ALBERT

Description: Abstract 4013 Background: In recent years, azacytidine (AZA) has become the standard of treatment for high risk myelodysplasia (MDS). The approved schedule of AZA uses a 75mg/m2/d s.c. regimen for 7 days based on the CALGB-9221 (Silverman, JCO 2002) and the AZA-001 studies (Fenaux, Lancet Oncol 2009). The clinical response rates after AZA have been extensively presented but there is only limited data on the rates of cytogenetic response (CyR). Based on the review of the literature, there are no specific cytogenetic data published on prospective trials. Methods: We based our analysis on a randomized phase 2 study from the US Leukemia Intergroup (E1905 study, NCT00313586) testing 10 days of AZA (50mg/m2/d s.c.) vs 10 days of AZA+ the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). MDS, CMML, and AML with myelodysplasia-related changes were included. This analysis includes all patients with cytogenetic abnormalities (at baseline or acquired following treatment) with available cytogenetic follow-up (cycle 6). Of 150 patients, 70 demonstrated baseline cytogenetic abnormalities. To date, forty patients (27 MDS and 13 AML) were evaluable for both time points. Karyotypes were performed at local laboratories, and reviewed centrally (RPK and GH). Cytogenetic response was assessed using IWG 2000 (Cheson et al, Blood 2000) criteria. Results: The clinical response rate (CR+PR+ trilineage HI) according to IPSS cytogenetic risk stratification were of 20%, 33%, and 35% for favorable, intermediate and poor cytogenetic risk groups respectively (p=NS). Patients with Chr 7 abnormalities (i.e. -7 or -7q, n=18) had a response rate of 28% including 17% CR. Of patients with complete cytogenetic data, the rate of overall CyR was 52% (n=21): 22% (n=9) complete CyR, 30% (n=12) partial CyR. This represents a complete CyR of 13% and a partial CyR of 23% as a proportion of all treated patients with initial cytogenetic abnormalities (including those who did not receive six cycles of therapy). To date, confirmatory FISH analyses were available for 4 patients with CyR (2 CCyR and 2 PCyR). All four had complete clearance of their cytogenetic clone. Among the cytogenetic responders, 15 had MDS and 6 had AML (p=NS). CyR did not differ between the two treatment arms. CyR and clinical response were highly correlated (p

Description: Introduction: Hypomethylating agents (HMAs) are used as induction therapy for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA therapy is frequently initiated in the hospital and some patients remain hospitalized through the initiation of cycle 2 (C2). Clinicians are often faced with the decision to administer C2 while the patient is still hospitalized, however, there is a paucity of prognostic information to guide treatment decisions in this common scenario. Methods: We conducted a retrospective review of patients diagnosed with treatment naïve, de novo and secondary AML who were ineligible for induction chemotherapy (at the discretion of the treating physician based on advanced age, comorbidities, or other reasons) at a single, tertiary, referral center. Patients were included if they received induction therapy with an HMA, including azacitidine and decitabine between 7/1/2008 and 7/1/2018. Exclusion criteria included receipt of intensive induction chemotherapy and inadequate electronic medical documentation. Patients were divided into four groups: patients who were discharged after completion of C1 and received C2 as an outpatient (discharged after C1), patients who received C1 and C2 during the same hospitalization (C1-C2 continuous hospitalization), those who received one total cycle (C1 only), and patients who received C1 as an outpatient (C1 outpatient). The groups were analyzed separately for the primary outcome of overall survival (OS), calculated by Kaplan Meier analysis. Results: Out of 105 patients identified who received an HMA, 100 patients were identified who met inclusion/exclusion criteria and their baseline characteristics are shown in Table 1. Most patients had de novo AML (39.0%), although 33.0% and 19.0% of patients had AML secondary to myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), respectively. Additionally, 8 patients (8.0%) had therapy related AML. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2 at induction. Patients who received C1 as an outpatient had a significantly better performance status than those who did not (p= 0.033) Decitabine was the most common HMA (57.0%) administered and was most often on 5-day schedule. Eight patients (8.0%) were continually hospitalized until C2, 5 because of active medical issues (most often fevers requiring intravenous antibiotics), 2 had physical debility precluding discharge home, and 1 was receiving intrathecal chemotherapy twice weekly for central nervous system involvement of AML. The median OS was 15.6 months (95% CI 2.66-28.6) in patients who received C1 outpatient, 10 months (95% CI 6.67-13.43) in patients discharged after C1, 4 months (95% CI 2.40-6.40) in the C1-C2 continuous hospitalization group, and 1 month (95% CI 0.61-1.30) in those who only received C1 as shown in Figure 1. Patients discharged after C1 had a significantly longer OS compared to the C1-C2 continuous hospitalization group (p=0.003). There was a trend (p=0.054) towards worse survival in patients who received C1 only compared to patients hospitalized continually from C1-C2. Conclusions: Continued hospitalization from C1 to C2 of HMA therapy led to an extremely poor median survival of 4 months in this cohort, compared to 10 months in patients who were able to be discharged after C1 and receive C2 as an outpatient. Patients who only received a single cycle of HMA did not have a significantly different survival as compared to patients who were continually hospitalized from C1 to C2. While this is a small retrospective series, these data suggest that AML patients still requiring hospitalization at time of C2 of HMA therapy should be re-evaluated for alternative therapeutic approaches including hospice given poorer outcomes. Although this grouping selects for patients who are sicker and unable to leave the hospital, there is apparent lack of significant benefit of continued HMA therapy in the majority of patients while inpatient. The impact on hospital length of stay, unnecessary utilization of healthcare resources, and patient's quality of life should also be considered in these cases. Prospective identification of these patients with a poorer prognosis could lead to better alternatives for therapeutic approaches. Disclosures Kremyanskaya: Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy. Navada:Onconova Therapeutics Inc: Research Funding. Mascarenhas:Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Flavopiridol has in vitro activity in CLL and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol administered using two different schedules has activity in CLL. Patients with previously treated CLL were enrolled on two sequentially performed phase II studies. Patients in the first trial received flavopiridol (50 mg/m2 daily) as a continuous infusion (CI) over 72-hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour intravenous bolus (IVB) daily for three days repeated every 3 weeks. Patients received up to 6 (CI cohort) or 8 (IVB cohort) cycles of therapy. Fifteen patients enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate (Rai stage I or II) and 9 (60%) high (Rai stage III and IV) risk stages. No responses were noted in this group with 27% having stable disease (SD) and 73% progressive disease (PD). Thirty-six patients enrolled in the IVB study, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) SD, and 13 (36%) PD. The progression-free survivals for responders in the IVB study were 2.9, 3.2, 8.7, and 19.3 months. The median progression-free survival was 2.1 months (95% confidence interval [CI] 1.8 – 3.8) for patients in the CI study and 3.2 months (95% CI [2.5 – 7.4]) for the IVB study. The median overall survival was 27 months (95% CI [20–42]) for the CI study and 24 months (95% CI [18–31]) for the IVB study. Toxicity was manageable and included mainly myelosuppression (granulocytopenia and thrombocytopenia), infections, diarrhea and fatigue. Grade 3 and 4 toxicities were 20% and 27%, respectively, on the CI study and 39% and 33% on the IVB study. One patient on the IVB study had tumor lysis syndrome that was managed medically and did not require dialysis. There was one on-study death following a myocardial infarction on the IVB study. We conclude that flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.

Description: Abstract 2061 Poster Board II-38 Background: We have previously reported efficacy and safety of clofarabine in patients = 60 with at least one unfavorable prognostic factor. Retrospective analyses have suggested that survival in AML is related to quality of response. [Estey, Clinical Advances in Hematology Oncology, 2008]. In this report, we present durability and survival data for complete responders in each of the prognostic subgroups in the CLASSIC II trial, and a landmark analysis to evaluate the relationship between complete response and survival. Methods: This single arm, Phase II, open-label study enrolled adults with untreated AML =60 years old with at least one adverse prognostic factor: age =70 years, ECOG performance status (PS)=2; antecedent hematological disorder (AHD); and/or intermediate/unfavorable risk karyotype. Clofarabine was given on days 1-5 at 30 mg/m2 during induction and 20 mg/m2 during re-induction/consolidation. Primary endpoint was ORR (CR + CRp). Secondary efficacy endpoints included duration of remission (DoR), disease-free survival (DFS) and overall survival (OS). Due to interest about outcome of CR alone with respect to remission durability, such secondary endpoints were analysed and are reported below for the overall population and for each prospectively defined prognostic subgroup. Analyses of overall survival (OS) using both best response and landmark timepoints were performed. Landmark analyses eliminate survivorship bias by evaluating the robustness of the relationship between response and survival in patients who survived until a landmark timepoint and using the response at this timepoint for assessment rather than best response. Since this analysis was defined post hoc, 3 analyses of median overall survival in patients who survived at least 30, 45, and 60 days were performed to eliminate time-to-response bias. Results: 112 patients were evaluable. For patients with complete response (CR, n=42), median duration of remission (DoR) was 65 weeks (95% CI 41, not estimable [NE]), median disease free survival (DFS) 48 weeks (28, 65), and median overall survival (OS) 72 weeks (53, NE). Patients = 70 years (n=69) had 33% CR, median DoR and DFS 65 weeks (17, NE), and median OS = 48 weeks (48, NE). Patients with ECOG PS2 (n=25) had CR 24%, median DoR 7 weeks (6,NE), median DFS 9 weeks (6, 12), and median OS 16 weeks (12, 33). Patients with AHD (n= 41) had 39% CR; median DoR, DFS, and OS are NE. Patients with intermediate/unfavorable karyotype (n= 108) had 39% CR, median DoR 65 weeks (41, NE), median DFS 48 weeks (28, 65) and median OS 72 weeks (53, NE). Patients with unfavorable karyotype (n=62) had 32% CR, median DoR 56 weeks (28, NE), median DFS 33 weeks (23, 56), and median OS 59 weeks (48, NE). Median OS was 59.1 weeks (95% CI=49.9 weeks, NE) for CR + CRp; 33.4 weeks (95% CI=19.3, 55.0 weeks) for CRp; and15.4 weeks (95% CI=12.0, 29.9 weeks) for non-responders. In the landmark analysis, patients who had a complete response to clofarabine survived longer than non responders (Table 1), regardless of starting point (30, 45, or 60 days). The survival benefit of responders was statistically significant for all time points (p 13 months in all prognostic subgroups except PS2, and complete responders lived longer than non-responders. Achievement of a CR correlates with clinical benefit and survival in older AML patients. Single agent clofarabine is an effective treatment option for older adult patients with untreated AML and unfavorable prognostic factors. Disclosures: Gabrilove: Genzyme: Research Funding. Faderl:Genzyme: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Claxton:Genzyme: Research Funding. Arellano:Genzyme: Research Funding. Lyons:Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding. Kovacsovics:Genzyme: Research Funding. Eckert:Genzyme: Employment. Huebner:Genzyme: Employment. Kantarjian:Genzyme: Research Funding.

Description: Inorganic arsenic trioxide (As2O3 ) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non–EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10−7 to 10−9 mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10−7 mol/L) exhibited morphologic characteristics of apoptosis. We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.

Description: The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with a high or intermediate/high risk IPI score. Five patients with a median age of 38 years (28–53) have been treated. All patients had rituximab previously. At transplant, 4 patients had relapse, chemosensitive to salvage in 3 patients, and untested in 1 patient. One patient had primary refractory disease, chemosensitive to salvage. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. Collection started when the CD34 count was ≥12/ul. High dose chemotherapy consisted of rituximab 375mg/M2 on day −8, carmustine 300mg/M2 on day −7, etoposide 200mg/M2/d on days −6 to −3, cytosine arabinoside 200mg/M2 on days −6 to −3 (8 doses) and melphalan 140mg/M2 on day −2. Patients received filgrastim post transplant and standard antibiotic prophylaxis. All patients are alive 11 to 306 days post transplant (median follow up 4.5 months). The median CD34+ cell dose collected was 8 x 106/kg (1.1 to 17.6). One patient had an inadequate CD34+ cell dose and required bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occured at a median of 11 days post transplant. Infectious complications included febrile neutropenia in one patient following mobilization and in 4 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II–IV LFT elevation without evidence of VOD, which resolved in two patients prior to discharge. The patient with grade IV hepatic toxicity had abnormal liver enzymes prior to study and known intrahepatic lymphoma. This patient continues to have grade III elevation of GGT 306 days post transplant with no evidence of infectious hepatitis or lymphoma (PET negative). One patient developed moderate hemorrhagic cystitis. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. R-BEAM HDC resulted in frequent elevations of LFTs. Further studies of rituximab with HDC warrant caution regarding hepatotoxicity.

Description: Abstract 2083 Poster Board II-60 Background: Outcomes in older patients with AML have not improved in several decades. Response rates decline and treatment related mortality increases with advancing age [Appelbaum, Blood 2006]. Older adults have a higher incidence of unfavorable prognostic factors, such as antecedent hematologic disorders (AHD) and unfavorable cytogenetics, and outcomes worsen with increasing numbers of unfavorable prognostic factors [Leith, 1997, Blood; Kantarjian, 2006, Cancer; Malfuson, 2008, Haematologica] Clofarabine has demonstrated remissions regardless of age, cytogenetics, AHD, or multiple unfavorable prognostic factors. We present data on durability of remission, 30 day mortality, and overall survival in prospectively defined subgroups from the CLASSIC II trial: age ≥ 70, intermediate or unfavorable cytogenetics, AHD, and in patients with 2 or more of these factors. Methods: CLASSIC II was a single-arm, multi-center, Phase II, open-label, study of patients with previously untreated AML, ≥60 years old, and at least one unfavorable prognostic factor: age ≥70 years, AHD, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or intermediate/unfavorable risk myeloblast karyotype. Single-agent CLO was administered on days 1-5 at 30 mg/m2 during induction and 20 mg/m2 during re-induction/consolidation for a maximum of 6 cycles. Overall response rate (ORR) was defined as Complete Response (CR) plus Complete Response with incomplete platelet recovery (CRp). Duration of remission (DoR) was measured from the time the patient achieved remission until relapse or death, censored for alternative antileukemic treatment at date of therapy initiation. Disease-free survival (DFS) was measured from the time of remission until relapse or death, regardless of any alternative antileukemic treatment. Overall survival (OS) was measured from the first dose of CLO. These 3 time-to-event endpoints were analyzed using Kaplan-Meier methodology. Results: 112 patients were evaluable for efficacy assessments. 78% had at least 2 unfavorable prognostic factors. ORR, CR, DoR, DFS, OS and 30 day mortality for each subgroup are presented in Table 1. In addition to the Table 1 analyses, we assessed results for specific combinations of prognostic factors. Patients with 2 unfavorable prognostic factors (n=45) had ORR of 51%, DoR 37 weeks (95% CI 17, NE) DFS 26 weeks (95% CI 12,41) and OS 37 weeks (95% CI 25, 53). Patients with 3 unfavorable factors (n=40) had OR 38% and OS 37 weeks (95% CI 16,57); DoR and DFS were not yet estimable (NE). 30 day mortality for patients with 1, 2 or 3 factors was 8%, 9%, and 10%, respectively. Patients ≥ 70 with intermediate or unfavorable karyotype (n= 25), had ORR 48% and CR 40%; in patients ≥ 70 with unfavorable karyotype (n=9) ORR and CR were 56%. Patients ≥ 70 with both AHD and unfavorable karyotype (n= 18), ORR was 33% and CR 22%. In patients ≥ 70 with AHD and intermediate karyotype (n=8), ORR and CR were 63%. Conclusions: Clofarabine produces durable response rates with low 30 day mortality in patients ≥ 70, with AHD, intermediate or unfavorable cytogenetics, and 2 or more of these factors; ORR was consistent across these subgroups. Among patients ≥ 70, ORR was maintained in those who also had AHD and/or intermediate or unfavorable cytogenetics. Disclosures: Erba: Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Claxton:Genzyme: Research Funding. Arellano:Genzyme: Advisory Committee. Lyons:Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding. Kovacsovics:Genzyme: Research Funding. Gabrilove:Genzyme: Research Funding. Eckert:Genzyme: Employment. Huebner:Genzyme: Employment. Kantarjian:Genzyme: Research Funding.