Academic literature on the topic 'B 20.5 UL 2013 V897'

Immune thrombocytopenia (ITP) is an acquired thrombocytopenia due to autoantibody-mediated destruction of platelets. Multiple therapies targeting antibody production, the reticuloendothelial system and platelet production are used to treat ITP, including glucocorticoids, intravenous immune globulin (IVIG), Rituximab, splenectomy and thrombopoietin-receptor agonists. The response to therapy is heterogeneous, supporting the concept that multiple mechanisms are ultimately responsible for thrombocytopenia. In vitro complement fixation assays have shown that serum obtained from 50% of patients with ITP is able to fix complement to the platelet surface. Autoantibodies to platelet surface antigens GPIIb/IIIa and/or GPIb/IX have also been shown to activate complement via the classical pathway. We suspect that complement fixation/activation plays an important role in platelet destruction in ITP. Proposed mechanisms include C3b deposition on the platelet surface leading to opsonization, direct damage to platelets by C5b-9, and a role for complement in the imbalance in T-cell regulator/effector activity. T-cell activity has been proposed to stimulate B-cell production of autoantibodies against platelet surface antigens. C1 esterase inhibitor (C1INH) is a member of the serine protease inhibitor family and interacts with C1 esterase to block activation of the classical pathway of complement activation. Case reports have demonstrated that C1INH can prevent C3-mediated lysis of PNH erythrocytes (DeZern 2014) and attenuate hemolysis in a patient with DAT C3d positive autoimmune hemolytic anemia (Wouters 2013). Based on these data, we hypothesized 1) complement activation/deposition may play an important role in persistent thrombocytopenia in refractory ITP, and 2) blockade of the classical pathway with C1INH may lead to prolonged platelet survival. Two female patients with a history of autoimmune disease (systemic lupus erythematosus (SLE) and Sjogren's) and primary refractory ITP [steroids, IVIG, Rituximab, and Romiplostim (23-38 days)] were treated with C1INH, Berinert 20 units/kg. Within 8 hours of first C1INH dose, platelet count improved significantly in both patients. Given the rapid increase in platelet count, each patient received two additional doses of C1INH. Both patients demonstrated a continued increase in platelet count with no further C1NH therapy. In patient 1, platelet count normalized on day 63 and remains normal without additional therapy 194 days post C1INH treatment. In patient 2, platelet count has risen to 568K 14 days after C1INH administration. These cases clinically illustrate a thought provoking relationship between antigen/antibody complexes, complement activation, and platelet destruction in ITP. We suspect a potential biphasic response to C1INH therapy. We hypothesize immediate inhibition of the classical pathway and subsequent decrease of C3b deposition on platelet surface may be responsible for the acute rise in platelet count, while a reset of T-cell regulatory/effector function via complement blockade may be accountable for the longevity of platelet count increase and normalization seen in our patients. Refractory ITP may involve antibody-mediated complement activation via the classical pathway. The destruction of platelets may be driven by C3b-mediated phagocytosis and/or by C5b-9-mediated membrane damage, as well as by modulation of the immune system and T regulator cell function. In our patients, the commercially available C1INH, Berinert, was well-tolerated and platelet count improvement was noted almost immediately after administration and has appeared to be sustained. Future studies evaluating treatments that target inhibition of the complement pathway may be an effective alternative or adjunctive therapy for refractory immune thrombocytopenia. Table 1. Platelet Counts Baseline Diagnosis Prior to 1st C1NH dose 8 hours post 1st C1NH dose Prior to 2nd C1NH dose 8 hours post 2nd C1NH dose Prior to 3rd C1NH dose Post 3rd C1NH dose 7 days post 1st C1NH dose 10 days post 1st C1NH dose 14 days post 1st C1INH dose Patient 162yo F H/O SLE 160 K/UL 0 K/UL 2 K/UL 12 K/UL 5 K/UL 9 K/UL 15 K/UL 30 K/UL 38 K/UL 105/UL 139K/UL Patient 247yo F H/O Sjogren's Unknown 1 K/UL 4K/UL 8K/UL 9 K/UL 18 K/UL 18 K/UL 25 K/UL 122 K/UL 469 K/UL 568 K/UL Disclosures Off Label Use: Berinert and its use in ITP.. Broome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Abstract Hematopoietic progenitor cells (HPCs) collected by apheresis of G-CSF-stimulated donors have surpassed bone marrow as the predominant graft source for hematopoietic stem cell transplantation in adults. Among healthy allogeneic donors, demographic characteristics (age, sex, and BMI) and baseline hematologic parameters have been shown to affect HPC mobilization, leading to significant variability in peak levels of CD34 cell egress into the blood and in quantity of CD34 cells harvested by apheresis. Racial differences in G-CSF-mediated HPC mobilization are less well characterized. Benign physiologic neutropenia is common among healthy African Americans (AAs), and may be due to decreased stem cell reserve, fewer G-CSF receptors, or Duffy (null) blood group antigen-mediated decrease in leukocyte trafficking into the circulation. However, preliminary studies have shown relatively robust CD34+ cell mobilization among non-Caucasians given G-CSF (Vasu et al., Blood 2006). We retrospectively analyzed 1,096 consecutive healthy allogeneic related and unrelated first-time donors who self-characterized their race as AA or Caucasian. They underwent G-CSF (filgrastim, Neupogen, Amgen) stimulated HPC collection by leukapheresis from April 1999 to May 2013. G-CSF dose ranged from 10-16 mcg/kg, given daily for 5 days. An unstimulated leukapheresis procedure for lymphocyte collection was performed in the 7 days preceding G-CSF in 336 subjects. Apheresis procedures were performed on the CS-3000 Plus or COBE Spectra device. Baseline lab data included CBC, serologic blood group antigen typing, and Hb electrophoresis in AA donors. CD34+ cell counts were performed on peripheral blood immediately pre-apheresis (2 hours after the 5th dose of G-CSF) and on the apheresis product. Values are given as mean ± SD. All AA (n=215) and Caucasian donors (n=881) with complete data sets were included. Sex ratio was similar among the groups (45 vs 52% male; p=0.09). AAs were younger (39 vs 43 yrs, p=0.001) and had greater weight (86 vs 81 kg, p=0.001) and BMI (30 vs 27; p<0.0001) than Caucasians. G-CSF dose/kg was similar in the 2 groups, but total daily dose of G-CSF was greater in AAs than Caucasians (920 vs 850 mcg, p<0.0001). After adjusting for age, sex, height, weight, and total daily G-CSF dose, peak CD34+ cell mobilization immediately pre-apheresis was higher among AAs than Caucasians (123 ± 87 vs 75 ± 47 cells/uL; p<0.0001) (Figure). When laboratory parameters such as baseline WBC, MNC, and platelet counts were included in the stepwise regression model, AA race remained a significant predictor of higher peak CD34 cell counts. At higher G-CSF doses (16 mcg/kg/d), the difference in mobilization responses between the 2 groups was less apparent (peak CD34 counts 123 vs 93 cells/uL, AA (n=33) vs Caucasian (n=73), p=0.07) than at lower doses (10 mcg/kg/d), where peak CD34 counts were 123 vs 74 cells/uL, AA (n=182) vs Caucasian (n=808), p<0.0001. AAs had lower baseline ANC (3.4 vs 4.0 x 103 cells/uL, p<0.001) than Caucasians, but demonstrated significantly higher peak WBC and MNC counts after G-CSF. In AA donors with known HbS status, presence of sickle cell trait had no effect on CD34 mobilization (peak CD34 counts 123 ± 91 vs 107 ± 72 cells/uL, HbAS (n=41) vs HbAA (n=84), p=0.34). Similarly, in AA donors with known Duffy phenotype, Duffy expression did not affect CD34 mobilization (peak CD34 counts 114 ± 81 vs 134 ± 85 cells/uL, Fya-b- (n=49) vs Fya+ &/Fyb+ (n=20), p=0.4). Lymph-apheresis prior to starting G-CSF was associated with significantly improved CD34+ cell mobilization; however the effect did not differ by race. CD34 apheresis yield was also greater in AAs than Caucasians (51 ± 35 vs 32 ± 21 x 106 cells per liter processed, p <0.0001), consistent with higher pre-apheresis counts. African Americans demonstrated significantly more robust CD34 mobilization responses to G-CSF than Caucasians. The effect was independent of age, BMI, HbS and other variables, and occurred despite physiologically lower neutrophil counts among AAs. A ceiling effect in response to increased doses of G-CSF (>10 mcg/kg) was seen in AAs but not in Caucasians, suggesting that dose titration based on race might be used to optimize HPC yields. Further evaluation of race-associated genetic polymorphisms in relation to G-CSF pharmacokinetics may help improve G-CSF dosing strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: Currently, there is no consensus regarding diagnosis and treatment of occult lymphomatous menigeal involvement of cerebrospinal fluid (CSF) in patients with systemic non-Hodgkin lymphomas (NHL), especially in patients with minimal number of clonal cells detected by flow cytometry (FCM) or by cytology. Aim of the study: To describe a cohort of patients with occult lymphomatous involvement in cerebrospinal fluid including the diagnostic methods as well as management. Patients and methods: CSF at diagnosis of B-NHL was examined by FCM, cytology, biochemistry and microRNA analysis in a cohort of 62 patients (systemic DLBCL N=45, MCL N=15, Burkitt lymphoma N=2) between 2010 and 2013. Occult meningeal involvement was defined by: a/ FCM: absolute positive number of clonal cells <20 and concomitant negative finding by cytology; b/ FCM negative for clonal cells and concomitant positive finding by cytology; c/ by abundance of increased levels (≥ 200% of the threshold levels) of oncogenic microRNAs (members of miR-17-92 cluster and miR-21, evaulated by Taq-Man RT PCR) in cerebrospinal fluid in patients either passing a/ or b/. The threshold of individual microRNA abundance was defined by statistical analysis of patients with or without CNS involvement. The patients qualified for occult meningeal involvement were considered to be at high risk of CNS relaps. As a control group, the patients with elevated oncogenic microRNAs and negative FCM or cytology of CSF (N=10), were used. All patients received some form of CNS prophylaxis as a part of standard first line treatment. Results and conclusions: According to described criteria we identified 8 patients with occult meningeal involvement at diagnosis (systemic DLBCL N=4, MCL N=3, Burkitt lymphoma N=1) out of 62 patients: 3 with negative FCM and positive cytology (2-14 cells/ul); and 5 with positive FCM <20 clonal cells and negative cytology, 3 out of them with positive microRNAs. None of these patients with occult meningeal involvement relapsed/progressed into CNS within 12 months. In contrast three out of ten control patients (characterized by elevated oncogenic microRNAs in CSF, but negative for FCM and cytology) relapsed to CNS within 6 months after diagnosis. None of ”triple” negative (FCM, cytology, microRNA) patients (N=44) developed clinically manifest CNS involvement. These results suggest that examination of oncogenic microRNA in CSF at diagnosis is more sensitive method than FCM and cytology of CSF to detect the patients with occult CNS involvement and higher risk of CNS involvement and this should be reflected in treatment strategy in further clinical trials. Grants: GACR305 13-12449P, UNCE204021, PRVOUK: P24/LF1/3, P27/LF1/1, P 27/2012 LF3 Disclosures Spacek: Roche: Consultancy, Travel grants Other.

Abstract Introduction Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed >6 months after receiving a rituximab-containing regimen was initiated. Methods Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed >6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status <2, and adequate organ function (creatinine <2 mg/dl, total bilirubin <1.5x ULN, and liver transaminases <2.5x ULN) and bone marrow reserve (neutrophils >0.75, and platelets >50,000/uL). Exclusion criteria included HBV+, HIV+, transformed lymphoma, primary cutaneous lymphoma, central nervous system involvement, <6 months expected survival, and active infection. Treatment consisted of ofatumumab 1,000 mg IV and bortezomib 1.6 mg/m2 IV given weekly for 4 weeks (induction), then every 2 months (maintenance) to complete 12 months of therapy. Valacyclovir or acyclovir was given for herpes zoster prophylaxis while on bortezomib. Acetaminophen, diphenhydramine and glucocorticoids were administered prior to ofatumumab infusions. Response was assessed based on the Cheson criteria (2007). A sample size of 44 patients was planned, and an interim analysis after enrollment of 10 patients was undertaken to evaluate safety and early efficacy. Results We present data on 10 patients enrolled between October 2010 and April 2013. Median age was 66 years (range 55-93 years); eight patients (80%) were 60 years or older. There were 7 (70%) men and 3 (30%) women. LDH was elevated in 8 patients (80%). ECOG performance status was 0 in 9 (90%) and 1 in 1 patient (10%). Six patients (60%) had a histological diagnosis of follicular lymphoma, 1 (10%) mantle cell lymphoma, 1 (10%) small lymphocytic lymphoma, 1 (10%) marginal zone lymphoma, and 1 (10%) low-grade B-cell lymphoma, not otherwise specified. Stage III/IV was seen in 5 patients (50%). Eight patients (80%) had a high-risk FLIPI score. Median time from initial diagnosis to current therapy was 65 months (range 20-204 months). Median time from last rituximab-containing regimen was 24 months (range 11-48 months). Median number of previous therapies was 2 (range 1-4). Three patients (30%) had previously received radiotherapy. One patient (10%) had previously undergone autologous stem cell transplantation. Response rates after induction therapy were: 1 (10%) complete response (CR), 3 (30%) partial response (PR), 3 (30%) stable disease, 1 (10%) progressive disease, and 2 (20%) not evaluable for response. With exception of 1 patient who continues on therapy, the patients who achieved a response or had stable disease after induction therapy showed progression of disease during maintenance. Median duration of response in patients who responded was 4 months (range 1-9 months). At the time of this report, 7 patients (70%) are alive with disease, 2 (20%) are alive without evidence of disease, and 1 (10%) has expired. Five grade 3 or 4 adverse events (AEs) occurred; grade 4: diarrhea (n=1) and hyperglycemia (n=1); grade 3: infusion reaction (n=1), nausea (n=1) and rash (n=1). No grade 3 or 4 peripheral neuropathy or hematological AEs were observed. The most common grade 1 or 2 AEs were: infusion reactions (n=6), anemia (n=5), thrombocytopenia (n=5), fatigue (n=4), diarrhea (n=4), hyperglycemia (n=4) and lymphopenia (n=4). No deaths have occurred while on therapy. Conclusions The combination of ofatumumab and bortezomib given weekly for 4 weeks induced a response in 40% and stable disease in 30% of the patients. However, most of the patients experienced progression of disease during the maintenance phase of the study. Furthermore, there were five grade 3 or 4 AEs associated with therapy. Based on this interim analysis, it was decided to stop enrollment. The combination of ofatumumab and bortezomib, however, appears potentially active and deserves further study. Different schemas of therapy with longer induction or different maintenance schedule could prove to be safer and more effective. Disclosures: No relevant conflicts of interest to declare.

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

Abstract Allogeneic stem cell transplantation (allo-SCT) remains the main therapeutic option for patients with high-risk hematologic malignancies, albeit with the requirement of a properly matched and timely available donor. Dual-unit umbilical cord blood transplantation (dUCBT) has become an alternative modality, which offers immediate access to allo-SCT for most adult patients who lack an appropriate volunteer donor. We retrospectively analyzed the outcomes of consecutive dUCBT procedures that were undertaken by our center over a seven-year period, with focus on factors affecting engraftment and survival. Between 2006 and 2013, 40 patients underwent dUCBT at a median age of 37 years (range, 16-60) for various hematologic malignancies (acute myeloid leukemia: 22, myelodysplastic syndrome: 5, chronic myelogenous leukemia: 2, acute lymphoblastic leukemia: 6, mixed-phenotype acute leukemia: 2, plasmacytoid dendritic cell neoplasm: 1, hepatosplenic T cell lymphoma: 1, chronic lymphocytic leukemia: 1). The majority of patients (73.7%) had advanced or intermediate-phase disease at the time of transplantation, with a median time from diagnosis to transplant of 17.7 months (range:3.1-92.3). Recipient body weight ranged from 48 to 110 kg (median, 73). The conditioning regimen was myeloablative in 33 (82.5%) patients (busulfan-based in 22, and total body irradiation-based in 11 cases). Antithymocyte globulin was not administered during conditioning, with the exception of one case. Most units (55/80, 68.75%) were 4/6 antigen matched to recipient at HLA-A, -B, and -DRB1 loci, and the remaining were 5/6 matched. By retrospective high-resolution typing for class I HLA alleles, histocompatibility was demoted in 62.3% of units. By additional allele-level typing at HLA-C and -DQB1 loci, the degree of compatibility varied from 8/10 to 3/10, with 80.5% of the units being ≤6/10 matched to the patient. The median dose of cryopreserved total nucleated cells (TNC) per unit was 2.53 x 107/kg (range, 1.09-5.66). At infusion, patients received in total a median of 4.55 x 107 TNC/kg (range, 2.65-9.3) and 1.7 x 105 CD34+ cells/kg (range, 0.54-5.14) from both units. The cumulative incidence (CI) of neutrophil engraftment was 92.5% (37/40 patients), with achievement of an absolute neutrophil count (ANC) greater than 500/uL at a median of 20 days (range, 12-52) (Figure 1). Platelet recovery (>50x109/L) occurred at a CI of 63.2%, and a median time of 84 days (range, 32-363). No influence of cell dose (TNC or CD34+) or of the degree of HLA match on the incidence and kinetics of engraftment could be detected. Acute graft-versus-host disease (aGVHD) of grades II-IV and III-IV developed in 85% and 12.65% of patients, respectively. The CI of chronic GVHD was 31% (extensive in 54.5% of cases). There was a statistical trend for increased incidence of cGVHD with <6/10 HLA match at the allele level (p=0.068; HR, 3.35; 95% confidence interval [ci], 0.92-12.24). Non-relapse mortality (NRM) reached 43.1% (95% ci, 27.0-58.2) at 10.3 months, but no case of NRM was noted thereafter (Figure 2). Major causes of NRM were infection/sepsis (n=11), GVHD (n=3), and engraftment failure (n=3). The CI of relapse was 22.7% (95% ci, 10.7-37.5). Relapse was the cause of death of 6 patients. With a median follow-up of 30 months (range, 2-84), overall (OS) and disease-free survival (DFS) rates at 2 years were 36.5% (95% ci, 21-52) and 34.2% (95% ci, 19.3-49.6), respectively (Figure 3). Sixteen of 40 patients are alive and disease-free for a median time of 30 months from transplant. Age ≤37 years, recipient CMV seronegativity, and early disease phase at transplant were associated with improved OS in univariate analysis. Age remained as the only independent risk factor for OS in multivariate analysis of OS (p=0.022). Age ≤37 years was also found to be associated with reduced NRM (p=0.055), and favorable DFS (p=0.04).Figure 1Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 1. Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 2Cumulative Incidence curve of non-relapse mortality.Figure 2. Cumulative Incidence curve of non-relapse mortality.Figure 3Overall Survival (Kaplan-Meier curve).Figure 3. Overall Survival (Kaplan-Meier curve). In conclusion, dUCBT can lead to stable donor engraftment even across multiple HLA disparities and can overcome the barrier of cell dose. Despite considerable early mortality, dUCBT offers the possibility of long-term survival in about one third of adult patients with poor-prognosis hematologic malignancies, for whom allo-SCT would not be otherwise feasible. Disclosures: No relevant conflicts of interest to declare.

Abstract Background A treatment option for patients with relapsed/refractory multiple myeloma (RRMM) is pomalidomide(pom) and dexamethasone (dex), with an overall response rate (ORR) of 33% and median progression free survival (PFS) of 4.2 months. Adding the alkylatingagent cyclophosphamide(Cy) to pom and steroids improves ORR and PFS. Baz et al (Blood, 26 May 2016) combined daily pom with weekly dosing ofCy anddex (PCD), with an ORR of 64.7% and a median PFS of 9.5 months, although grade 3/4 neutropenia increased from 31% to 52%. In our experience, compared to weekly Cy, low dose daily oral Cy is better tolerated with less myelosuppression. Palumbo et al (Blood, 17 Oct 2013) in fact combined pom with alternate day dosing ofCy and prednisone, with an ORR of 51% and a median PFS of 10.4 months and a grade 3/4 neutropenia rate of 42%. However, importantly, granulocyte stimulating factor (G-CSF) and platelet transfusion support wereprohibited, resulting in a lower maximum tolerated dose of pom of 2.5 mg (vs 4 mg in the Baz) and therefore, the rates of neutropenia cannot be compared between the two studies. In the present study, we explored PCD at the doses/schedule shown in table 1 with hematologic support even in patients with baselinecytopenias. This type of metronomic therapy has demonstrated efficacy in refractory B cell malignancies, possibly because the anti-angiogenic effects of metronomic therapy may be synergetic with conventional anti-neoplastic agents. Methods This was an open label, single arm, and single center phase 2study. The primary objective was to evaluate the best ORR. Secondary objectives were to evaluate safety, clinical benefit response (CBR), PFS, and overall survival (OS). Inclusion criteria included lenalidomide refractory, pom naïve RRMM patients with at least 2 prior lines of therapy. Patients were required to have measurable disease, adequate performance status, Cr <3 mg/dL, normal hepatic function, and ANC > 1000/uL and platelets > 50,000/uL if bone marrow plasma cells were < 50%, otherwise >30,000/uL. G-CSF and platelet support were permitted during screening and study treatment if needed. Each drug was administered at the doses and schedule shown in Table 1. Results Overall, 28 evaluable patients with progressive disease (PD) at screening have been enrolled. The median age is 66 (57% > 65 yr) with a median of 3 lines of prior therapy over 5 years since diagnosis. 3 (11%) had ANC<1.5 and 2 (7%) hadplts<50,000/µL at study entry.High-risk molecular findings were present in 13 patients (46%), including 3 with del p53 and 6 with gain of 1q21 by FISH (2 with concurrentt(4;14) and 2 with concurrent del p53). With 8 patients still on study therapy, responses include 3 complete responses (CR), 7 very good partial responses (VGPR), 9 partial responses (PR), 3 minor responses (MR), 5 stable disease (SD), and 1 PD, for an ORR of 67%, CBR (i.e. MR or better) of 78% and a median PFS of approximately 14.5 months. The median OS has not been reached. The most common grade 3/4 toxicity (regardless of drug attribution) was neutropenia with 20 (71%) of subjects experienced grade 3/4 neutropenia. Importantly, there was only 1 episode of febrile neutropenia during study therapy. Grade 3/4 thrombocytopenia was seen in 25% of subjects, and 3/4 anemia seen in 18%. The most common grade 3/4 non-hematologic toxicity was pulmonary disease with Grade 3 lung infections occurring in 21% of subjects (3 viral, 2 bacterial, 1 unknown) and 1 additional grade 3 URI. Of note, all of these admissions occurred at local hospitals and none of these occurred in the setting of neutropenia. One additional pt hadpneumonitisattributed to pom requiring study discontinuation. Grade 3rashwas also observed in 14% of subjects leading to pom dose reductions. Correlative data from peripheral blood and bone marrow aspirates taken at baseline, Cycle 3 Day 15, and at disease progression from all patients will be updated at the time of conference. These include PCD-associated changesin gene expression, clonal evolution and immune microenvironment during therapy and on progression. Conclusions With toxicities similar to those in other studies, the ORR of 67% and PFS of 14 months in our study of PCD compares very favorably to pomdexas well as other triplet regimens containingCy. Disclosures Chari: Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Catamero:Celgene: Honoraria, Speakers Bureau. Verina:Celgene: Speakers Bureau. Jagannath:Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction Remission induction rates after a second or greater relapse is a critical endpoint in phase II trials of childhood acute lymphoblastic leukemia (ALL). A robust benchmark is crucial for identification of novel multi-agent regimens worthy of further study. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium previously reported the response rates of children with multiply relapsed and refractory (R/R) ALL treated between 1995 and 2004, which provided a benchmark for clinical trials. To define more recent treatment patterns and test the robustness of this benchmark, we performed a retrospective cohort review of children with R/R ALL who experienced second or greater treatment failure at TACL consortium sites between 2005 and 2013. Patients and Methods Eligible patients were identified at participating TACL institutions. This cohort was comprised of patients with medullary R/R B-cell precursor ALL who experienced at least 2 treatment failures or relapsed after hematopoietic stem cell transplant. Patient demographic data and details of the initial and R/R disease characteristics were abstracted from medical records and entered into a central database. This study was approved by the IRB of each participating institution. Treatment failure was defined by the presence or re-emergence of circulating blasts, M2/M3 BM, or extramedullary (EM) disease despite therapy. Complete remission (CR) was defined as M1 marrow, no EM disease and evidence of peripheral count recovery. For the purpose of statistical analysis, patients who met these criteria without platelet recovery (CRp) or normal blood count recovery (CRi) were included as CR. Univariate and multivariate logistic regression were utilized to evaluate the risk of re-induction failure. Predictors included in this preliminary analysis were NCI risk criteria at diagnosis, duration of the prior remission, the treatment attempt number, and the EM and BM status at the start of each therapy attempt. Results This report includes 214 patients. Fifty-six percent were male. At initial diagnosis, 32% were at least 10 years old, 26% had initial white blood cell (WBC) counts over 50,000/µL, and 39% were classified as high risk by the NCI risk criteria (Table 1). Therapy involved various combinations of agents and ranged between 2 and 10 attempts. The CR rate was 42% for third treatment attempt and 24% for fourth and subsequent treatment attempts (Table 2). Treatment failures were significantly associated with increased number of treatment attempts (p < 0.001), shorter duration of previous CR (p < 0.001) and NCI risk category at diagnosis (p = 0.018). Conclusion This preliminary analysis found similar CR rates in patients with third treatment failure compared to the 1st TACL retrospective study of the prior decade (42% vs. 44%, Ko et al, 2010) and an Austrian report with a small cohort of patients (Reismüller et al, 2013). Further analysis will be performed in comparison to the initial TACL retrospective study cohort once enrollment to this study has been completed (approximately 400 patients). A robust, contemporary historical control may serve as an alternative to a randomized control when outcome with past therapies in unacceptably poor. Table 1. Patient Characteristics at Initial Diagnosis of Patients with ALL who received at least two treatment attempt (n = 214 patients) Characteristic No of patients % Age, years < 1 (infants) 18 8 1-9 126 59 10 and over 70 33 WBC count/uL < 50K 128 60 50K and over 56 26 Unknown 30 14 NCI risk criteria at diagnosis Non-infants, standard risk 82 38 Non-infants, high risk 84 39 Non-infants, unknown 30 14 Infants 18 8 Sex Female 94 44 Male 120 56 CNS disease Yes 42 20 No 148 69 Unknown 24 11 Karyotype1 Normal 68 30 11q23 (MLL gene) rearranged 19 8 Hypodiploidy 7 3 Hyperdiploidy 26 12 iAMP21 2 1 t(12;21) 6 3 t(1;19) 7 3 t(9;22) 15 7 Other 46 21 Unknown 28 12 1 Karyotype is available for 214 unique patients; 2 entries were reported for 7 patients, and 4 entries were reported for 1 patient. Table 2. Achievement of CR/CRp/CRi After Treatment of R/R ALL by Preceding Remission Duration and Treatment Attempt Third treatment attempt Fourth through tenth treatment attempt Duration of preceding CR Response Total % Response Total % Not achieved (refractory) 24 63 38 20 86 23 < 18 months duration 28 78 36 11 49 22 18 to 36 months duration 9 15 60 3 5 60 ≥ 36 months duration 8 8 100 0 1 0 All patients combined 69 164 42 34 141 24 Disclosures Sun: Gateway for Cancer Researchy: Research Funding; Amgen: Research Funding. Wilkes:Healthcare Research and Quality: Research Funding; Alex's Lemonade Stand Foundation: Research Funding. Gaynon:Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Sigma Tau: Speakers Bureau; JAZZ: Speakers Bureau. Wayne:Medimmune: Honoraria, Other: travel support, Research Funding; NIH: Patents & Royalties; Kite Pharma: Honoraria, Other: travel support; Pfizer: Honoraria; Spectrum Pharmaceuticals: Honoraria, Other: travel support, Research Funding. Whitlock:Amgen: Honoraria.

Abstract Mortality from relapsed disease remains a significant barrier to long term survival (OS) after HI HSCT despite presumed heightened alloreactivity from the mismatched graft. The Jefferson group uses a 2 step approach to HI HSCT where patients are typically conditioned with 12 Gy total body irradiation (TBI) in 8 fractions of 1.5 Gy over 4 days, immediately followed by an infusion of 2 x 108/kg donor CD3+ cells (DLI). After 2 rest days, cyclophosphamide (CY) 60 mg/kg daily x 2 is given for bidirectional tolerization, followed a day later by a CD34 selected stem cell infusion. In an attempt to maximize graft versus tumor (GVT) effects, we changed the timing of the TBI in the 2 step approach. In this updated regimen, TBI was given in 6 fractions of 2.0 Gy over 3 days, resulting in a 24 hour delay between conditioning and DLI. Theoretically, the extra time reduced residual disease burden prior to the introduction of the DLI, in turn reducing the number of donor T cells activated by tumor, thus avoiding their elimination by CY. Major HSCT endpoints of OS (Kaplan Meier), relapse and non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) [cumulative incidence (CI)-EZR Software v 1.37] were assessed using this updated 2 step HI HSCT approach. Forty patients, median age 51 (range 19-65) years with AML (13), MDS (7), B ALL (7), PH+ ALL (4), T cell ALL (2), Burkitt (2), and other heme malignancy (5) with revised disease risk assessment scores of intermediate (21), high (17), and very high (2) were treated from 2013 to 2017. Median follow-up is 36 (range 15 to 56) months. At 24 months, probability of OS was 59%, CI NRM and relapse were 34% and 15% respectively. CI aGVHD (grades 2-4), (grades 3-4), and cGVHD were 38%, 5%, and 20%. Median d+28 T cell chimerism of 36 patients engrafted and alive was 100% (range 97% to 100%). Median CD3/4 and CD3/8 counts at d +28 were 49 (range 9-417) and 54 (8-1329) cells/ul. Of the 4 remaining patients, two without donor specific antibodies rejected their graft, one with a large burden of CMML at the time of HSCT. An additional patient relapsed prior to the attainment of sustained donor T cell chimerism and one patient died of sinusoidal obstructive syndrome prior to d+28. Causes of death were infection (7), regimen toxicity (4), GVHD (2), and disease (3). This updated 2 step regimen was associated with a highly acceptable 2 year OS rate and low rates of disease recurrence. Of the patients that died, cause of death was primarily due to NRM and not relapsed disease suggesting that the added extra day may have enhanced GVT effects. In the absence of donor specific antibodies, the 2 early and 1 late graft rejections are atypical for a 2 step MA HI HSCT approach and were potentially caused by a rebound recipient hematopoiesis allowed by the delay in the DLI in a minority of patients. While formal comparison to prior patient cohorts is not feasible, this relapse rate compares favorably to the 2 year 27% relapse rate in similar patients treated on our initial trial.(Grosso, et al., Blood, 2011, 118:47320). The concept of allowing time for malignancy burden to decline in high risk patients prior to introduction of DLI warrants further evaluation going forward in efforts to reduce relapse after HSCT. Table. Table. Disclosures Porcu: Innate Pharma: Consultancy.

Background Chronic myelomonocytic leukemia (CMML) is a rare de novo clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The diagnosis is challenging and carrying risk for leukemic transformation. The median age at CMML diagnosis is ~71-73 years, with a male preponderance. According to the 2016 World Health Organization (WHO) classification of myeloid neoplasms, CMML is characterized by the presence of sustained (&gt;3 months) peripheral blood (PB) monocytosis (≥1 × 109/L; monocytes ≥10% of white blood cell count) along with dysplastic features in the bone marrow (BM). &lt; 20% blasts/blasts equivalent in the PB and BM. It has recommended categorization of CMML into "proliferative" (MPN-CMML) and "dysplastic" (MDS-CMML) sub-types; based on a total leukocytic count (TLC) (of ≥13 × 109/L for MPN-CMML). Also, based on PB and BM blast %, CMML can be sub-classified into three categories; (a) CMML-0 (&lt;2% PB blasts including promonocytes and &lt;5% BM blasts), (b) CMML-1 (2-4% PB blasts including promonocytes and 5%-9% BM blasts), and (c) CMML-2 (&gt;5% PB blasts including promonocytes and 10%-19% BM blasts and/or when any Auer rods are present. Objective: To retrospectively analyze the cases of CMML diagnosed in the Hematology Department, National Center for Cancer Care and Research (NCCCR), Doha, Qatar from January 2013 to July 2020 with the assessment of risk and prognosis. Materials and methods: The results from flow cytometry, cytology, PB, and BM morphology, cytogenetics and molecular genetics were re-estimated. The CMML-specific prognostic scoring system (CPSS) was used for the risk stratification. Results:12 patients diagnosed as CMML were detected and included in the study, 10 males and 2 females, with a median age of 64 years. 3 Arabs and 9 non-Arabs. 10 patients were transfusion dependent. 6 patients had splenomegaly and 2 of them had massive splenomegaly (&gt;20 cm in craniocaudal length). According to the TLC, 8 were myeloproliferative (CMML/MP) and 4 were myelodysplastic CMML. 4 of our patients were below 40 years (classified as young adults as per WHO) and all were of the proliferative type. The flow cytometry of PB and/or BM was done to 11 patients. The monocytic cells were characterized by co-expressing CD14 and CD64 and showed aberrant expression of CD56 on 5 patients. According to the morphology of the BM, one case was described as MDS/MPN or MPN, and the rest of the cases were diagnosed as MDS/MPN. According to WHO 2016 diagnostic criteria of CMML: one case was diagnosed as CMML0, one case was diagnosed as CMML1, 9 cases were diagnosed as CMML2 and one case was diagnosed as MPN/MDS -CMML2 or as MPN. The cytogenetic risk was high in 4 patients, intermediate in one patient, and low in 7 patients. According to CPSS, one patient was an intermediate risk I, 4 was intermediate-risk II, and 7 were high risk. Molecular analysis and NGS were done for 4 patients that were most recently diagnosed. One case showed NRAS in 30%, one case showed KRAS in 57%, one case showed DNMT3A and NPM1 each 42% and one case showed WT1 (36%), FLT3 (33%) and NPM1 (15%). Regarding management and supportive care, 10 out of 12 patients required transfusion support. 4 patients (3 Proliferative and one Dysplastic) were not eligible for active management and received only symptomatic treatment. 5 patients of the proliferative type were started on hydroxyurea. The other 3 patients were of dysplastic subtype who received hypomethylating agent +/- allogenic bone marrow transplant. 6 patients traveled back to their home country and lost follow up, 5 expired, and one patient still alive. Conclusion: CMML is a unique and rare hematopoietic neoplasm with complex biology and pathology. It is an aggressive rare disease that carries a dismal prognosis, with poor survival and a high risk of transformation. The therapeutic options are limited. In our clinic, for the 7 years period, CMML was confirmed only in 12 patients. The great majority of them were old males of the non-Arab nationality, transfusion-dependent, presented with TLC (&gt; 13x10^3/ul Proliferative) of CMML2 subtype and high CPSS risk score. 33% of our patients were young adults (less than 40 years old) and were of the proliferative type. The combination of clinical, morphological, immunophenotyping, cytogenetic and molecular information is required to improve the accuracy of CMML prognostication. Disclosures No relevant conflicts of interest to declare.