, all of them responders; 10 patients remain on danazol, and 9 patients stopped drug prior to 2 years. Blood counts in all patients have been stable with drug discontinuation, with median follow up of 258 days (range 31-335). In conclusion, male hormones are safe and efficacious in patients with inherited bone marrow failure associated with telomeropathies, producing clinically meaningful hematologic improvement. Increased mean telomere content in patients, suggests that in vitro demonstration of up-regulation by sex hormones of TERT and of telomerase enzymatic activity is the mechanism of action of androgens in vivo. To our knowledge, this is the first successful prospective effort to favorably modulate telomere length by pharmacologic intervention in humans. Sex hormones may be useful in other conditions of accelerated telomere attrition, as for example after chemotherapy, and other drugs and small molecules may be usefully screened for their effects on telomerase in vitro. Disclosures Off Label Use: we want to determine if treatment with male hormone danazol is safe and improves hematologic response as first-line treatment in patients with AA and telomere disease(www.clinicaltrials.gov NCT01441037)..

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Tran, Kathy M., Hagop M. Kantarjian, Syed M. Kazmi, et al. "Cytogenetic and Molecular Characterization of Genitourinary Extramedullary Disease in Acute Myeloid Leukemia." Blood 120, no. 21 (2012): 4326. http://dx.doi.org/10.1182/blood.v120.21.4326.4326.

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Abstract Abstract 4326 Background: Extramedullary (EM) disease is a well-known manifestation of acute myeloid leukemia (AML). Despite its recognized incidence, little is known about organ-specific EM-AML, including genitourinary (GU) AML. The purpose of this study is to identify the patients (pts) who develop GU-AML and to characterize the clinicopathologic, cytogenetic, and molecular features of this population. Methods: A database of 2,181 consecutive patients who were diagnosed with AML and underwent induction therapy from 2000 to 2011 at M.D. Anderson Cancer Center was reviewed retrospectively. All pts with histologically proven EM-AML were included in this series. Clinicopathologic, cytogenetic, and molecular data were examined and statistically analyzed. Results: A total of 1,120 pts underwent at least one EM biopsy and 244 were diagnosed with EM-AML. Of these, 9 pts (6 females) demonstrated GU-AML (0.4% of total population, 3.7% of EM-AML pts). Furthermore, 3 GU-AML pts demonstrated additional EM-AML in non-GU sites. At AML dx, GU-AML pts demonstrated median bone marrow blasts of 35% (range 1–69%) and median peripheral blood blasts of 1% (range 0–46%). CBC included median WBC of 3.5 K/uL (range 1.6–21.0 K/uL), median Hgb level of 9.4 g/dL (range 8.0–14.3 g/dL), and median platelet count of 118 K/uL (range 28–206 K/uL). Median age of AML dx in GU-AML pts was 45 years (range 28–69 years) and was significantly younger than the median age of AML dx in all other non-GU pts (60 years, range 12–89 years, p=0.025, Student's t-test). A total of 78% of GU-AML dx were made before or at AML presentation and 89% of GU-AML dx were made within 3 months of AML presentation. A total of 67% of GU-AML pts demonstrated cytogenetic abnormalities. Cytogenetic features included inversion 16 (inv (16), 33%), trisomy 8 (33%), diploid (33%), trisomy 22 (22%) and complex (22%). For all pts with GU-AML, no molecular mutations were present in RAS (0/9), FLT3 (0/7), NPM1 (0/2) or JAK2 (0/2). CR was achieved by 78% of pts with GU-AML. The pts who did not achieve CR expired early in induction therapy (within 29 days) due to sepsis. Of the GU-AML pts with CR, CR duration was 50.7 months (95% CI 15.2–86.2 months). CR duration of GU-AML pts was significantly longer than that of EM-AML pts with no GU sites (18.0 months, 95% CI 14.1–22.0 months, p=0.03, Kaplan-Meier method). Overall survival (OS) for all GU-AML pts was 41.6 months (95% CI 12.7–70.5 months) and was statistically equal to OS of pts without GU-AML and to OS of EM-AML pts with no GU sites. Conclusion: GU-AML is a rare but noteworthy manifestation of AML that tends to be diagnosed before or at AML presentation. Pts with GU-AML developed AML at a significantly younger age by 15 years than pts without GU-AML (p=0.025). Most GU-AML pts demonstrated cytogenetic abnormalities but none demonstrated molecular mutations. The presence of GU-AML, rather than EM-AML in other sites, may contribute to extended duration of CR (p=0.03). However, despite this finding and other advantages such as majority achievement of CR and young age of AML dx, there was no statistical advantage in OS in pts with GU-AML compared to those pts without GU-AML or to pts with EM-AML in non-GU sites. Disclosures: No relevant conflicts of interest to declare.

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Logan, Aaron C., Robert Su, Tracy I. George, Holbrook E. Kohrt, Bruno C. Medeiros, and Ash A. Alizadeh. "High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis." Blood 114, no. 22 (2009): 1359. http://dx.doi.org/10.1182/blood.v114.22.1359.1359.

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Abstract Abstract 1359 Poster Board I-381 Background Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in which dysregulation of innate immune effectors including natural killer (NK) cells and macrophages leads to destruction of hematopoietic elements. HLH is most frequently reported in association with malignancies or viral infections, with heritable deficiencies in cytotoxicity pathways predisposing children (and rarely adults) to HLH. Criteria for diagnosing HLH include: histological evidence of hemophagocytosis, two or more cytopenias, hyperferritinemia, hypofibrinogenemia or hypertriglyceridemia, elevated soluble IL-2R, decreased in vitro NK cell function, fever, and splenomegaly. Patients meeting >=5 of these criteria are diagnosed with HLH. Source: We identified 19 consecutive adult patients (53% male; median age 43y, range 16-83) admitted to Stanford Hospital with clinical suspicion for HLH and histological evidence of hemophagocytosis between 1997 and 2009; 2 patients were excluded from analysis due to incomplete data. Of the remaining 17 patients, 11 (65%) met criteria for a diagnosis of HLH. Results At presentation, all patients were anemic with a median Hgb concentration of 8.6 g/dL. Leukopenia was present in 8/11 (73%) with a median WBC count of 2 K/uL. Thrombocytopenia was present in 10/11 (91%) patients with a median Plt count of 30 K/uL. In 6 patients not meeting HLH criteria, median hematologic findings were Hgb 8.6 g/dL, WBC 2.6 K/uL, and Plts 126 K/uL. All patients demonstrated marked elevations of ferritin, median 3915 ng/dL (range 1039 – 29,700). Triglycerides were elevated in 7/10 (70%) for whom data were available, median 296 mg/dL (range 204 – 1,506). Fibrinogen was decreased in 3/13 (23%). Soluble IL-2 receptor level was above normal limits in all patients in whom it was measured (range 796 – 17,378 U/mL), but met the >2,400 U/mL criteria in only 3/6 (50%). In vitro NK function was diminished in 2/5 (40%) patients tested. Fever and splenomegaly were found in 94% and 59% of patients, respectively. Of 11 patients meeting HLH criteria, 5 had associated malignancies (DLBCL, NK cell leukemia, T cell lymphoma, AML, and Kaposi sarcoma) and 4 had concomitant viral infections (2 EBV, 1 EBV/B19, and 1 HIV-1/HHV-8). Three patients had isolated viral infections (all EBV), while 3 had idiopathic HLH. Amongst 6 patients not meeting HLH diagnostic criteria, 2 (33%) had an associated malignancy (SLL and NK cell lymphoma), 1 had an isolated EBV infection, and 3 had idiopathic disease. At a median follow-up of 16 months for surviving patients, the case fatality rate amongst those with established HLH diagnoses was 55%, with all deaths occurring within 2 months from diagnosis. Five patients were treated according the HLH-94/04 protocol combining dexamethasone, cyclosporine and etoposide. Two patients died within 2 months of initiating treatment, and 3 remain alive (survival to date ranges 4-31 months). The longest surviving patient underwent allogeneic HCT. A patient who presented with AML-associated HLH underwent induction chemotherapy then proceeded to allogeneic HCT and remains alive 9 months after diagnosis. Amongst 6 patients not meeting HLH criteria, the case fatality rate was 67% with a median survival of 2.3 months. None of these patients were treated with the HLH-94/04 protocol; however, 2 were treated with cyclosporine and remain alive 16 and 24 months after diagnosis. Conclusions Of the HLH diagnostic criteria, multiple cytopenias, hyperferritinemia, and hypertriglyceridemia were sensitive measures, whereas hypofibrinogenemia, markedly elevated sIL-2R, and decreased in vitro NK cell function were found in fewer than half of patients. At our institution, EBV-associated HLH predominates (7/17 cases, 41%). Most of the malignancy-associated HLH we have seen also occurred in the context of EBV infection. The case fatality rate amongst all patients with histologic evidence of hemophagocytosis, including those not meeting HLH criteria, is high. In most patients, treatment according to HLH-94/04 may be appropriate and likely improves survival. In our experience with the HLH-94/04 protocol, 60% of patients remain alive. Until sufficient evidence emerges that this treatment strategy leads to durable remissions in the majority of patients, allogeneic HCT should remain a consideration for most patients. Disclosures No relevant conflicts of interest to declare.

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Schanz, Julie, Heinz Tüchler, Francesc Sole, et al. "Prognostic Impact of Monosomy 7 as a Single Anomaly In Primary MDS – Reclassification From Poor to Intermediate Prognosis." Blood 116, no. 21 (2010): 1861. http://dx.doi.org/10.1182/blood.v116.21.1861.1861.

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Abstract Abstract 1861 Introduction: Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method: Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, patients with primary MDS who received supportive care, short courses of oral chemotherapy or hemopoietic growth factors were included. Univariate and multivariate analysis were performed for overall survival (OS) and risk of AML-transformation (AML-t). In multivariate analysis, site, age, gender, bone marrow blast count, date of first diagnosis and number of peripheral cytopenias were defined as co-variables. Results: In total, 60 patients (2.1% of all pts/4.4% of abnormal cases) with an isolated -7/del(7q) were detected. The median age of these pts was 66.1 years, which is significantly lower compared to pts without monosomy 7 (70.0 years; p<0.01; t-test, 2-sided). Regarding peripheral blood count, the mean hemoglobin in -7/del(7q) pts (9.2 g/dl) as well as ANC (1.7*103/ul) did not differ significantly as compared to pts without -7/del(7q) whereas the platelet count in pts with -7/del(7q) was significantly lower (82*103/ul vs. 125*103/ul; p<0.01). The median overall survival in -7/del(7q) pts was 16.0 (95% CI 14.0–21.4) months and the Hazard ratio (HR; as compared to a normal karyotype with a median survival of 47.4 (44.0-53.4) months as the reference category) was 1.6 (1.1-2.3; <0.01). Regarding the risk of AML-transformation, the median time to AML was 42.2 (14.4-not reached) months and the HR 1.7 (0.9-3.2; p<0.01). In comparison, this differed significantly from the median survival- (p<0.0001) and time to AML-transformation (p=0.027) for complex abnormalities, which are included with -7/del(7q) in the poor risk IPSS cytogenetic subgroup and were 5.7 (4.7-6.8) and 8.2 (6.4-14.0) months, respectively. The HR for complex abnormalities was 4.3 (3.4-5.4; p<0.01) for OS and 5.2 (3.8-7.5; p<0.01) for AML-transformation. Conclusions: The re-analysis of -7/del(7q), based on the largest MDS patient cohort yet published, confirms that the prognostic impact of an isolated total or partial monosomy 7 for overall survival as well as the risk of AML-transformation is intermediate, rather than poor. This finding is anticipated to be considered in the upcoming revision of the IPSS. Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Bennett:Johnson & Johnson: Consultancy.

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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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Castillo, Jorge J., Joshua Gustine, Maria Demos, et al. "Clinical and Genomic Factors Are Predictive of Response and Prognostic of Progression-Free Survival in Patients with Waldenström Macroglobulinemia Treated with Ibrutinib." Blood 134, Supplement_1 (2019): 2823. http://dx.doi.org/10.1182/blood-2019-125069.

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Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

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Idrees, Afshan, Xiaohui Zhang, Reza Setoodeh, Samir Dalia, Ling Zhang, and Lubomir Sokol. "Clinical Features and Outcomes of 24 Cases of Blastic Plasmacytoid Dendritic Cell Neoplasm-Single Institutional Experience." Blood 126, no. 23 (2015): 3755. http://dx.doi.org/10.1182/blood.v126.23.3755.3755.

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Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematopoietic malignancy originating from precursor plasmacytoid dendritic cells. Clinically, patients usually present with skin lesions and simultaneous involvement of peripheral blood, bone marrow, lymph node, spleen and central nervous system. Median survival from diagnosis has been reported to range from 9 to 12 months (Julia F et al. Br J Dermatol. 2013;579-86). The optimal treatment for BPDCN has not been established yet. Majority of patients demonstrate response to lymphoma or acute lymphoblastic leukemia-like chemotherapy induction regimens. A consolidation with autologous or allogeneic hematopoietic stem cell transplantation may improve outcome of selected patients. Limited data are available regarding prognostic and predictive factors. In this study we analyzed clinical and laboratory characteristics and assessed their impact on clinical outcome. Methods and Materials: Patients with diagnosis of BPDCN at Moffitt Cancer Center between 2000 and 2015 were retrieved from a clinical database. The diagnosis was confirmed by morphology, laboratory data, and immunopehnotying, according to 2008 WHO Classification of Hematopoietic Neoplasms. The relevant clinicopathologic features extracted from electronic medical records were recorded. Treatment modalities and responses to therapy were correlated with clinical outcomes. A univariate linear discriminant analysis was used for risk stratification. Overall survival was analyzed by Kaplan-Meier method. Results: We identified 24 patients with a median age of 74 years (range: 36-94 years) and a male:female ratio of 23:1. Mean hemoglobin was 11.83 2.48 g/dL; mean platelet count was 134 ± 84 k/µL; and mean white blood count was 6.34 ± 7.25 k/µL. Only one patient had an Eastern Cooperative Oncology Group (ECOG) performance status greater than 2. Four patients demonstrated skin lesions only. Twenty patients (83.3%) demonstrated extracutaneous or systemic involvements. Peripheral blood, bone marrow, lymph node, spleen and cerebrospinal fluid (CSF) involvements were found in 11 (45.8%), 16 (66.7%), 8(33.3%), and 4(17%) patients, respectively. Six of 20 (30%) patients with systemic involvement were treated with CHOP. Two of 6 patients were treated with hyper-CVAD followed by an allogeneic hematopoietic stem cell transplant. Autologous transplant was administered to one patient who was treated with both CHOP and ICE induction regimens. Median overall survival (OS) of the cohort was 49.9 months (95% CI, 19.9 - 81 months) and median follow up duration was 33.5 months (95% CI, 3-147 months). Statistical analysis showed the following parameters were not prognostic predictors of OS at diagnosis: hemoglobin level (<10 g/dL), leukocytosis (>11,000/ul), thrombocytopenia (<100,000/ul), age >60, peripheral blood and bone marrow involvement (p=0.51, p=0.278, p=0.684, p=0.9288, p=0.2074, and p=0.8633, respectively). Lymph node involvement at diagnosis was associated with a shorter OS compared to those without lymph node involvement (p=0.0305). CHOP versus more aggressive chemotherapies did not show difference in OS (p=0.8939). Bone marrow transplant (1 autologous and 2 allogeneic) showed a trend to have longer OS (86 versus 64 months; p=0.12). Conclusion: BPDCN has an aggressive biological behavior. Median overall survival of 49.9 months observed in our study compares favorably with OS of 12 months in previous reports. Lymph node involvement at diagnosis may have adverse impact on clinical outcomes. Larger scale studies are needed to identify risk factors that may have impact on outcomes and to establish standardized therapy in patients with BPDCN. Disclosures Sokol: Seatle Genetics: Research Funding; Spectrum: Consultancy; Celgene: Consultancy.

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Wang, Luhua M., Donna M. Weber, Kay B. Delasalle, and Raymond Alexanian. "VTD (Velcade, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed Multiple Myeloma." Blood 104, no. 11 (2004): 210. http://dx.doi.org/10.1182/blood.v104.11.210.210.

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Abstract The combination of thalidomide and dexamethasone (TD) has induced disease remission in 69% of 132 newly diagnosed patients with multiple myeloma (MM) treated at our center, with preventable and/or manageable side effects, and represents our primary treatment of choice. By adding bortezomib (Velcade), the 3-drug combination (VTD) has induced remission in 55% of patients with myeloma resistant to standard therapies, twice the frequency observed with bortezomib alone (Zangari, Barlogie et al, 2003). From 6/03 to 6/04, we combined bortezomib with thalidomide (100–200 mg each evening) and dexamethasone (20 mg/m2 on days 1–4, 9–12, 17–20) with therapeutic anticoagulation for 25 previously untreated patients with MM. Bortezomib was given at a dose of 1.0 (n=2), 1.3 (n=11), 1.5 (n=7), 1.7 (n=4) or 1.9 (n=1) mg/m2 IV on days 1, 4, 8 and 11, every 4 weeks to patients for 2–3 cycles of VTD. Median age was 63 (39–81), median B2M 5.1 mg/L (1.7–19), Hgb <10.5 g/dl in 60%, corrected serum calcium >11.5 mg/dl in 17%, and high tumor mass in 32% of patients. Grade 3 or 4 toxicities included non-neutropenic infection (2), orthostatic hypotension (1), DVT (1), neutropenia (1), thrombocytopenia (1); grade 3 or 4 neuropathy was not seen. Median nadir of ANC was 2360/ul and of platelets 135,000/ul with no correlation between bortezomib dose and myelosuppression. An initial dose of bortezomib of 1.5 mg/m2 IV x 4 was safe unless age > 70 and/or drugs for hypertension were taken concurrently. Responses were confirmed (>75% reduction serum myeloma protein and/or >95% reduction Bence Jones protein) in 19 patients (76%) and when defined by less stringent Blade criteria in 21 patients (84%); median time to remission was 0.6 mo (range 0.3–1.8) by either criteria in comparison with 1.1 mo (range 0.3–8.1) after TD (p<.01). Disease resistance was recognized by one month in 5 of 6 patients rated as unresponsive. Autologous blood stem cells were collected easily with G-CSF alone in 12 patients who were intensified a median 3.6 months after initial therapy; all 4 patients with primary resistant disease who received such therapy achieved partial remission. The frequency of CR to VTD could not be assessed because of early intensification. All patients are alive after median follow-up of 6 months (range 2–14). VTD induced a slightly higher frequency of PR, and significantly more rapid onset of remission, than those observed in similar patients treated previously with TD. No more than 2 courses of therapy were necessary before intensification or maintenance, so that the potential side effects and cost of more therapy were avoided. Results appeared superior to those observed with any prior program for previously untreated patients with MM at our center.

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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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Oliveira, M., and A. V. Machado. "Microscopy as a Powerful Technique to Characterise Polymer Matrix Nanocomposites." Microscopy and Microanalysis 19, S4 (2013): 131–32. http://dx.doi.org/10.1017/s143192761300127x.

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Polymer nanocomposites are a recent class of materials that have drawn considerable attention in recent years, due to the significant improvements in several properties. Even though a lot of research has been performed on the preparation of these materials, the homogeneous dispersion of nanoparticles in polymeric matrices, especially in non-polar, is still a difficult task. Thus, frequently nanocomposites exhibited worst properties than conventional polymers that limit their effective application. One way to improve nanoparticles dispersion is by using an in situ sol-gel method, which is based on a reaction between a precursor, containing the inorganic particle, and a polymer followed by hydrolysis-condensation reaction. Therefore, the present work aims to use microscopy techniques to investigate the dispersion of nanoparticles containing aluminium in PP and EVA matrices, prepared by a sol-gel process in the melt.Polypropylene modified with maleic anhydride (PP-g-MA, Polybond 3200) supplied by Crompton and ethylene-vinyl acetate (EVA) with 12 wt.% (EVA12, Escorene Ultra UL 00112) and 27 wt.% (EVA27, Escorene Ultra UL 00328) of vinyl acetate supplied by Exxon Mobil, were used as organic matrices to prepared the nanocomposites. The precursor, aluminium isopropoxide (Al(Pr-i-O)3), used as received in powder state, was supplied by Sigma Aldrich. Nanocomposites with the same composition were prepared by melt mixing in an internal mixer under constant processing conditions, as previously describe by Oliveira. The hybrid nanocomposite (HN) synthesized with PP-g-MA was called HN-Pr, with EVA12 was HNEVA12 and the one synthesized with EVA27 was HNEVA27.Samples characterized by SEM were fractured at low temperature and gold coated. Samples analysed by TEM were sectioned by cryo-ultramicrotomy using a diamond knife at -60 ºC and -140 ºC under liquid nitrogen for EVAs and PP-g-MA nanocomposites, respectively. X-ray microanalysis mapping was performed in 300 μm2, in the same place where SEM analysis was made, with an energy dispersive X-ray Spectrometer (EDS) from Link eXL II from Oxford Instruments attached to the SEM.SEM micrographs presented in Figure 1a, b and c show that while HN-Pr has a homogeneous and rough surface, HNEVA12 and HNEVA27 have homogeneous and smoother surfaces. The presence of nanoparticles agglomerations can not be observed in the micrographs, which indicates a good dispersion and interaction between organic and inorganic components. Therefore, in order to investigate nanoparticles dispersion TEM analysis were performed and the results presented in Figure 2 evidence different degrees of nanoparticles dispersion in polymeric matrices and distinct sizes. The best dispersion was achieved in HN-Pr followed by HNEVA27. The average particle size is 200, 130 and 120 nm for HN-Pr, HNEVA12 and HNEVA27, respectively. The differences in particles dimension can be explained by the extension of the chemical reaction, which in agreement with other techniques, it was higher for EVA27. EDS analysis results presented in Figure 3 render 2.84, 5.07 and 3.49 % of aluminium content in the analysed area of HN-Pr, HNEVA12 and HNEVA27, respectively.In this study, it was observed that reaction extension has a great influence on size and dispersion of the generated nanoparticles. According to SEM and TEM results, the smallest nanoparticles were achieved in EVA27. Moreover, for the three nanocomposites prepared well dispersed nanoparticles were obtained. The EDS spectrum confirmed the presence of aluminium in nanocomposites structure.This work showed that microscopic technics are very powerful on the characterization of new polymer matrix nanocomposites.The authors are grateful to the Portuguese Foundation of Science and Technology (FCT) Project SFRH / BD / 39085 / 2007 for the financial support.

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Kim, Moon-Jin, Jeong-Yeal Ahn, Pil-Whan Park, et al. "The Comparison of Platelet Parameters in Patients with Thrombocytopenia Associated with Acute Myeloid Leukemia and Immune Thrombocytopenia." Blood 120, no. 21 (2012): 3317. http://dx.doi.org/10.1182/blood.v120.21.3317.3317.

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Abstract Abstract 3317 Parameters associated with platelets (PLT) other than total PLT count, mean platelet volume (MPV), and platelet distribution width (PDW) are not widely used in clinical fields, although recent researches about them are increasingly reported. Additional platelet parameters can be helpful to evaluate the underlying cause of thrombocytopenia induced by two mechanisms-insufficient production and destruction of platelets. We investigated the significance of platelet parameters by evaluation of patients with ineffective platelet production (acute myeloid leukemia, AML) and destruction of platelets (immune thrombocytopenia, ITP). 49 adults newly diagnosed with AML (median age: 60, range: 21–86 years old) who had thrombocytopenia (<150 ×103/uL) and 47 adults with ITP (median age: 44, range: 22–82 years old) who were diagnosed with the bone marrow (BM) study were retrospectively reviewed. PLT and PLT parameters - MPV, PDW, PLT crit (PCT), mean PLT component (MPC), mean PLT mass (MPM), and large PLT count (LPLT) were measured by the ADVIA 2120 Hematology System (Siemens, USA) at the time of diagnosis. The percentage of LPLT (LPLT%) was calculated (LPLT/PLT ×100). The mean values of each group were compared using independent T-test on SPSS. The sensitivity and the specificity of each item to differentiate AML and ITP were determined by receiver operating characteristic (ROC) curve analysis. The mean values of platelet parameters of 480 male and female Korean adults in different age groups (120 in each group) who had hemoglobin level of 12–16.5 g/dl in female and 13–18.5 g/dl in male, white blood cell count of 4–10 ×103/ul, and PLT of 150–450 ×103/ul are shown in table I. The mean values of MPV, PDW, MPC, MPM, and LPLT% of ITP patients were significantly higher than those of AML (p<0.05). PLT, PCT, and LPLT did not show the difference between AML and ITP patients (Table II). Also, MPV, PDW, MPC, MPM, and LPLT% appeared significant to differentiate two diseases (p<0.05) upon ROC curve analysis (Table III). Table I. Platelet parameters in 480 Korean adults Platelet parameters Mean ¡¾ SD Total Male under 50Y Male over 50Y Female under 50Y Female over 50Y Reference range PLT (×103/¥ìl) 261 ¡¾ 53 257 ¡¾ 52 241 ¡¾ 47 259 ¡¾ 51 280 ¡¾ 59 150–450 MPV (fl) 7.9 ¡¾ 1.0 7.7 ¡¾ 0.7 7.9 ¡¾ 0.7 7.9 ¡¾ 0.7 8.0 ¡¾ 1.8 9–13 PDW (%) 51.3 ¡¾ 7.5 51.6 ¡¾ 7.5 52.1 ¡¾ 7.1 52.2 ¡¾ 5.8 49.0 ¡¾ 9.0 N PCT (%) 0.20 ¡¾ 0.04 0.20 ¡¾ 0.04 0.19 ¡¾ 0.04 0.20 ¡¾ 0.06 0.20 ¡¾ 0.04 N MPC (g/dl) 26.0 ¡¾ 1.3 26.2 ¡¾ 1.4 25.8 ¡¾ 1.3 26.4 ¡¾ 1.0 25.5 ¡¾ 1.5 N MPM (pg) 1.9 ¡¾ 0.2 1.9 ¡¾ 0.2 1.9 ¡¾ 0.2 2.0 ¡¾ 0.2 1.9 ¡¾ 0.2 N LPLT (×103/¥ìl) 4.7 ¡¾ 2.7 4.5 ¡¾ 2.7 4.6 ¡¾ 3.1 4.9 ¡¾ 2.3 4.7 ¡¾ 2.8 N LPLT% (%) 1.7 ¡¾ 0.6 1.8 ¡¾ 1.3 2.0 ¡¾ 1.4 2.0 ¡¾ 1.1 1.8 ¡¾ 1.2 N Abbreviations: SD, Standard deviation; Y, years old; N, Not determined; see text. Table II. Platelet parameters in AML and ITP patients Platelet parameters Disease Mean ¡¾ SD Reference range PLT (×103/¥ìl) AML 59 ¡¾ 35 150-450 ITP 54 ¡¾ 29 MPV* (fl) AML 9.8 ¡¾ 2.1 9–13 ITP 10.9 ¡¾ 2.8 PDW* (%) AML 53.9 ¡¾ 17.0 N ITP 60.6 ¡¾ 12.1 PCT (%) AML 0.06 ¡¾ 0.04 N ITP 0.06 ¡¾ 0.03 MPC* (g/dl) AML 22.3 ¡¾ 2.1 N ITP 25.4 ¡¾ 2.2 MPM* (pg) AML 2.0 ¡¾ 0.3 N ITP 2.4 ¡¾ 0.4 LPLT (×103/¥ìl) AML 3 ¡¾ 5 N ITP 4 ¡¾ 6 LPLT%* (%) AML 4.7 ¡¾ 5.2 N ITP 8.3 ¡¾ 9.4 Abbreviations: See table I; see text. * p<0.05. Table III. AUC for differentiation of AML and ITP with cut-off values ¡¡ AUC (95% CI) Cut-off value Sensitivity (%) Specificity (%) PLT 0.48 (0.36–0.59) 68 ×103/¥ìL 34.0 74.6 MPV* 0.66 (0.55–0.77) 10.2 fL 57.4 78.0 PDW* 0.63 (0.53–0.74) 56.3 % 66.0 69.5 PCT 0.51 (0.40–0.62) 0.07 % 40.4 72.9 MPC* 0.84 (0.78–0.92) 2.1 g/dL 87.2 76.3 MPM* 0.85 (0.75–0.91) 22.5 pg 78.7 76.3 LPLT 0.61 (0.50–0.71) 5.5 ×103/¥ìL 21.3 89.8 LPLT%* 0.67 (0.57–0.77) 4.1 % 72.3 61.0 Abbreviations: AUC, areas under the curves; CI, confidence interval; see text. * : p<0.05. In AML, deficient platelet production in the BM causes thrombocytopenia. Immune mediated destruction in the peripheral blood induces thrombocytopenia in ITP in spite of activated PLT production in BM. MPV, PDW and platelet large cell ratio (P-LCR measured by Sysmex-XE2100) had been reported to reflect production rate (MPV and PDW) and percentage of immature platelets (P-LCR) so that being higher in ITP than aplastic anemia (Kaito et al, 2004). MPV, PDW, MPC, MPM, and LPLT% were higher in ITP than AML in our study. They are also proven to differentiate AML and ITP upon ROC curve analysis. MPV, PDW, and LPLT% can be used as markers to predict the status of thrombopoiesis differentiating two mechanisms of thrombocytopenia, deficiency of production and destruction of platelets. 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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Dimicoli, Sophie, Elias Jabbour, Gautam Borthakur, et al. "Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome." Blood 118, no. 21 (2011): 1731. http://dx.doi.org/10.1182/blood.v118.21.1731.1731.

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Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

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Grosso, Dolores, Onder Alpdogan, Matthew Carabasi, et al. "A 2 Step Approach To Myeloablative Haploidentical Hematopoietic Stem Cell Transplantation (HSCT): Low Non-Relapse Related Mortality (NRM) and High Overall Survival (OS) Rates Confirmed In Second Generation Trial." Blood 122, no. 21 (2013): 3360. http://dx.doi.org/10.1182/blood.v122.21.3360.3360.

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Abstract Over 7 years ago, we developed a 2 step myeloablative approach to haploidentical HSCT in which patients, after conditioning with 12 Gy of total body irradiation (TBI days -9 to -6), receive a fixed dose of 2 x 108/kg of donor T cells (DLI-step 1 of HSCT) immediately after the last fraction of TBI. This large dose of haploidentical lymphocytes results in high fever, and in some cases, diarrhea and rash, developing on days-5 and -4. Cyclophosphamide (CY) 60 mg/kg, given on days -3 and -2 for T cell tolerization, results in complete resolution of this “alloreaction.” Tacrolimus and MMF are begun on day-1, followed by a CD 34 selected donor product infused on day 0 (Step 2 of HSCT). The separation of the lymphoid and myeloid portions of the graft (1) avoids the exposure of allogeneic stem cells to CY, (2) avoids the polarization of T cells to a TH2 phenotype because the donor T cells are collected prior to the initiation of G-CSF, (3) allows the administration of a fixed dose of T cells establishing a consistent platform from which to compare outcomes, and (4) provides a method to deliver higher doses of T cells. Recent data suggests that T cell doses > 1.1 x108/kg are associated with superior GVT effects as compared to lower T cell doses (Guo et al. JCO, 2012;30:4084 and Colvin et al. BBMT, 2009;15:421). To date, over 180 patients have undergone 2 step haploidentical myeloablative and reduced intensity HSCT at our institution. In the initial myeloablative haploidentical trial (2006-2009), twenty-seven patients underwent treatment using this approach. Immune reconstitution was brisk with median CD3/4 and CD3/8 counts at day +28 of 33.6 and 28.7 cells/ul respectively Cumulative incidences of grades III-IV graft versus host disease (GVHD), NRM, and relapse-related mortality were 7.4%, 22.2%, and 29.8% respectively. OS for the 12 patients without disease at HSCT was 75% and 48% for the whole cohort with 51-79 (median 63) months of follow-up. A 2nd generation myeloablative 2 step trial specific to patients without morphologic evidence of disease at the time of their haploidentical HSCT completed accrual in 2013. Twenty-eight patients with AML (15), ph+ ALL (4), B cell ALL (4), T cell ALL (2), MDS (1), mantle cell NHL (1), and hepatosplenic NHL (1), were treated and are 3-32 (median 14) months post HSCT. All patients engrafted and no patients died of GVHD or infection. Median CD3/4 and CD3/8 counts at 28 days were 74 and 47 cells/ul respectively. The only death related to treatment occurred in a patient who suffered a subdural hematoma after an LP performed for fever. Four patients have relapsed (14%), 3 of whom have died of their disease. The probability of OS of the patients treated on the current trial is 85% at 15 months. The combination of the most recently treated 28 patients with the 12 patients treated on the initial trial who were in morphologic CR at the time of HSCT, has resulted in a probable OS rate of 78% with 3 to 79 (median 18 months of follow-up). For patients without morphologic evidence of their disease at the time of HSCT, the 2 step myeloablative approach to haploidentical HSCT has been associated with robust immune reconstitution resulting in low rates of infectious death. There have been no deaths from GVHD, and very low rates of treatment-related mortality. OS rates of the good risk patients treated on this approach are very high due to this low degree of NRM. The results of this 2nd generation trial have confirmed that the 2 step myeloablative approach to haploidentical HSCT is safe and efficacious and produces outcomes that are comparable to those reported by CIBMTR (2000-2010) for recipients of matched related or other alternative donor grafts. This approach has become our alternative HSCT strategy of choice allowing virtually every patient to be treated with HSCT rapidly at our institution. Disclosures: Kasner: Roche: Research Funding.

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Yang, Yanqin, Yubo Zhang, Jun Zhu, et al. "Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia." Blood 126, no. 23 (2015): 3616. http://dx.doi.org/10.1182/blood.v126.23.3616.3616.

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Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.

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Uldrick, Thomas S., Mark N. Polizzotto, Armando Filie, et al. "Clinical, Immunologic, and Virologic Findings in Kaposi Sarcoma Herpesvirus (KSHV)-Associated Lymphomas Suggest KSHV-Associated Inflammatory Syndromes Contribute to Symptoms and Disease Pathogenesis." Blood 120, no. 21 (2012): 2708. http://dx.doi.org/10.1182/blood.v120.21.2708.2708.

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Abstract Abstract 2708 Background: KSHV, also known as human herpesvirus-8, is the etiologic agent of a lymphoproliferative disorder, KSHV-associated multicentric Castleman disease (KSHV-MCD), two lymphomas: primary effusion lymphoma (PEL) and large cell lymphoma arising in KSHV-MCD (together, KSHV-NHL) and Kaposi sarcoma (KS). KSHV-associated diseases mainly occur in patients with HIV. KSHV is notable for its modulation of host immune response, including induction of IL6 and IL10; and an IL6-related KSHV-associated inflammatory cytokine syndrome (KICS) has been described in HIV/KSHV infected patients without KSHV-MCD. The clinical features and natural history of KSHV-NHL are not well understood. We hypothesize KSHV-NHL is associated with pathophysiologic features similar to those of KSHV-MCD, and is unique among HIV-associated lymphomas. Methods: Clinical records of patients with KSHV-NHL diagnosed 2000-12, treated in the HIV and AIDS Malignancy Branch Clinic were reviewed, and evaluated for clinical, and laboratory abnormalities using our criteria for KICS (NCT01419561): at least 2 select clinical and laboratory manifestations, not otherwise explained; elevated c-reactive protein [CRP]; and KSHV viral load greater than 100 copies/106 PBMC; Additionally, serum inflammatory cytokines, (IFN-gamma, TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, IL12p70; Mesoscale Discovery, Gathersburg, MD) as well as PBMC-associated KSHV viral load, platelets, hemoglobin, and albumin were evaluated in KSHV-NHL patients, and compared to patients with A) Symptomatic KSHV-MCD and no KSHV-NHL, and B) Other HIV-associated lymphomas. Comparisons used exact two-tailed Wilcoxon rank sum tests, p<0.005 was considered statistically significant, p<0.05 strong trends. Results: Study cohort: 14 patients with HIV and KSHV-NHL; men (13), woman (1); median (med) age 42 yrs (26, 60); African American (4), African (2), Hispanic (4), white (4). Diagnoses included PEL (12, 5 with extracavitary manifestations) and large cell lymphoma in KSHV-MCD (2). Of the 14, 5 had pathologically confirmed KSHV-MCD, and 10 had cutaneous KS. Laboratory data: med CD4 126 cells/uL (15,1072), HIV viral load <100 copies/ml (7). All 10 KSHV-NHL with complete CRP and KSHV data either met criteria for KICS or had a history of KSHV-MCD; med CRP 48.8 g/dL (4.6, 114). Controls: A) KSHV-MCD (n=19): med age 43 (29, 54), med CD4 266 (67,1319). B) Other HIV-associated lymphoma (n=28): med age 37 (21, 60); med CD4 29 cells/uL (0, 730). Laboratory, immunologic, and virologic parameters were comparable between KSHV-NHL and KSHV-MCD, with no significant differences or trends towards differences in CRP, hemoglobin, platelets, CD4 count, albumin, sodium, KSHV viral load, or any measured cytokine. Compared to patients with other HIV-associated lymphomas, those with KSHV-NHL had statistically significant elevated serum IL10 (med 513 vs 12.2 pg/ml, p<0.0001), IL6 (29 vs 4.1 pg/dl, p=0.0011), KSHV viral load (med 3913 vs. 0 copies/106 PBMC, p<0.0001), and hypoalbuminemia (med 1.8 vs 3.5 mg/dL, p=0.001) (Figure). Strong trends towards statistically significant thrombocytopenia (med 87 vs 246 K/uL, p = 0.0064), anemia (med 8.9 vs 11.1 gm/dl, p=0.019), hyponatremia (med 134 vs 137 mEq/L, p=0.03), and elevated IL1beta (1.6 vs. 0.5 pg/dL, p=0.024), and IFNgamma (med 6 vs 2.9 pg/dl, p=0.038) were also observed. Conclusions: In the era of antiretroviral therapy, KSHV-NHL in HIV occurs at a broader range of CD4 counts than previously appreciated, often in the setting of suppressed HIV. Significant overlap exists between KSHV-associated lymphoproliferative disease and KSHV-NHL. Essentially all KSHV-NHL patients presented with inflammatory symptoms, elevated CRP, hypoalbuminemia, and cytopenias, and either had KSHV-MCD or met our working criteria for KICS. Elevated KSHV-infected PBMCs and associated KSHV modulation of host immune response leading to marked elevations in IL10 and IL6 likely contribute to symptoms and KSHV-NHL pathogenesis. KSHV-MCD and KICS Natural History studies are ongoing, and evaluation of curative-intent regimens for KSHV-NHL incorporating strategies to target these unique immunologic and virologic abnormalities is warranted. Disclosures: No relevant conflicts of interest to declare.

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Kumar, Shaji, Martha Lacy, Angela Dispenzieri, et al. "Stem Cell Mobilization Following Initial Therapy with Lenalidomide and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma." Blood 112, no. 11 (2008): 3467. http://dx.doi.org/10.1182/blood.v112.11.3467.3467.

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Abstract Background: Autologous stem cell transplantation is an effective therapy for patients with multiple myeloma. We and others have previously reported the influence of lenalidomide based regimens on the ability to harvest adequate number of stem cells for successful transplantation. In order to identify factors predicting for poor mobilization we studied a large group of patients who underwent an attempt at stem cell mobilization after receiving lenalidomide and dexamethasone as primary therapy for myeloma. Methods: We identified sequential patients who received lenalidomide and dexamethasone as initial therapy for their myeloma and then underwent stem cell mobilization for immediate or future stem cell transplantation. Patients who received any other regimen prior to the stem cell mobilization were excluded. Between July 2004 and May 2008, 106 patients, satisfying the above criteria were identified from the Mayo Clinic transplant database. Medical records and collection sheets were examined for the data. Results: The median (range) age at mobilization was 60 yrs (29–75); 34 (32%) were over 65 yrs and 59 (55%) were males. The median duration of lenalidomide therapy was 4 months (range; 1–13). The strategy for stem cell mobilization was GCSF alone in 92 patients (87%), cyclophosphamide (CTX) and GCSF in 11 pts and 3 pts received AMD3100 and GCSF. Among the GCSF mobilized patients, 10 pts (11%) failed to collect at least 2.5 million cells required for one transplant, including 8 patients who never achieved the minimum peripheral count threshold to initiate the collection. Two of the 11 pts undergoing primary mobilization with CTX/GCSF failed to collect any cells, while all of the 3 pts mobilized with AMD3100 were successful. Five of these pts subsequently underwent successful salvage mobilization with CTX/GCSF, 1 with AMD3100, one failed to mobilize with CTX and the rest did not repeat mobilization. Given that the total CD34 collection and the number of days of collection are influenced by the CD34 goal, we examined patient characteristics that correlated with the CD34 collections over the first 2 days. Increasing patient age and the duration of lenalidomide therapy, both correlated with decreasing 2-day CD34 collection, while the time between last dose of lenalidomide and the start of GCSF had no effect. We then performed ROC analysis to find best cut-off points that predicted the inability to collect adequate (2.5 million) CD34 cells in 3 days. Lenalidomide therapy of more than 4 months (P =0.03) and age > 63 yrs (P = 0.04) best predicted inability to achieve this endpoint. In addition, a peripheral blood CD34 count < 5/uL on day 5 after start of GCSF was highly predictive of failure to reach this endpoint. Conclusions: Inability to collect adequate stem cells with lenalidomide appears to be related to patient age and the duration of lenalidomide therapy. We recommend early stem cell collection and storage, if a delayed transplantation approach is taken. Patients receiving more than 4 cycles of therapy and those over 65 years should undergo mobilization with CTX+G-CSF, rather than G-CSF alone. Majority of the patients who fail G-CSF based collection can be mobilized using CTX and G-CSF. Early identification of failures after G-CSF administration using the peripheral CD34 counts can potentially allow salvage using strategies such as AMD3100.

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Nearman, Zachary P., Marcin Wlodarski, Chris Hung, et al. "Immunogenetic Factors Determining Evolution of T-Cell Large Granular Lymphocyte Leukemia and Associated Cytopenias." Blood 106, no. 11 (2005): 2211. http://dx.doi.org/10.1182/blood.v106.11.2211.2211.

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Abstract T cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of cytotoxic T cells (CTL). T-LGL presents with cytopenias, implying a relationship to other immune-mediated bone marrow failure states. T-LGL is often accompanied by autoimmune diseases, suggesting a clonal transformation in the context of an initially polyclonal autoimmune response. Immunogenetic predisposition factors have been described for both immune-mediated bone marrow failure as well as other autoimmune conditions and it is possible that some of these factors can promote evolution of T-LGL and/or the development of cytopenias. Here, we analyzed the association of T-LGL (and clinical variants) with a number of immunogenetic factors, including HLA and KIR genotype, KIR-L/KIR mismatch, CTLA4 (−658T/C, −318C/T, +49A/G) and cytokine single nucleotide polymorphisms (SNP) including: TNF-a (−308G/A), TGF-b 1 (codons 10 C/T, 25 G/C), IL-10 (−1082 G/A, −819 T/C, −592 C/A), IL-6 (−174 C/G), and IFN-g (+874 T/A). We studied a large cohort of patients with T-LGL (N=79) systematically followed at our institution. Using molecular analysis of TCR utilization as previously described (Wlodarski et al, Blood 2005) we have determined the relative and absolute size of the clonal LGL population for each case. We performed HLA typing as certain alleles serve as KIR ligands and can determine quality of immune response. HLA-B37 and Cw-7 were over expressed in LGL patients (13 vs 2%, p<.001; 60 vs 45%, p=.039); no other alleles correlated with the disease. No HLA association was found in patients presenting with neutropenia or splenomegaly, however HLA-Cw7 was found in 100% of patients with an increased number of clonal CTL (>1900/uL; N=13 vs 45% in controls and 33% in patients with low LGL count; p<.001). HLA-Cw alleles can be divided into C1 and C2 groups based on recognition by KIR; in the above 13 patients, C1/C1 phenotype was significantly increased compared to normal controls while C2/C2 was absent (p<.001, p=.04, respectively). This finding suggests a protective function for the C2/C2 phenotype in T-LGL patients. Subsequently, we analyzed KIR genotype by SSP PCR; no association between a specific KIR genotype and disease was found. LGL patients did not vary from controls in the ratio of inhibitory to stimulatory KIR. As KIR genotype may exert pathogenic influence in the context of KIR/KIR-L interactions, we hypothesized that a KIR/KIR-L mismatch would result in less regulation of CTL response and thus more severe cytopenias. According to the subdivision of HLA-Cw alleles into group C1 (ligands KIR2DL2 and 2DL3) and C2 (ligands 2DL1), genetic mismatch between KIR-L and KIR was found in 50% of patients, but proved statistically insignificant compared to normal controls. The severity of cytopenias and other hematologic manifestations was greater in patients without KIR-L/KIR mismatch. This finding may be due to an overshooting CTL response resulting from silencing NK-cells. SNP in cytokines and their promoters may play a pathogenic role in autoimmune conditions, as such we also analyzed the frequency of multiple cytokine polymorphisms in T-LGL to determine a potential secretion/stimulation phenotype. Among cytokine SNP studied in T-LGL, overrepresentation of TNF-a -308G/A polymorphism (for A/A: 14 vs 1% in controls, p=.009), and CTLA4 +49 SNP A/A genotype was found (50 vs 27%, p=.013), suggesting that the presence of G allele is protective.

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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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Grosso, Dolores, Matthew Carabasi, Janet Brunner, et al. "A Two Step Myeloablative Approach to Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Hematological Malignancies From HLA Partially-Matched (Haploidentical) Related Donors." Blood 114, no. 22 (2009): 2292. http://dx.doi.org/10.1182/blood.v114.22.2292.2292.

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Abstract Abstract 2292 Poster Board II-269 Lack of a matched donor remains a major obstacle to the application of allogeneic HSCT in all appropriate patients. We developed a haploidentical 2 step myeloablative transplant regimen that used Cyclophosphamide (CY) tolerization to avoid severe GVHD while still allowing rapid post-HSCT immune reconstitution. We refer to this as a two step approach because the patients receive the lymphoid and stem cell portions of the graft at different times during the transplant regimen rather than as a single transplant inoculum. Between 2006 and 2009 twenty-seven patients, median age of 52 years (range 19-67), with high risk hematological malignancies were transplanted from haploidentical donors that were mismatched for HLA-A, B, C, and DR in the GVHD direction at 4 antigens (13), 3 antigens (11), and 2 antigens (2). One patient had no mismatches in the GVHD direction but was a 3 antigen mismatch in the rejection direction. The patients were given a conditioning regimen consisting of eight fractions (total dose 12 Gy) of total body irradiation (TBI) followed immediately thereafter by a donor lymphocyte infusion (DLI) of 2 ×10e8 CD3+ donor T cells, the first step of the transplant process. Within 24 hours, this dose of T cells consistently produced an in-vivo allogeneic reaction characterized by fever (median temperature 103.8f) and in many cases rash and diarrhea. Skin biopsies performed on 2 of the patients with rash were consistent with GVHD. After a median time of 63 hours (range 60-66 hours) following the DLI, CY (60 mg/kg/day) was given for 2 days to eliminate alloactivated donor and host T cells. The symptoms caused by the DLI typically disappeared 24 hours after completion of CY. The second step of the transplant occurred when a CD34 selected HSC product from the same donor was infused 24 hours after the end of the infusion of CY. GM-CSF was used post HSCT to accelerate white cell recovery and to promote a TH1 type immune response. Tacrolimus and mycophenylate mofetil were used for GVHD prophylaxis. Donor apheresis was performed over 2 days for lymphocyte collection followed by administration of G-CSF for 5 days and an additional 2 aphereses for HPC collection on days 4 and 5 of G-CSF administration. Fifteen of 27 patients (56%) are alive without evidence of their disease 3 to 32 months past HSCT. One additional patient is alive but with relapsed disease. Kaplan-Meier estimates of survival are 70% in patients without disease at the time of HSCT and 43% in patients not in remission at HSCT. Eleven patients (41%) died, 5 from relapsed disease, 3 from toxicity, and 3 from infection. Of the 6 relapses, 5 occurred in mothers who received transplants from their children. There were no deaths attributable to GVHD and only 1 brief occurrence of severe (grade III gut) GVHD. Fifteen patients (55%) developed grade 1-2 GVHD, mostly of the skin and easily controlled with steroids in 11 or with steroids plus photopheresis in 4 patients. Three patients developed limited chronic GVHD, one of whom is off immunosuppressive therapy. Immune reconstitution was brisk. Patients typically reached CD3+CD4+ counts of >100 cells/ul within a few months of discontinuation of immunosuppressive therapy. Two multiparous females with pre-existing anti-donor antibodies experienced humorally mediated rejections. Both died of toxicities related to a second HSCT. The other toxic death occurred in the patient with no mismatches in the GVHD direction who experienced a flare of his Crohn's disease shortly before conditioning. Three infectious deaths occurred, one due to progression of preexisting aspergillus lung disease and bacteremia, 1 due to RSV pneumonia, and 1 due to brain abscess. This 2 step technique; 1) allows for the administration of a prescribed amount of tolerized lymphocytes in an effort to promote consistent immunologic outcomes post transplant, 2) prevents exposure of the donor HSC to CY, 3) prevents exposure of the donor lymphocytes to G-CSF thus avoiding skewing to a TH2 T cell phenotype, and 4) allows for a greater separation between TBI and CY in the conditioning regimen which may help decrease regimen related toxicity. The high overall survival rate in patients in remission at the time of transplant illustrates the importance of early identification of patients for haploidentical HSCT who are without well matched donors. These encouraging clinical outcomes suggest that this novel 2 step approach to HSCT should be further explored. Disclosures: Off Label Use: Off Label Use of CD34 selection Device.

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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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Rivero, Gustavo A., Dangayach Priti, Jun Zhang, and Marylin Li. "Acute Differentiation Syndrome Is a Biological Consequence Of Treatment With Azanucleoside In Isocitrate Dehydrogenase-1 (IDH-1) and SFR2 mutated Myelodysplasia Derived Acute Myelogenous Leukemia." Blood 122, no. 21 (2013): 4982. http://dx.doi.org/10.1182/blood.v122.21.4982.4982.

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Abstract Background Treatment related toxicity complicates outcome in elderly patients with AML (Estey et al. Blood. 2006). Conventionally, 7+3 induction (anthracycline plus cytarabine) results in Complete Remission rate of about 30%. Regimens with less toxicity, such as 10-days (d) schedule of DAC, seem promising with CR rate of 47% (Blum et al. PNAS. 2010). In secondary MDS derived AML, response prediction could be derived from mutation status in epigenetic modifiers (IDH1, IDH2, DNMT3 A, TET2), transcriptional regulators (RUNX1, CBL), and genes in spliceosome machinery, such as SF3B1 and SRSF2 (Husseinzadeh et al. American Society of Hem Meeting. Abstract # 1698. 2012). IDH-1 mutation is known to induce hypermethylator phenotype (fig 1) (Figueroa et al. Cancer Cell. 2010) and might be present in conjunction with SRSF2 mutations, an unique unreported molecular subset, feasible for exploring azanucleoside response prediction. Herein, we report a case of trisomy 8 MDS derived IDH1 and SRSF2 mutated AML who underwent rapid morphological blast differentiation in the context of acute differentiation syndrome while treated with 10 days (d) of hypomethylating dose of DAC. Methods A 61-year-old male with performance status (PS) = 3 presented with leukocytosis of 18.9 K/uL (peripheral blast 90%). He had a history of low-grade MDS diagnosed 2 years before AML transformation. After morphological confirmation of M5 AML, fluorescent in situ hybridation (FISH) revealed 81% nuclei with trisomy 8. Extracted DNA was tested with a custom-designed Leukemia Cancer Gene Mutation Panel using AmpliSeq™ technology and showed IDH1 c.394C>T(p.R132C) mutation (Fig. 2B) and c.284C>T(p.P95L) mutation of SRSF2 gene (Fig. 2C). DAC was initiated at 15 mg/m2 for a total of 10 days every 28 d cycle. Results By day 5 of cycle (C)1 of DAC treatment, brisk and significant rebound leukocytosis of 60 K/uL (Fig. 3) was observed, along with shortness of breath, hypoxemia and radiological evidence of floppy bilateral pulmonary infiltrates suggestive of acute-like differentiation syndrome. In addition to broad-spectrum antimicrobial and antifungal, dexamethasone at 4 mg intravenously (IV) every 8-hour (h) and hydroxyurea at 1 g orally every 8 h resulted in progressive normalization of peripheral blood count and hypoxemia after 48 h. Patient (pt) recovered from C1 and proceeded with C2 of treatment. A similar episode of brisk/robust leukocytosis was observed by day 5 of C2 requiring dexamethasone and hydroxyurea. Progressive morphological differentiation was observed to full mature and morphologically normal monocytes and neutrophil (Fig. 4). Pt expired as result of severe clostridium difficile colitis during C3 of DAC. Conclusions In our case, we observed robust acute differentiation syndrome characterized by rapid increase of WBC, shortness of breath and hypoxemia associated with azanucleoside treatment. Beside a novel association of IDH-1 and SRSF2 mutations, acute differentiation might suggest potential feature for azanucleoside response phenotype. Our case adds body of evidence of connection between epigenetic regulator and spliceosome mutations. Further studies on the impact of dual mutations in epigenetic reprogramming, leukemia transformation, and azanucleoside response will allow improved decision algorithm and therapeutic design. Disclosures: No relevant conflicts of interest to declare.

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Mushtaq, Muhammad Umair, Sibgha Gull Chaudhary, Laura C. Michaelis, et al. "Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia." Blood 132, Supplement 1 (2018): 2708. http://dx.doi.org/10.1182/blood-2018-99-113764.

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Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

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Benajiba, Lina, Clementine Salvado, Jean-Hugues Dalle, et al. "HLA-Matched Related Donor Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Conditioned with a Combination of Cyclophosphamide and Fludarabine : A Study on Behalf of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)." Blood 124, no. 21 (2014): 4391. http://dx.doi.org/10.1182/blood.v124.21.4391.4391.

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Abstract Background. Fanconi anemia (FA) is a rare, phenotypically heterogeneous, inherited disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF) and a predisposition to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is the only curative option for FA patients. However, finding the best conditioning regimen is still challenging for clinicians. To reduce toxicities, we used progressively lower doses of cyclophosphamide (CY) for conditioning through non-irradiation based regimens. A reduced conditioning regimen based on CY 60mg/kg alone was proposed by Bomfim et al (BBMT, 2007). Survival rates were excellent but some patients experienced primary (n=1) or late (n=4) graft failure (11% of the patients). Mucositis was a major problem as 25 patients (60%) presented grade 3 / 4 mucositis. The rate of Chronic graft versus host disease (GvHD) was 29%. We hypothesized that tapering the dose of CY to 40mg/Kg and adding fludarabine (FLU) at 90mg/m2 might improve engraftment, decrease GvHD rates and eventually improve overall toxicity in FA patients transplanted with HLA matched siblings. Method. In 2004, the French reference centre for aplastic anemia and the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) recommended to use FLU 90mg/m2 (30mg/m2 days -4, -3, -2) and CY 40mg/kg (10mg/kg days -5, -4, -3, -2) for FA patients transplanted from matched family donor. Indication for transplantation was based on hematological complications (transfusions and/or infections). FA patients with morphologic signs of clonal evolution (myelodysplastic syndrome or acute myeloid leukemia) were excluded. All patients in France who received a first Allo-HSCT for FA from a matched related donor between October 2004 and January 2013 using this approach were analyzed (n=20). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centres. All patients received uromitexan. Ciclosporin A and micophenolate mofetil were used as GVHD prophylaxis. Six patients received an in vivo T cell depletion using antithymocyte globuline because of local policy at their centre. The guidelines were approved by Saint-Louis hospital ethical committee. Results. The median age at transplant was 9 years (range: 6-19). Stem cell source was bone marrow in 16 cases and matched related cord blood in the remaining transplants. None of the patients received peripheral blood stem cells. All patients had severe or moderate BMF (median hemoglobin: 8.9g/dl, median platelets: 31 103/ul, median neutrophils: 0.88 103/ul) at time of transplant. Two patients had chromosomal abnormalities (47,XX,i(1)(q10)[10]/48,idem,+8[3] and 47,XX,+der(1;3)(q10;q10)[14]/46,XX[6]); however, none of them developed overt myelodysplasia/leukemia before transplant. Patients belonged to complementation groups FANC-A (n=17) and FANC-G (n=2). Transplantation was performed within a median of 30 months from FA diagnosis (range: 7-143). A median of 3.8. 108 nucleated marrow cells were infused (range: 0,65-8,97). Within a median follow up of 2 years (range: 0.2-7.4), overall survival was 95% (figure 1). Only one patient with an atypical form of FA associated with severe immunodeficiency prior to transplant died subsequently due to uncontrolled cerebral toxoplasmosis. Engraftment rate was 100% with a median time to neutrophils and platelets recovery of 16.5 (11-28) and 15 (4-29) days, respectively. No grade 3/4 regimen related toxicity was observed and only 1 patient experienced mucositis (grade 2) using this conditioning regimen. Total acute GvHD grade 3 / 4 was only observed in 3 patients (15%) and chronic GvHD was extensive in 2 patients (10%) and limited in 3 patients (15%). Median alive patients karnofsky scored 100% (range 90 – 100%). No secondary malignancy was observed in our cohort so far. Conclusion. The combination of low dose CY (40mg/Kg) plus FLU (90mg/m2) in HLA-matched donor HSCT in patients with FA resulted in an excellent engraftment rate (100%) with no secondary graft failure, low rates of acute and chronic GvHD, low rates of regimen related toxicity, eventually resulting in an excellent overall survival (95% at 2 years). A longer follow-up in this cohort is needed to confirm such excellent results long-term, namely the continued absence of secondary cancer. Figure 1. Figure 1. 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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Weinberg, Olga K., Mahesh Seetharam, Li Ren, et al. "Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System." Blood 112, no. 11 (2008): 922. http://dx.doi.org/10.1182/blood.v112.11.922.922.

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Abstract Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup. Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 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. Available flow cytometry immunophenotyping results were reviewed and 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 and multivariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65). Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. Figure Figure

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Chakrabarti, Sakti, Y. Takahashi, R. Srinivasan, et al. "Durable Engraftment and Long-Term Survival Following Fludarabine-Based Nonmyeloablative Hematopoietic Cell Transplantation (HCT) in Patients with ATG-Refractory Severe Aplastic Anemia (SAA) and Other Nonmalignant Hematological Disorders." Blood 104, no. 11 (2004): 252. http://dx.doi.org/10.1182/blood.v104.11.252.252.

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Abstract We evaluated the toxicity-profile, engraftment potential, and efficacy of fludarabine-based nonmyeloablative allogeneic HCT in patients with a variety of nonmalignant hematological disorders. Twenty three patients (median age 29 years; range 11–52) with nonmalignant hematological disorders including ATG refractory SAA (n=13), severe paroxysmal nocturnal hemoglobinuria (PNH: n=9), and pure red cell aplasia (PRCA; n=1) were transplanted from 5/99 – 8/2004 at the NHLBI. The majority of patients had an extensive transfusion history including 11/23 who had HLA allo-antibodies and 4/23 with allo-antibodies to RBCs. Conditioning with fludarabine (25 mg/m2 x 5 days), ATG (40mg/kg x 4 days) and cyclophosphamide (60mg/kg x 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched sibling (n=18), parent (n=2), or single antigen mismatched sibling (n=3). GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=11). Despite a high prevalence of pre-transplant allo-immunization, all patients achieved sustained donor engraftment in both myeloid and T-cell lineages. Myeloid recovery (neutrophils >500cells/uL) occurred at a median 14 days post transplant (range 8–18 days). Conversion from mixed to full donor myeloid and T-cell chimerism occurred in all patients by 110 days post-transplant. CMV reactivation occurred in 11/21 patients at risk (KM probability 52%) without any cases of CMV disease. Grade II–IV and III–IV acute GVHD was the major transplant complication occurring in 13/23 (KM probability 60%) and 8/23 (KM probability 38%) patients respectively. Fourteen of 21 evaluable patients developed chronic GVHD (limited in 11 cases), which resolved completely with low-dose alternate day steroids and/or CSA in all but 1 case. One patient who received an allograft from his HLA matched father died 16 months post-transplant from complications related to chronic GVHD. With a median follow up of 25 months (range 1–64 months), 20/21 patients evaluable more than 100 days post-transplant survive in complete remission with full donor chimerism in all lymphohematopoietic lineages (KM probability of long-term survival 92.8 %-see figure ). Conclusion: Fludarabine-based nonmyeloablative transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and allo-immunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure.

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Ottlakán, Aurél, Tibor Géczi, Balázs Pécsy, et al. "Myasthenia gravis miatt végzett három különböző típusú csecsemőmirigy-eltávolítás sebészeti és korai neurológiai eredményei." Magyar Sebészet (Hungarian Journal of Surgery) 68, no. 6 (2015): 219–24. http://dx.doi.org/10.1556/1046.68.2015.6.1.

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Absztrakt Célkitűzés: A myasthenia gravis (MG) kezelésében számos nyitott, illetve minimálisan invazív thymectomia ismert. A tanulmány ugyanazon intézeten belül a transsternalis (TS), illetve kétféle minimálisan invazív thymectomia (video-assisted thoracoscopic extended thymectomy – VATET; unilateral video-assisted thoracoscopic surgery – UL-VATS) eredményeit hasonlítja össze. Anyag és módszerek: Három különböző időintervallumban 71 betegnél történt thymectomia MG miatt (60 nő, 11 férfi): 23 transsternalis thymectomia (1995. január–2004. szeptember), 22 VATET (2004. szeptember – 2009. augusztus) és 26 UL-VATS thymectomia (2009. szeptember – 2011. december). Az eredmények értékelésénél a műtéti idő, MG-hez társuló neurológiai és a műtét utáni sebészi szövődmények, valamint az MG státuszában az egyéves utánkövetéskor észlelt neurológiai változások szerepeltek. Eredmények: Perioperatív mortalitás nem fordult elő. A műtéti idő 112, 211, 116 perc (p = 0,001), a kórházi napok száma: 8,9, 5,6 és 4 nap (p = 0,001) volt a TS-, VATET- és UL-VATS-csoportban. Az MG-hez kapcsolódó postoperativ neurológiai szövődmények 21,7%, 18,2% és 7,7% (p = 0,365) értékeket mutattak. A sebészi szövődmény 4,3%, 13,7%, 0% (p = 0,118) volt. Az MG tüneteinek javulása 91,3%, 94,7%, 87,5% (p = 0,712), míg komplett remisszió 13%, 10,5%, 11,5% (p = 0,917) volt a TS-, VATET- és UL-VATS-csoportokban. Következtetések: A műtéti idő, valamint a kórházban eltöltött napok száma UL-VATS esetében volt a legrövidebb. A kisebb sebészi beavatkozáshoz alacsonyabb sebészi, illetve MG-s neurológiai szövődmények társultak. Az MG-tünetek javulásában mindhárom módszernél kiváló eredményt értek el.

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Schlueter, Annette J., Judith K. Glasgow, Werner Wilke, et al. "Dendritic Cell Reconstitution Following Autologous Stem Cell Transplant with GM-CSF Support for Multiple Myeloma." Blood 110, no. 11 (2007): 951. http://dx.doi.org/10.1182/blood.v110.11.951.951.

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Abstract High dose therapy followed by autologous stem cell rescue for the treatment of multiple myeloma has been shown to be associated with improved outcome including increased complete response rates and survival. It is unclear what role, if any, autologous dendritic cell (DC) reconstitution patterns play in determining outcome. DC in peripheral blood (PB) can be divided into two subsets: DC1, which favor Th1 responses and DC2, which favor Th2 responses and in some cases appear to be immunosuppressive. In this companion study to a tandem stem cell transplant research protocol, PB DC subsets were studied just prior to the administration of mobilizing chemotherapy (baseline), at the time of stem cell collection, and on transplant d. 0, 15, 30, 60, and 90 following the first and second transplants. DC were identified as lineage (CD3/14/16/19) negative, HLA-DR+. Of these cells, DC1 = CD11c+CD123− or CD33hiCD4lo, and DC2 = CD11c−CD123+ or CD33lo/−CD4+. Precursor DC numbers (Pre-DC1 = CD45loCD34+HLA-DR+CD86+; Pre-DC2 = CD45loCD34+HLA-DR+CD10+) were also assessed in the stem cell products. GM-CSF (sargramostim) was used as part of the mobilization regimen as well as to enhance neutrophil recovery post-transplant. Twenty patients were enrolled and all are >90 d. post transplant #1. Six patients received a 2nd transplant. Median followup time is 25 months (range 3–56 months). Seven patients are in complete remission (CR), 7 have had a partial response, 4 have progressive disease, and 2 died of recurrent disease. In most cases, DC1 counts were higher than DC2 counts at all time points examined. At baseline, this was true for 70% of patients, indicating that immediately prior to transplant most patients maintain the DC1>DC2 ratio found in healthy humans. DC subset numbers generally increased over baseline in mobilized PB, and correlated well with the patients’ baseline DC counts. Similarly, baseline DC subset numbers were highly correlated (R>0.7) with the number of pre-DC1 or pre-DC2 found in the stem cell products. No patients with pre-DC1<pre-DC2 achieved a CR. Post-transplant, DC1 recovery to baseline levels occurred in most patients by d. 60. DC2 recovery was often more rapid, with baseline levels reached in many patients at d. 30. Patients who had high (>10/ul) PB DC1 numbers at d. 90 consistently remain in CR. This study is the first to systematically examine DC subset reconstitution following autologous transplant for multiple myeloma. Our results provide preliminary evidence that the presence of high numbers of PB DC1 at d. 90 may predict a good long term prognosis, perhaps by promoting an effective endogenous immune response against residual disease. Furthermore, pre-DC1<pre-DC2 in the stem cell product might predict a poor outcome, and increase early consideration of post-transplant adjunctive therapy. As GM-CSF is known to mobilize proportionately more DC1 (relative to DC2) than G-CSF (Vela-Ojeda 2006, Ann Hematol 85:308–14), use of GM-CSF may provide a long-term disease free benefit in addition to facilitating stem cell collection and limiting post-transplant neutropenia in patients with multiple myeloma.

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Poulter, Elana Y., Piotr Truszkowski, Alexis A. Thompson, and Robert I. Liem. "Acute Chest Syndrome Is Associated with History of Asthma in Hemoglobin SC Disease." Blood 112, no. 11 (2008): 2485. http://dx.doi.org/10.1182/blood.v112.11.2485.2485.

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Abstract Acute chest syndrome (ACS) is a frequent cause of morbidity and the leading cause of death among individuals with sickle cell disease. Prior studies of ACS in hemoglobin SC disease, however, have been limited in scope and the risk factors and clinical outcomes associated with ACS in individuals with hemoglobin SC versus SS disease remain unclear. The objective of this study was to compare the presentation and clinical course of ACS in individuals with SC disease to that observed in individuals with SS disease. We hypothesized that in SC disease, ACS is associated with a more severe clinical course compared to that observed in SS disease. Using available hospital medical records, we performed a retrospective analysis of all episodes of ACS diagnosed either on admission or during hospitalization in patients with SC disease over a 20-year period from 1987 through 2007. Control cases meeting identical criteria in patients with hemoglobin SS disease were randomly sampled within a 5-year period of the occurrence of each SC episode. We performed standard descriptive analysis and compared both continuous (Mann-Whitney test) and categorical data (Pearson’s χ2 analysis) in SC and SS episodes of ACS. Standard regression analysis was performed to evaluate predictors of length of hospitalization, our primary outcome for clinical severity. A total of 71 episodes of ACS in 30 SC patients and 137 episodes in 92 SS patients were reviewed. We found that in episodes involving SC patients, median age (7.0 vs. 5.0 years, p=0.014), baseline hemoglobin (10.5 vs. 8.1 g/dL, p=0.001) and oxygen saturation on presentation (97 vs. 94%, p=0.001) were significantly higher when compared to that in episodes involving SS patients. In SC cases, a history of asthma or wheezing (50.7 vs. 34.3%, p=0.022, OR=1.98) was significantly more common than in SS cases. In addition, complaints of chest pain (40.8 vs. 22.8%, p=0.007, OR=2.34) and wheezing (11.3 vs. 3.7%, p=0.033, OR=3.34) on presentation were significantly more frequent in the SC group. At the time of diagnosis of ACS in SC patients, median total white blood cells (15.3 vs. 19.6 x103 cells/uL, p=0.001), platelets (206 vs. 343 x103/uL, p=0.001), nucleated red blood cells (0 vs. 2.0 per 100 WBC, p=0.001), reticulocytes (3.0 vs. 12.7%, p=0.001) and percent lymphocytes (15.0 vs. 22.5%, p=0.002) were lower, but hemoglobin (9.3 vs. 7.4 g/dL, p=0.001) and total percent neutrophils and bands (74.5 vs. 65.0%, p=0.001) were higher than at diagnosis in the SS group. Other significant findings included less hypoxia on admission (9.2 vs. 29.3%, p=0.002, OR=0.25) as well as less oxygen use (45.1 vs. 64.2%, p=0.008, OR=0.46) and less transfusion support (31.0 vs. 72.3%, p=0.001, OR=0.17) documented during hospitalization in the SC group. Despite the more frequent history of asthma and complaint of wheezing on presentation in the SC group, neither the use of asthma medications nor the duration of oxygen support in those patients who required it differed during episodes of ACS in SC versus SS patients. The frequency of vaso-occlusive pain on admission, transfusion support during hospitalization and time to transfusion also did not differ between the 2 groups. No deaths were recorded in any hemoglobin SC patients, while 1 death occurred in the SS group. There was no significant difference in median length of hospitalization in ACS episodes involving SC versus SS patients (3.0 vs. 4.0 days, p=0.107). A model that included age, baseline hemoglobin, time to transfusion and total days of oxygen support accounted for 75% and 60% of the variation in length of hospitalization in the SC and SS groups, respectively. Age, time to transfusion and duration of oxygen support represented independent contributors in both groups. In conclusion, our data suggest for the first time that asthma and wheezing may represent significant risk factors for ACS more commonly in SC patients when compared to SS patients. Clinical severity, as determined by length of hospitalization, was similar in episodes of ACS involving patients with hemoglobin SC and SS disease. Other markers of clinical severity associated with ACS, such as transfusion and oxygen requirements, appear related to baseline differences in laboratory and clinical presentation between individuals with SC and SS disease. Future studies to definitively evaluate in SC patients the relationship between asthma and ACS, as well as its impact on management of ACS, are warranted.

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Young, Patricia A., Daria Gaut, Davis A. Kimaiyo, et al. "Consolidative High Dose Chemotherapy and Autologous Stem Cell Transplant for Patients with Primary Central Nervous System (CNS) Lymphoma or Non-Hodgkin Lymphoma with CNS Involvement Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen." Blood 132, Supplement 1 (2018): 4611. http://dx.doi.org/10.1182/blood-2018-99-117225.

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Abstract Background Both primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement carry a poor prognosis. While there has been interest in intensification of treatment with high-dose chemotherapy and autologous stem cell transplant (ASCT), the side effect profile and long-term efficacy of consolidative transplant are not yet clear. Our aim was to investigate the efficacy and safety of a conditioning regimen of thiotepa, busulfan, and cyclophosphamide (TBC) (Soussain C., et al, J. Clin. Oncol., 19:742-749, 2001) followed by ASCT in patients with PCNSL or NHL with CNS involvement. Methods A retrospective analysis was performed among consecutive patients undergoing consolidative ASCT with TBC conditioning for PCNSL or NHL with CNS involvement between July 2006 and December 2017. For patients with PCNSL, a uniform induction therapy was given that consisted of rituximab and high dose methotrexate for 2-4 cycles followed by rituximab / cytarabine / thiotepa for 1-2 cycles based on published data (Illerhaus et al, Blood 120, no. 21 (2012): 302). For patients with secondary CNS lymphoma or relapsed disease, a variety of chemotherapy regimens were used at the discretion of the treating physician. Progression-free survival (PFS) was defined from the date of transplant to the date of relapse or any cause of death. Overall survival (OS) was calculated from the date of transplant to death. Results Forty-eight patients with NHL who underwent ASCT with TBC conditioning were identified: 27 patients with PCNSL, 12 patients with secondary CNSL, and 9 patients with relapsed disease with CNS involvement. Twenty-nine patients (60%) were in their first complete response (CR1) at the time of transplant. The median time from diagnosis to transplant was 7.1 months (range 3.7- 144.4). The median follow-up time after transplant was 23.9 months (range 8.6 - 59.6 months). The median time to neutrophil recovery (absolute neutrophil count > 500/uL) and platelet recovery (>20,000 x 103/μL for > 2 consecutive days) were 9 days (range 7-12 days) and 7 days (range 1-40 days), respectively. Four patients were noted to have anemia (hemoglobin decrease >2 g/dL from baseline). Most patients (89.5%) experienced febrile neutropenia and 68.6% were found to have infection. Other common side effects included mucositis (89.5%, 35.4% with grade 3 or higher), electrolyte abnormalities (89.5%), dermatologic sequelae (31.3%), reversible neurotoxicity (18.8%), renal injury (16.7%), and hemorrhagic cystitis (8.3%). Four patients (8.3%) experienced treatment-related mortality, 3 of which had secondary CNSL. No evidence of pulmonary toxicity or veno-occlusive disease was noted. The 1-year PFS was 78% (95% CI 63.3%-88.0%), and 1-year OS was 80.5% (95% CI 66%-89.8%). When analyzed according to primary diagnosis, 1-year PFS was 82.6% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.69). According to diagnosis, 1-year OS was 87% for PCNSL, 70% for secondary CNSL, and 75% for relapsed disease with CNS involvement (p = 0.47). Univariate analysis was performed to analyze gender, ethnicity, age > 60, Karnofsky score ≥ 80, diagnosis, cell of origin, and transplant in CR1 versus CR2 or partial response as independent predictors of PFS and OS. Only age (p = 0.001, 95% CI 1.9-42.6 for PFS; p = 0.030, 95% CI 0.99-23.42 for OS) and Karnofsky score ≥ 80 (p = 0.017, 95% CI 0.07-0.81 for PFS; p = 0.047, 95% CI 0.06-1.03 for OS) were found to be significant. Conclusion High dose chemotherapy and autologous stem cell transplant using TBC conditioning for PCNSL and secondary CNSL appears to have encouraging long term efficacy with manageable side effects. Future studies looking at longer follow-up periods and comparison with other conditioning regimens is warranted. Disclosures Schiller: Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding.

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Roboz, Gail J., Hartmut Döhner, Marco Gobbi, et al. "Results from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 815 Patients with Treatment Naïve (TN) AML Unfit for Intensive Chemotherapy (IC) ASTRAL-1 Study: Analysis By Number of Cycles." Blood 134, Supplement_1 (2019): 2591. http://dx.doi.org/10.1182/blood-2019-127253.

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Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs Treatment Choice (TC) with azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The primary ITT results were previously presented (Fenaux et al, EHA abstract S879, 2019). Clinical guidelines for single agent HMAs recommend a minimum of 4 to 6 treatment cycles for maximum benefit. We describe here the results of the study based on number of treatment cycles administered. M ethods: TN-AML patients ineligible for IC due to age ≥ 75 y, or coexisting morbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard dose/schedule. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. Complete response (CR) and overall survival (OS) were co-primary endpoints. We analyzed patients' characteristics, number of treatment cycles, reasons for treatment discontinuation, CR, and OS including analyses by number of cycles received including prospective subgroups, and OS analyses of responders and non-responders. Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥75 y in 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), and poor risk cytogenetics in 34.3% vs 34.6%. Most patients were assigned to an HMA at randomization (759, 93%) with only 56 patients (7%) randomized to receive LDAC. Both CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were similar and not significantly different between G and TC. Many patients in both arms did not receive the recommended minimum of 4 cycles (42.4% vs 40.8% for G vs TC respectively), or 6 cycles (54.2% vs 53.8% for G vs TC). The proportions were well balanced between the 2 treatment arms. Characteristics of patients who received at least 4 or 6 cycles were also well balanced between the 2 treatment arms for age, PS 2-3, secondary AML, poor risk cytogenetics, BM blasts >30%, and proliferative AML (total white cell count ≥20,000/uL). The primary reasons and proportions for treatment discontinuation were similar for the 2 treatments arms. For patients with <4 and <6 cycles respectively they are, in descending order, early deaths (16.7% and 20.7% of the overall ITT population), progression (7.6% and 11.7%), adverse events (5.8% and 6.9%), and patient decision (5.5% and 7.1%). In patients who received at least 4 cycles more patients achieved CR on G (33.6%) vs TC (28.6%), and median OS was longer on G (15.6 months for G vs 13 for TC, HR 0.78, 95% CI 0.64-0.96, log-rank p 0.02, Fig 1). Similarly, in patients who received at least 6 cycles, there were more CR on G (40.1%) vs TC (36.2%) and median OS was longer on G (19.5 months for G vs 15.0 for TC, HR 0.69, 95% CI 0.54-0.88, log-rank p 0.002, Fig 2). Subgroup analyses of OS in patients who received at least 4 or 6 cycles showed that survival benefit from G over TC was consistent in all prospective subgroups including against each of the 3 TCs (AZA, DEC, and LDAC). OS analyses in patients who received at least 4 or 6 cycles also favored G vs TC in both responders (CR, CRp, CRi, or PR) and non-responders with maximum benefit in patients who received at least 6 cycles (G vs TC OS HR 0.66, 95% CI 0.45-0.96, log-rank p 0.028 for responders, and HR of 0.73, 95% CI 0.53-1.00, log-rank p 0.048 for non-responders). Summary/Conclusions: In a large global 815-patient randomized study of G vs TC composed mainly of first generation HMAs, G was at least as effective as TC based on the primary ITT analysis of CR and the narrow 95% CI of OS HR (0.83-1.14). Analyses of patients by number of treatment cycles showed that those who received at least 4 or 6 cycles achieved longer OS in G vs TC with the largest benefit in those who received at least 6 cycles. The benefit was observed in all subgroups, and in both responders and non-responders. Treatment with single agent guadecitabine should continue as long as the patient can still benefit and for at least 6 cycles to gain the maximum survival benefit. Disclosures Roboz: Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Krauter:Pfizer: Honoraria. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding. Novak:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations. Jedrzejczak:Takeda: Consultancy; Amgen: Consultancy, Other: travel support for hematology meetings; Celgene: Other: travel support for hematology meetings; Novartis: Research Funding; Roche: Other: travel support for hematology meetings. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Brandwein:Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Novartis: Consultancy, Honoraria. Demeter:Angelini: Other: Advisory Board; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Bristol Myers Squibb: Other: Advisory Board; Amicus: Other: Advisory Board; Amgen: Other: Advisory Board; Roche: Other: Advisory Board. Griffiths:Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Yee:Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Perumbeti, Ajay, Tomoyasu Higashimoto, Fabrizia Urbinati та ін. "Correction of Sickle Cell Anemia with γ-Globin Gene Delivered by Lentivirus Vector in the Setting of Myeloablative or Reduced Intensity Conditioning, and Establishing Critical Determinants for Successful Gene Therapy for Sickle Cell Disease." Blood 112, № 11 (2008): 2354. http://dx.doi.org/10.1182/blood.v112.11.2354.2354.

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Abstract While genetic delivery of recombinant anti-sickling β-globin genes have been shown to correct murine sickle cell anemia (SCA), correction of SCA by delivery of a natural hemoglobin, fetal hemoglobin (HbF), the proportion of genetically modified hematopoietic stem cells (HSC), or amount of HbF necessary to correct the disease is unknown. We designed a lentivirus vector carrying γ-globin exons with β-globin regulatory elements and non-coding sequences, GbG. First, GbG or mock transduced Berkeley sickle HSC were transplanted using a myeloablative (lethal irradiation) transplant model, to acheive full donor chimerism. GbG mice showed high HbF expression (HbF 41 ± 5% measured by HPLC) that was sustained in primary (6 mo) and secondary (7.5 mo) transplant recipients, and resulted in effective correction of hematological and functional RBC parameters, and reduction of inflammation that results from sickle cell disease. We found significantly reduced irreversibly sickled cells (2.3 ± 0.7% in GbG versus 10.2 ± 0.3% in mock mice; p<0.001), minimal sickling of RBC when exposed to graded hypoxia using tonometry, improved RBC deformability (performed by ektacytometry), and a four-fold increase in RBC half-life (by in vivo biotin labeling) in the GbG group of mice. There was correction of anemia, and reduction in hemolysis (measured by LDH levels), reticulocytes, and leukocytosis (Table 1). This was accompanied by a dramatic improvement in chronic organ damage that is seen in untransplanted Berkeley/mock group of mice: there was a significant reduction in spleen weights and normalization of splenic follicular architecture, correction in bone marrow myeloid:erythroid ratios, and a notable absence of kidney infarction and atrophy, and liver infarction and extramedullary hematopoiesis that was observed in mock mice. Untransplanted Berkeley and mock mice showed shortened survival consistent with a severe SCA phenotype. Genetic correction with GbG improved survival to 100% compared to a 20% survival in the mock transplanted. Notably, in our proof-of principle studies, comparable functional sickle RBC correction was also seen in the Townes knock-in sickle mice (Wu et al, Blood 2006) transduced with GbG. Myeloablative conditioning in this setting allowed non-competitive repopulation of donor genetically modified HSC, resulting in high HbF and correction of disease. However, myeloablation in SCA is associated with peri-transplant mortality and long-term effects, and may not be necessary for achieving correction of phenotype. To address this, we used a unique reduced-intensity conditioning transplant model. We transplanted GbG-modified Berkeley HSC into sub-lethally irradiated Berkeley mice. In this model, when HbF was <10%, there was a small and variable improvement in hematological and functional sickle RBC parameters. However, when HbF was γ10%, there was consistent long-term correction in RBC sickling, deformability, RBC survival, and improvement in hematological parameters for 10–11 months (Table 1). Impressively, when HbF was γ10%, there was a significant reduction in splenomegaly, absence of liver and kidney pathology, and a dramatically improved overall survival of the mice, comparable to that seen in the myeloablative model. Comparison of the proportion of F-cells (HbF containing RBC) and HbF/F-cell to the assays showing correction of SCA revealed that >30% HbF/F-cell and >60% F-cells consistently corrected SCA. The mean HSC transduction (assessed by secondary HbF+ CFU-S at 6 months post transplant) was 50% and 30% in the myeloablative and reduced intensity transplant models, respectively, with 1–3 GbG copies/ cell. Furthermore, three GbG mice showed correction of SCA with 20% HSC transduction, a clinically achievable goal. Taken together, this study is the first demonstration of correction of SCA with gene therapy using γ-globin, and defines critical determinants for effective gene therapy of this disease. Mouse Model Hb (g/dl) RBC 106/ul) Reticulocyte (%) WBC (K/ul) *p<0.05; ** p<0.001 Mock Myeloablative 7.6±0.7 5.8±0.4 40.0±3.0 29.7±1.4 GbG Myeloablative 10±0.8* 9.4±0.8** 15.8±3.2** 10.6±3.1** GbG, HbF ≥ 10% Reduced intensity 9.3±0.6* 8.1±0.5** 21.2±1.9** 13.4±1.1**

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Hsieh, Matthew, Kay Chin, Beth Link, et al. "Benign Ethnic Neutropenia in Individuals of African Descent: Incidence, Granulocyte Mobilization, and Gene Expression Profiling." Blood 106, no. 11 (2005): 3069. http://dx.doi.org/10.1182/blood.v106.11.3069.3069.

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Abstract Introduction: Benign ethnic neutropenia (BEN) is a condition observed in individuals of African descent, and is characterized by a reduced absolute neutrophil count (ANC) less than 1500/uL in the absence of secondary causes. In contrast to other causes of neutropenia, BEN does not increase risk of oral or systemic infections. BEN has been described in up to 40% of certain ethnic groups, but its incidence in African Americans is unknown. Additionally, the pathogenesis is currently unknown. Through this study, we wish to determine the incidence of BEN, compare the neutrophil increment after dexamethasone (Dex) and granulocyte-colony stimulating factor (G-CSF), and compare peripheral blood (PB) granulocyte gene expression profiles by microarray and PB protein array to controls in order to better understand BEN. Methods: Complete blood count (CBC) data were obtained from the National Health and Nutrition Examination Survey (NHANES) III. White blood cell and absolute neutrophil counts were compared in non-Hispanic whites, non-Hispanic blacks, Mexican-Americans, and others. Normal volunteers of African descent were recruited through an IRB approved study at NIH. Each volunteer underwent three PB leukaphereses: baseline, one day after 8mg of Dex, and one day after 5ug/kg G-CSF. CBCs were measured before and after each drug treatment. Granulocytes were enriched by gravity sedimentation with 6% hetastarch, hypotonic saline lysis of erythrocytes, and density gradient centrifugation using Ficoll-Pague. Granulocyte mRNA were applied to Affymetrix U133 plus 2.0 chips following extraction using a phenol-chloroform based method (RNA Stat 60, Tel-Test) and DNA removal. The gene expression pattern of BEN was compared to that of normals (ANC >4000/uL). Results: The NHANES III sample size included 25,925 individuals. Mean ANC for the each ethnic groups were 4.55 (white), 3.67 (black), 4.80 (Mex-Am), and 4.52 (others) k/uL. The incidence of neutropenia (<1500/uL) was 0.25% (white), 4.05% (black), 0.35% (Mex-Am), and 0.98% (others). Our local incidence of BEN was 5.7% (4 of 70 volunteers screened). The mean WBC in our BEN were 4.13 +/− 0.72 (baseline), 8.57 +/− 0.59 (Dex), and 16.9 +/− 2.3 (G-CSF) k/uL, compared to those of normals, 7.56 +/− 0.95 (baseline), 12.17 +/− 2.13 (Dex), and 29.22 +/− 4.8 (G-CSF) k/uL. The absolute neutrophil increment of BEN volunteers was 4.95 k/uL (94.7% of neutrophil increment in normal volunteers) after Dex, and 12.7 k/uL (60.2% of normal) after G-CSF. Gene expression profile comparisons showed that at baseline, several genes were upregulated more than 10 fold in BEN, including apoptotic factors, metalloproteases 8 and 13, TREML 3&4, TGF-beta, and endothelial factors (endothelin 1, endothelin receptor B, and fibroblast growth factors). These differences were less pronounced after Dex or G-CSF. Additionally, gene expression pattern is markedly different after Dex vs. G-CSF, regardless of the neutrophil count. Conclusions: Our results establish the incidence of BEN in the US at approximately 4%, significantly lower than that suggested by prior small reports. Additionally, the neutrophil increment is much lower in BEN following stimulation with G-CSF, suggesting the mechanism of granulocyte mobilization differs between Dex and G-CSF. Neutrophil mRNA in BEN showed increased expression of apoptotic, endothelial, and some leukocyte specific transcripts. Real-time PCR of candidate genes, accrual of more BEN subjects, and analyses of protein array are ongoing.

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Sorror, Mohamed, Michael Maris, Barry Storer, et al. "Nonmyeloablative Conditioning and Hematopoietic Cell Transplantation (HCT) from HLA-Matched Related or Unrelated Donors for Chemotherapy-Refractory Chronic Lymphocytic Leukemia (CLL)." Blood 104, no. 11 (2004): 2323. http://dx.doi.org/10.1182/blood.v104.11.2323.2323.

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Abstract Sixty-four patients (pts) with chemotherapy-refractory CLL who were ineligible for ablative allogeneic HCT due to age and/or comorbidities were given nonablative-HCT from related (n=44) or unrelated donors (n=20) between 1997-2003 (Table). Median pt age was 56 (range 44–69) years, interval from diagnosis to HCT was 4.4 (3–25) years, and number of prior regimens was 4 (range 1–12). Sixty-one pts were refractory to at least 1 regimen, 56 to fludarabine (FLU), 19 to alkylating agents, 14 to rituxumab and 4 to CAMPATH, and 2 had failed autologous HCT. Twenty-three pts (36%) had disease responsive to last chemotherapy [28% partial (PR) and 8% complete remission (CR)] while 34 were nonresponsive and 7 had untested relapse. Conditioning for HCT consisted of 2 Gy TBI alone (n=11) or combined with FLU (n=53), 90 mg/m2. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Pts received G-CSF mobilized peripheral blood mononuclear cells. After HCT, pts became neutropenic for a median of 11 days. Forty-four percent of pts had thrombocytopenia (<20,000 cells/ul). Three pts had graft rejection; 1 died with aplasia and 2 are alive with disease relapse. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic GVHD was 50% at 2-years. With median follow up of 24 (range 2.8–62.8) months, the overall response rate was 67% (50% in CR). URD-pts had significantly higher CR rate than MRD-pts. All 11 responding patients tested had molecular eradication of their disease. Overall, 39 patients are alive; 25 in CR, 5 in PR, 2 with stable disease, and 7 with relapse/progression. Twenty-five pts died, 10 from progression, 10 from infections ± GVHD, 2 from cardiac causes, 1 from metastatic lung cancer, 1 from cerebral stroke and 1 from rejection and aplasia. Estimated 2-year rates of non-relapse mortality, disease free survival, and overall survival were 22%, 52%, and 60% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher non-relapse mortality and worse survival while bulky lymphadenopathy predicted increased risk of progression. CLL appears susceptible to graft-versus-leukemia effects particularly after URD grafts and nonablative-HCT should be explored in phase II trials in pts with FLU-refractory CLL. Table: Results Related (n = 44) Unrelated (n = 20) P Acute GVHD grade II, III, and IV 39%, 11%, and 2% 40%, 20%, and 0% 0.41 2-year chronic extensive GVHD 44% 69% 0.56 Median follow up (range) 31 (3–63) months 12 (3–39) months CR at 2-years 42% 78% 0.005 Relapse/progression at 2 years 34% 5% 0.08 Surviving pts 13 CR, 3 PR, 2 stable, 5 progression, 1 relapse 12 CR, 2 PR, 1 relapse 2-year non-relapse mortality 22% 20% 0.75 2-year disease free survival 44% 75% 0.15 2-year overall survival 56% 74% 0.33

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Kang, Elizabeth M., Matthew Hsieh, Jonathan D. Powell, et al. "A Novel Allogeneic Transplant Conditioning Regimen Designed for Tolerance Induction in Patients with Severe Sickle Cell Disease." Blood 106, no. 11 (2005): 5429. http://dx.doi.org/10.1182/blood.v106.11.5429.5429.

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Abstract Allogeneic transplantation of hematopoietic stem cells remains the only curative approach for patients with sickle cell disease (SCD), yet procedural toxicities and graft-versus-host disease limit this approach to children. We chose a low-dose radiation approach utilizing rapamycin based upon its unique ability to promote T cell tolerance even when T cells are stimulated in the presence of costimulation (Powell, et al, J Immunol. 1999). We confirmed this approach in vivo in a murine bone marrow transplantation model comparing a short course of conventional immunosuppression with cyclosporine to that with rapamycin, with long-term, high-level chimerism attained only in mice treated with rapamycin (Powell et al., manuscript submitted). We have now begun accrual to an IRB approved clinical trial testing this approach in adults with SCD and herein report the results in our first two subjects. Protocol entry criteria include those previously reported (Walters, et al, NEJM, 1996) with the addition of pulmonary hypertension defined as a tricuspid-regurgitant jet velocity (TRV) > 2.5 m/s (Gladwin et al, NEJM, 2004). Additionally, patients must have failed a 6-month course of hydroxyurea. The conditioning regimen consists of a single radiation dose of 300cGy, alemtuzumab (1mg/kg total), and oral rapamycin targeting trough levels between 10–20 ng/ml. The graft consists of unmanipulated mobilized peripheral blood progenitors obtained from an HLA-matched sibling. The first patient is a 24-year-old female referred due to recurrent transient ischemic attacks and strokes despite chronic exchange transfusions. Her initial evaluation was notable for evidence of significant hemolysis with a total bilirubin of 9.8 mg/dl, an LDH 1,172 units/L (range 113–226), an absolute reticulocyte count of 318,000/uL and an undetectable haptoglobin. Cardiac doppler-echocardiogram revealed a TRV of 3.7 m/s, consistent with severe pulmonary hypertension. The conditioning was well tolerated and the patient did not require parenteral antibiotics or nutritional support. Assessment of donor chimerism, measured by microsatellite PCR and hemoglobin electrophoresis, revealed an early peak of myeloid chimerism which has stabilized at approximately 60%, with lower levels of lymphoid chimerism at approximately 5–10% now more than 300 days post-transplant. Hemoglobin levels stabilized at 11–12 g/dL, without detectable sickle hemoglobin, now allowing for therapeutic phlebotomy. Remarkably, the LDH and TRV fell concurrently toward the normal range. Patient 2 is a 26 year old male with frequent crises requiring hospitalization twice monthly. At one month post-transplant, myeloid chimerism is 97%, with lymphoid chimerism currently unmeasurable due to lymphopenia, and similar to that seen in patient 1 at the same time point. Patient 2 also required neither parenteral antibiotics nor nutritional support. Finally, neither patient to date has developed any symptoms or signs of either acute or chronic GVHD. Thus with two patients accrued to date, we have demonstrated the ability of allogeneic HSC transplantation to achieve mixed hematopoietic chimerism without the development of GVHD and for the first time, established the reversibility of the associated pulmonary hypertension.

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Takeshita, Masataka, Risen Hirai, Akira Tanimura, Miki Nakamura, Shotaro Hagiwara, and Akiyoshi Miwa. "Application of Hematopoietic Progenitor Cell Count: To Optimize Peripheral Blood Stem Cell Harvest." Blood 124, no. 21 (2014): 5837. http://dx.doi.org/10.1182/blood.v124.21.5837.5837.

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Abstract background. High dose therapy and autogenic or allogeneic stem cell transplantation plays an important role in the treatment course of hematological malignancies. In some countries, major method of unrelated stem cell donation programs had shifted from bone marrow harvest (BM) to peripheral blood stem cell harvest (PBSCH). PBSCH is a heavy duty not only for donor or patient, also for medical staffs. In some cases, poor mobilization may cause poor collection of stem cells. Hemogram needs time for May-Giemsa stain, and CD34 count needs complicated technique and running cost. New simple tool to predict the count of mobilized stem cell is needed to optimize PBSCH. methods. Since 2009, we started measuring peripheral blood hematopoietic progenitor cell (HPC) with Sysmex XE-5000(R) blood cell counter. With IMI channel method, we could rapidly know the count of circulating stem cells. Daily HPC count and yielded CD 34 positive cell count were analyzed. results. 189 samples were collected from 122 donors/patients. Diagnosis of patients: malignant lymphoma (n=29), leukemia (3), multiple myeloma (74), amyloidosis (5), cryoglobulinemia (1). 10 healthy donors were also included. Age: 18-66, Sex: male 82/female 40. Mobilization regimen: G-CSF 57, chemo+G-CSF 74, G-CSF+plerixafor 1 HPC count (cells/ul) and collected CD34 positive cells (106cells/kg) had positive correlation. When HPC count was above 25/ul, collected CD34 positive cells were above 1x106/kg (positive predictive value: 80.9%). Number of PBSCH operation was 1.59 in average. We also show three cases in which HPC count was useful to make clinical decision of initiating PBSCH. discussion. HPC and CD34 had positive correlation, and HPC >25/ul seems to be appropriate cut-off to start PBSCH. With our former threshold of PBSCH (G-CSF day>4, WBC >3000/ul), 241 operations were to be planned. Including HPC count, we could reduce PBSCH operation to 204. Hematopoietic progenitor cell count is rapid and inexpensive method. Within 5 minutes, mobilized stem cells can be measured, and it may be also useful in outpatient-based harvest settings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Nguyen, Julia, Fuad Abdulla, Chunsheng Chen, et al. "Phenotypic Characterization the Townes Sickle Mice." Blood 124, no. 21 (2014): 4916. http://dx.doi.org/10.1182/blood.v124.21.4916.4916.

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Abstract The HbSS-Townes mouse model, developed in Dr. Tim Townes laboratory, University of Alabama, Birmingham (and kindly provided by him to our laboratory) were created on a mixed genetic background in which the murine adult α-globin genes were replaced with the human α-globin gene (genotype: Hba hα/hα) and the murine adult β-globin genes were replaced with human sickle βS- and fetal Aγ-globin gene fragments linked together (genotype: Hbb hAγβS/hAγβS) (Wu LC et al. Blood 2006;108: 1183-1188). HbSS-Townes mice have anemia, a shortened RBC half-life of 2.5 days and a severe disease phenotype. Control HbAA-Townes mice were created by replacing the murine globin genes with human α-globin gene (genotype: Hba hα/hα) and linked human βA- and fetal Aγ-globins (genotype: Hbb hAγβA/hAγβA), while HbAS-Townes heterozygous mice were developed by breeding HbAA and HbSS mice. Many laboratories are utilizing these mice but complete phenotypic description of these three models has not been described including: hematology, kidney and liver function, inflammatory markers, haptoglobin and hemopexin levels, red cell half-lives, organ histopathology and vascular responses to vaso-occlusive stimuli. Table 1 summarizes our findings. There was a clear difference in histopathology between the HbSS and other groups (HbAA and HbAS). HbSS mice had hepatic necrosis, increased erythropoiesis and increased hemosiderin within the liver and some subtle lesions involving the glomeruli in the kidneys. Additional findings were a marked increase in size of spleen (7.0-7.6 x by % body weights) attributed to severe congestion and increased erythropoiesis. No lesions were observed in the lungs and other tissues. The tissues evaluated in the HbAS and HbAA groups were essentially normal. In contrast, HbSS mice had multifocal irregular areas of necrosis within the liver, with reactive leukocyte infiltrates (mainly neutrophils in the more acute lesions with a greater proportion of mononuclear cells (macrophages etc.) in more chronic lesions. MPO immunohistochemistry confirmed the presence of neutrophils in the liver. There was a substantial increase in iron (and hemosiderin) in the livers of HbSS mice, confirmed by a Prussian Perls stain and low, but detectable, levels of iron in the proximal convoluted tubules of the kidney. This is consistent with increased red cell turnover in the HbSS mice. Total iron mass in the markedly enlarged spleen is very high. There is a somewhat subtle glomerulopathy present in the kidney, with enlarged glomeruli with variable ectasia of vessels, and mesangial derangement. In conclusion the Townes mouse models provide a spectrum of severe hemolytic disease that in many ways mimic the human disease albeit imperfectly. TableTable 1 HbAAHbASHbSSHb (g/dL)12.0 ± 0.610.6 ± 0.59.5 ± 1.4*Hematocrit (%)49.6 ± 2.345.0 ± 4.2*29.2 ± 0.9*#WBC (K/µL)10.8 ± 1.213.2 ± 4.038.2 ± 4.9*#Platelet Counts (K/uL)854 ± 78889 ± 1421004 ± 179Monocytes (%)8.0 ± 1.17.6 ± 1.77.4 ± 1.0Lymphocytes (%)60 ± 3.063.8 ± 5.667.5 ± 9.1Neutrophils (%)28.6 ± 5.926.1 ± 8.727.8 ± 2.2Reticulocytes (%)7.8 ± 1.78.6 ± 4.556.8 ± 2.6*#RBC Half-Life (days)15.710.62.4Expired CO (nmoles/h/g)0.92 ± 0.241.27 ± 0.236.33 ± 1.08*Serum Bilirubin (mg/dl)3.5 ± 0.94.3 ± 0.65.6 ± 0.4*Urine Creatinine (mg/dL)44.1 ± 3.845.9 ± 3.856.2 ± 7.0*Urine Osmolality (mOsm/kg H2O)2147 ± 761707 ± 2651361 ± 32*Serum Haptoglobin (µg/ml)39.3 ± 3.80.5 ± 0.2*2.3 ± 1.4*Serum Hemopexin (µg/ml)802 ± 266169 ± 51*124 ± 35*Serum SAP (µg/ml)20.9 ± 7.214.1 ± 12.086.7 ± 20.2*#Stasis at 1h in Response to Hb (%)10.0 ± 3.219.8 ± 2.7*30.0 ± 3.4*#Mortality at 24h in Response to Heme (%)00100*#Liver % of Body Weight4.95 ± 0.484.39 ± 0.356.22 ± 0.21*#Spleen % of Body Weight0.79 ± 0.140.87 ± 0.396.61 ± 0.75*#Kidney % of Body Weight0.65 ± 0.270.72 ± 0.190.73 ± 0.24Liver Necrosis Score0.0 ± 0.00.25 ± 0.502.38 ± 0.25*Liver Fe Score0.0 ± 0.00.25 ± 0.53.0 ± 0.0*Lung Fe Score0.0 ± 0.00.0 ± 0.0*1.0 ± 0.0*#Spleen Fe Score3.0 ± 0.03.0 ± 0.02.0 ± 0.0*#Kidney Fe Score0.0 ± 0.00.25 ± 0.51.75 ± 0.5*#Liver Gr1 Score1.0 ± 0.01.25 ± 0.52.25 ± 0.5*Lung Gr1 Score1.0 ± 0.01.0 ± 0.01.25 ± 0.5Spleen Gr1 Score1.5 ± 0.62.0 ± 0.02.0 ± 0.0Kidney Gr1 Score0.25 ± 0.50.25 ± 0.50.75 ± 0.5* p<0.05 vs HbAA; # p<0.05 vs HbAS Disclosures No relevant conflicts of interest to declare.

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Cisneros López, Migleth, Bella Maldonado Guerrero, Aníbal Bonilla Núñez, Andrés Gonzalez Cabrera, and Jessica Andrade Rada. "Caso Clínico: Citopénia Autoinmune como complicación inmunológica de Trasplante Alogénico de Donante no emparentado, en paciente pediátrico con Anemia Drepanocítica." Oncología (Ecuador) 29, no. 3 (2019): 189–98. http://dx.doi.org/10.33821/462.

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Introducción: La enfermedad de células falciformes es una condición heredada en la que se produce una hemoglobina anómala que desfavorece a la oxigenación tisular, crisis vaso-oclusivas y reacciones hemolíticas. Los pacientes con esta enfermedad presentan una activación anómala de la vía del complemento llevándolos al aumento en frecuencia de infecciones y enfermedades autoinmunes. Presentamos un caso de asociación de una enfermedad autoinmune en un paciente con enfermedad de células falciforme. Caso clínico: Niño de 10 años con Anemia drepanocítica (2009) con esplenectomía y crisis veno-oclusivas recurrentes, fue sometido a trasplante Alogénico en abril del 2019 fuera de la institución con donante isogrupo O+ no emparentado (10/10). Tratado con: Fludarabina – Busulfan, Timoglobulina+ y Metotexate. Desarrolló Bicitopenia autoinmune y síndrome febril al día +165 post TPH. Glóbulos blancos: 360 uL, neutrófilos: 14 %, hemoglobina: 7.90 g/dL, plaquetas: 25000 uL, ferritina: 4695 ng/ml, IgG total: 9.88 gr/l, LDH: 190 UI/l. Proteína C reactiva: 2.79 mg/dL, procalcitonina 0.13 ng/mL. Evolución: posterior a descartar infección viral, se completó un tratamiento antibiótico de amplio espectro y se realizó la suspensión del tratamiento inmunosupresor por sospecha de toxicidad, sin respuesta. Se realizó un estudio medular por citometría de flujo determinando una disminución de la línea linfoide B, y se concluye Citopénia autoinmune como complicación inmunológica del trasplante. Desenlace: recibió terapia transfusional (plaquetoferesis + glóbulos rojos concentrados). Se utilizó metilprednisolona IV por 3 días y prednisona 30 mg por 14 días con reducción posterior gradual para inicio de Rituximab y ciclosporina. Se completó el tratamiento con Imnunoglobulina 6g IV por 5 días. Al alta glóbulos blancos: 5080 uL, neutrófilos: 67%, hemoglobina: 9.20 g/dL, plaquetas: 20000 uL, después de 18 días de ingreso hospitalario. Conclusión: Los resultados con el tratamiento en este caso sugieren que puede ser razonable considerar las citopenias autoinmunes como una manifestación hematológica diagnóstica de la EICH crónica. Alternativamente, es posible que el tratamiento de citopenia inmune con esteroides, rituximab y otros inmunosupresores.

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Case, D. C., M. A. Boyd, J. A. Hedlund, and T. J. Ervin. "Gemtuzumab ozogamicin for treatment of relapsing/refractory acute myelogenous leukemia (AML)." Journal of Clinical Oncology 24, no. 18_suppl (2006): 16531. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.16531.

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16531 Background: Gemtuzumab ozogamicin is a calicheamicin-conjugated anti-CD 33 monoclonal antibody studied and utilized in relapsed and refractory acute myelogenous leukemia. Methods: At our center we treated a series of refractory patients (<60 years old) and relapsed patients (>60 years old) with gemtuzumab ozogamicin over a 3 year period. We treated 20 patients: 14 males and 6 females with an age range of 21 to 77 years (median 64 years). Seven patients were refractory to multiple regimens (<60 years old) and 13 were relapsing from initial therapy (>60 years old). Cytogenetic analysis revealed 60% were intermediate-risk and 40% were poor-risk. The goal of therapy was complete remission (≤ 5% leukemia blast cells in the marrow. ≥ 9 g/dl hemoglobin, ≥1500/ul absolute neutrophil count, and platelet count ≥100,000/ul). Patients received gemtuzumab ozogamicin 9 mg/m2 I.V. days 1 and 5. All patients received at least one dose. Patients achieving complete remission were eligible to receive monthly doses of gemtuzumab ozogamicin after complete remission was obtained. Results: Of the 7 refractory patients (<60 years old), there were no complete remissions. Of 13 relapsing patients (>60 years old) there were 2 complete remissions. One patient was 64 and the other 67 years old. Both remissions lasted 2 months. All patients were treated in the hospital. Chills/fever with treatment occurred in 40% of patients. Fever/neutropenia was universal. Thirty percent had elevation of liver function tests. Conclusions: Gemtuzumab ozogamicin as a single agent is capable of producing complete remission in a small number of relapsing patients >60 years old. Remissions are short. No significant financial relationships to disclose.

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George, Biju, Auro Viswabandya, Ansu Abu Alex, et al. "The Addition of Meloxicam to G-CSF Is Associated with Good Mobilization Rates, Faster Engraftment and Reduced Toxicity and Hospital Stay after Autologous Stem Cell Transplantation – a Phase II Study." Blood 124, no. 21 (2014): 2455. http://dx.doi.org/10.1182/blood.v124.21.2455.2455.

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Abstract Mobilization failure is seen in 10-15% of patients undergoing G-CSF or Chemo mobilization and the use of plerixafor is limited by its cost in developing countries. This phase II study is being undertaken to study whether the addition of Meloxicam to standard G-CSF will improve rates of mobilization (CTRI/2014/06/004671). After informed consent, patients received Meloxicam 15 mg once daily for 5 days from Day -7 to -3 and G-CSF 5 ug/kg BD from Day -4 to -1. Peripheral blood stem cell harvest was performed on Day 0 and on the following day is the initial harvest CD34 dose was < 4 x 106 CD34/Kg. Patients with myeloma proceeded immediately to an autologous transplant (auto SCT) with Single agent Melphalan conditioning while patients with lymphoma and acute myeloid leukemia had cryopreservation of harvest and then proceeded with transplant using either BEAM or BuCy2 conditioning. Between November 2013 till July 2014, 25 patients (20 males and 5 females) with a median age of 51 years (range: 25-63) received meloxicam with G-CSF. There was no toxicity in any of the patients during the 5 days of administration of meloxicam. A cell dose of > 2 x 106 CD34/kg was achieved in 21 (84%) with a cell dose of > 3 x 106 CD34/kg being achieved in a single harvest in 15 (60%). Four patients needed additional cyclophosphamide mobilization to achieve the target cell doses. Analysis of peripheral blood CD34 counts revealed that 20 (80%) had counts > 20/ul on Day 0 [median count of 65.5/ul (range: 21.1 – 313.02) and of these 15 (60%) had achieved counts of > 20/ul on Day -1 itself [median count of 45.3/ul (range: 21.4 – 130.2)]. None of the patients had toxicity related to meloxicam. Subsequently 21 patients underwent auto SCT and their data was compared with 50 age and disease matched controls who had mobilization and auto SCT at our centre between January 2013 and March 2014. Though mobilization rates and cell doses were not significantly different, the use of meloxicam and G-CSF was associated with faster neutrophil engraftment. Following auto SCT, there was lower Grade III – IV toxicity, lower transfusion requirement of red cells and reduction in the duration of hospital stay post SCT [Table 1]. Conclusion: The addition of meloxicam to G-CSF improves stem cell mobilization and is associated with faster engraftment, no additional toxicity, lower supportive care and lower duration of hospitalization. It is also potentially possible that we may be able to harvest the patients a day earlier depending upon the peripheral blood CD 34 counts achieved. This data warrants a prospective randomized trial comparing Meloxicam + G-CSF with G-CSF alone as a mobilization strategy prior to autologous stem cell transplantation. Table 1 – Comparison of demographic data, mobilization characteristics and post transplant outcome in patients using meloxicam + G-CSF compared with historical controls Abstract 2455. Table 1VariablesMeloxicam + GCSF (n = 25)G-CSF alone (n = 50)P valueMedian age (years)51 (25 – 63)50 (18 -65)0.902Sex M: F20: 536:140.577Diagnosis MM NHL/HD APML/AML15 (60%) 8 (32%) 2 (8%)32 (64%) 14 (28%) 4 (8%)Successful mobilization (> 2 x 106 CD34/kg after 2 harvets)21 (84%)42 (84%)1.000CD 34 > 5 x 106 /kg12 (48%)18 (36%)0.138CD 34 > 3 x 106/Kg20 (80%)32 (64%)0.191Conditioning regimen High dose Melphalan BEAM Bu/Cy215 (60%) 8 (32%) 2 (8%)32 (64%) 14 (28%) 4 (8%)ANC > 500/cumm (days)11.09 + 0.5311.53 + 0.920.044ANC > 1000/cumm (days)11.61 + 0.4511.95 + 0.990.216Platelet count >20000/cumm (days)14.7 + 4.516.4 + 6.30.291Platelet count >50000/cumm (days)17.4 + 7.524.7 + 19.30.143Platelet count >100000/cumm (days)23.1 + 11.951.2 + 58.20.025Number of red cell units transfused1.19 + 1.12.31 + 2.450.031Number of platelet units transfused12 + 9.117 + 160.327No of pts with Grade III-IV toxicity7/21 (31.8%)33/47 (59.5%)0.040Duration of hospital stay from day 0 (days)16 + 3.320 + 7.30.025 Disclosures Srivastava: Octapharma: Consultancy, Other.

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Journal articles on the topic 'G 60 UL 2009'

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