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: Previous CALGB trials published by Silverman et al (JCO2002;20:2429) have shown azacitidine to be efficacious and well tolerated in the treatment of MDS at a dosing schedule of 75 mg/m2/day x 7 days every 28 days. The objective of this phase II, multicenter, randomized, open-label trial was to study treatment response in patients with MDS with 3 alternative, subcutaneous azacitidine dosing regimens, each eliminating the need for weekend injections. The 3 alternative dosing schedules, repeated in 28-day cycles, were AZA 5-2-2 (75 mg/m2/day x 5 days, followed by 2 days of no treatment, followed by 75 mg/m2/day x 2 days), AZA 5-2-5 (50 mg/m2/day x 5 days, followed by 2 days of no treatment, followed by 50 mg/m2/day x 5 days), and AZA 5 (75 mg/m2/day x 5 days). Eligible MDS patients must have had a life expectancy of ≥ 7 months and an ECOG performance status grade of 0–3, with a FAB classification of RA, RARS, RAEB, RAEB-T, or CMML. RA and RARS patients must also have had either hemoglobin 〈 110 g/L with transfusion requirements, a platelet count 〈 100 x 109/L, or an ANC 〈 1.5 x 109/L. Patients experiencing International Working Group response criteria for MDS (Blood2000;96:3671) defined as complete remission, partial remission, stable disease, or hematologic improvement (major or minor) after 6 cycles of treatment were eligible to receive an additional 12 cycles. A total of 44 patients have been randomized to date with 22, 14, and 8 receiving either AZA 5-2-2, AZA 5-2-5, or AZA 5, respectively. As the AZA 5 day dosing schedule was added later to the protocol by amendment, no patients in this arm are currently evaluable for response. Most patients are male (64%) and elderly with a median age of 74 years. Most patients have RA, using either FAB (45%) or WHO (36%) definitions; another 27% and 16% have RAEB or RAEB-1, respectively. As azacitidine is incorporated into DNA/RNA through successive cell cycles, patients often require a minimum of 4 to 6 cycles of azacitidine before responses are observed. Early results show that the efficacy and tolerability observed with the alternative dosing schedules are consistent with the 75 mg/m2/day x 7 days dosing results from previous studies.

Description: Background: Karyotype is the strongest independent prognostic factor for survival in AML. The randomized phase 3 AZA-AML-001 study of older patients with AML showed AZA prolonged overall survival (OS) compared with CCR (10.4 vs 6.5 months, respectively; P=0.101) (Dombret et al, Blood, 2015). In a prospective subanalysis of the study, AZA was shown to meaningfully prolong OS by 3.2 months compared with CCR (P=0.0185) in the subgroup of patients with NCCN-defined poor-risk cytogenetics (Döhner et al, Blood, 2014: Abstract 621). Aim: This analysis evaluates treatment effects of AZA vs CCR on OS in subgroups of patients with specific cytogenetic abnormalities as well as in patient subgroups defined by cytogenetic risk per modified European LeukemiaNet (ELN) recommendations (not considering molecular markers) (Döhner et al, Blood, 2010). Methods: Patients aged ≥65 years with newly diagnosed AML (〉30% bone marrow [BM] blasts), ECOG performance status score ≤2, intermediate- or poor-risk cytogenetics per NCCN 2009 criteria, and WBC count ≤15x109/L were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: intensive chemotherapy (cytarabine 100-200mg/m2IV x7d + anthracycline IV x3d induction), low-dose ara-C (20mg SC BID x10d/28d), or best supportive care only. Karyotypes obtained from BM were reviewed centrally by an independent cytogeneticist. OS was evaluated in subgroups of patients with frequent specific abnormalities, including -5/del(5q), -7, -7/del(7q), abnormal (17p) or complex karyotype (based on specific abnormalities, patients may have been evaluated in more than one category). OS was also assessed for patients in ELN-defined karyotype risk subgroups: Intermediate (Int)-I (normal karyotype), Int-II (all abnormalities not classified as Favorable or Adverse), and Adverse karyotype. OS was assessed using Kaplan-Meier methods and compared using a weighted log-rank test. Results: Centrally reviewed cytogenetic data were available for 485/488 patients (99.4%). In all, 220 patients (45.4%; AZA n=114, CCR n=106) had Int-I karyotype, 111 patients (22.9%; AZA n=53, CCR n=58) had Int-II karyotype, and 154 patients (31.8%, AZA n=73, CCR n=81) had Adverse karyotype (Figure 1). OS was comparable between AZA and CCR in patients with Int-I karyotype (14.1 vs 10.1 months, respectively; hazard ratio [HR] 0.83, 95%CI 0.60, 1.1; P=0.44) and patients with Int-II karyotype (8.9 vs 9.6 months; HR 1.19, 95%CI 0.79, 1.8; P=0.78). There was a significant 2.4-month median OS difference in favor of AZA in patients with Adverse karyotype (5.3 vs 2.9 months with CCR; HR 0.71, 95%CI 0.51, 0.99; P=0.046; Figure 2), with 1-year survival rates of 29.1% vs 14.7% for AZA and CCR, respectively. AZA was associated with longer median OS and higher 1-year survival compared with CCR for all subgroups of patients with the specific cytogenetic abnormalities under study: -5/del(5q), -7, -7/del(7q), abnormal (17p), and complex karyotype, with HRs ranging from 0.54 to 0.69(Table). Median OS in the CCR arm was less than 3 months for each of these subgroups. Similar to what has been reported in MDS (Ravandi et al, Cancer, 2009), AML patients with chromosome 7 abnormalities responded particularly well to AZA, with an improvement in median OS of 4.1 months over CCR. Patients with complex karyotypes also had meaningful improvements in OS, with ~15% more AZA-treated patients alive at 1 year than CCR patients. Conclusions: Prognosis is dismal for older AML patients with adverse karyotypes, and is especially poor for patients with complex karyotypes. Median OS and 1-year survival in patients with ELN-defined Adverse karyotype treated with AZA were almost double those of patients treated with CCR. AZA-treated patients with the specific cytogenetic abnormalities and/or complex karyotype in this analysis had a 31-46% reduction in risk of death vs CCR, and proportions of patients alive at 1 year were 11-22% greater with AZA. These data suggest AZA should be the preferred treatment for older patients with AML and adverse karyotypes. Disclosures Seymour: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini:Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Celator: Consultancy; Novartis: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Morrill:Celgene: Employment, Equity Ownership. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Menarini: Honoraria; Menarini: Honoraria; Servier: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

Description: Background: AML is characterized by molecular heterogeneity and specific mutations are prognostically important (Papaemmanuil, Gerstung et al, NEJM,2016). Mutational analysis of NPM1, CEBPA, and FLT3 is included in the 2010 European LeukemiaNet recommendations for AML (Döhner et al, Blood, 2010). Additional recurrently mutated genes have since been identified with potential value for prognosis and prediction of treatment (Tx) response. The phase 3 AZA-AML-001 study showed AZA prolonged median overall survival (OS) vs CCR (10.4 vs 6.5 months [mos]; P=0.101) and improved 1-year survival (46.5% vs 34.2%) in older patients (pts) with AML (Dombret et al, Blood, 2015). Aim: To investigate relationships between gene mutations and OS in the subpopulation of AZA-AML-001 pts with available baseline bone marrow (BM) for molecular analyses ("biomarker" cohort). Methods: Eligible pts were age ≥65 years with newly diagnosed AML (〉30% BM blasts), ECOG performance status (PS) score 0-2, WBC count ≤15x109/L, and NCCN-defined intermediate- or poor-risk cytogenetics. Pts received AZA (75 mg/m2/day [d] x 7d/28d cycle) or a preselected CCR: intensive chemotherapy (7 + 3 regimen), low-dose ara-C, or best supportive care only. DNA was isolated from BM mononuclear cells and targeted sequencing of 39 genes was performed with Haloplex target enrichment (Agilent) on Illumina HiSeq 2500 using 2x100bp read lengths. FLT3 tyrosine kinase domain (TKD) mutations were determined by next-generation sequencing (NGS) and internal tandem duplications (ITD) were determined by capillary electrophoresis sizing of PCR amplicons. Target regions varied by gene from all exons to hot-spots. Log-rank test, stratified by ECOG PS score (0-1 vs 2) and cytogenetic risk (intermediate vs poor) at baseline, was used to assess OS of pts with mutations (mut) in genes detected in ≥5 pts vs OS in pts with wild-type (wt) genes within the AZA and CCR arms. Median OS was estimated using Kaplan-Meier methods. Results: The biomarker cohort comprised 156 of all 488 pts in AZA-AML-001 (32%; AZA n=83, CCR n=73). Baseline characteristics and hematologic response rates were well-matched between biomarker and non-biomarker pts. Mutations were detected in 33 of 39 sequenced genes. The most frequently mutated genes were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140 15%, R172 8%]), TP53 (21%), RUNX1 (18%), NPM1 (16%), NRAS (12%), FLT3 (12% [-ITD 10%, -TKD 5%]), ASXL1 (11%), and STAG2 (10%). Stratified log-rank tests showed that median OS was significantly reduced for CCR pts with TP53mut (2.4 vs 12.5 mos with TP53wt; P=0.026) and with NRASmut (4.3 vs 10.3 mos with NRASwt; P=0.020). In the AZA arm, median OS was not significantly different between pts with TP53mutor TP53wt (7.2 vs 12 mos; P=0.40) or between pts with NRASmut or NRASwt (11.8 vs 8.9 mos; P=0.95), but was reduced in pts with FLT3mut (5.4 vs 12.0 mos with FLT3wt; P=0.017). Compared with similar pts treated with CCR, pts with TP53mut and/or NRASmut treated with AZA had nominally better median OS (7.2 vs 2.4 mos for TP53mut; 11.8 vs 4.3 mos for NRASmut), and pts with FLT3mut had nominally worse OS (5.4 vs 6.4 mos) (Table). Median OS was similar for pts with or without mutations in each of the genes known to influence DNA methylation (DNMT3A, IDH1, IDH2, and TET2); however, there was a statistical difference in OS within the AZA arm for pts with TET2mut (P=0.005) despite similar median OS for pts with TET2mut vs TET2wt (9.6 vs 9.5 mos) that was not observed within the CCR arm (P=0.45). Median OS for pts with a mutation in any 1 of the DNA methylation genes listed above was similar in the AZA and CCR arms (Table). Conclusion: These exploratory analyses suggest older AML pts with TP53 or NRAS mutations have a better prognosis when treated with AZA than with CCR. Mutations in genes that regulate DNA methylation did not impact median OS with AZA Tx, although the potential negative effects of TET2mut and FLT3mut warrant further evaluation. Prognostic implications of isolated gene mutations can vary due to co-mutations; larger pt cohorts are needed to establish the influence of recurring co-mutational patterns in AZA-treated pts. Disclosures Tang: Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding. Dombret:Agios: Honoraria; Sunesis: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Menarini: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Pfizer: Consultancy; Sunesis Pharmaceuticals: Consultancy; Karyopharm: Consultancy; ONO: Consultancy; Jansen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Beach:Celgene Corporation: Employment, Equity Ownership.

Description: Background: AML and MDS are distinct, though largely overlapping, diseases, especially in older patients (pts) (Vardiman, Blood, 2008). Injectable AZA is the reference first-line treatment (Tx) for pts with higher-risk (HR) MDS ineligible for alloSCT (NCCN guidelines, v1.2016), as it improved overall survival in this population in the phase 3 AZA-001 (AZA-MDS) trial (Fenaux, Lancet Oncol, 2009). The safety profile of AZA in pts with MDS is well-established from clinical trials and post-marketing reporting (Santini, Eur J Haematol, 2010; Vidaza Package Insert, 2014). Recently, the safety and efficacy of AZA in older pts (≥65 years [yrs]) with AML and 〉30% marrow blasts were evaluated in the phase 3 AZA-AML-001 (AZA-AML) study (Dombret, Blood, 2015). Objective: Compare the safety and tolerability profile of AZA Tx in pts with HR-MDS in the AZA-MDS study with that in older pts with AML in the AZA-AML study. Methods: Safety analyses included all pts who received ≥1 AZA dose. The 2 studies used the same dosing regimen: SC AZA 75 mg/m2/day on days 1-7/28-day cycle. Eligible pts in AZA-MDS were age ≥18 yrs and in AZA-AML were ≥65 yrs. Safety was assessed based on frequency and severity (per CTCAE) of Tx-emergent adverse events (TEAEs), defined as new/worsening AEs during Tx. Tolerability was assessed by overall AZA Tx duration, median cycle length (dosing could be delayed or reduced based on toxicities), rate of AZA dose adjustments, and frequency of TEAEs leading to dose interruption, reduction, or discontinuation. Results: In AZA-MDS, median age of the AZA safety population (N=175) was 69 yrs (range 42-83) with 22% of pts ≥75 yrs. AZA pts in AZA-AML (N=236) were generally older, consistent with study design: median age 75 yrs (range 64-91) with 56% of pts ≥75 yrs. AZA-AML pts generally had higher ECOG PS (Grade 0-1, 77.6%; Grade 2, 22.5%) than pts in AZA-MDS (Grade 0-1, 92.0%; Grade 2, 6.9%). Pts in AZA-AML had lower median ANC at baseline (0.3x109/L [range 0-12] vs 0.9x109/L [0-38] in AZA-MDS), though median platelet (52 and 61 x109/L, respectively) and hemoglobin (95 and 96 g/L) values were similar. Pts in AZA-MDS received a median of 9 Tx cycles (range 1-39) and pts in AZA-AML received a median of 6 Tx cycles (1-28); overall exposure to AZA was similar: 169 pt-years in AZA-MDS and 175 pt-years in AZA-AML. In AZA-MDS and AZA-AML, respectively, 68% and 53% of pts received ≥6 AZA cycles and 36% and 32% received ≥12 cycles. In AZA-MDS and AZA-AML, 86% and 88% of pts, respectively, received all AZA cycles with no dose adjustments. The most common TEAEs in both studies were hematological and gastrointestinal, which tended to decrease with continued AZA Tx (Figure). Higher frequencies of grade 3-4 thrombocytopenia and neutropenia were reported in AZA-MDS, whereas, frequencies of grade 3-4 febrile neutropenia and pneumonia were higher in AZA-AML (Table). TEAEs that resulted in AZA dose delays or reductions, respectively, were most frequently hematological and occurred in 47% and 11% of pts in AZA-MDS, and 49% and 3.4% in AZA-AML. In AZA-MDS and AZA-AML, TEAEs leading to discontinuation (excluding progression to AML in AZA-MDS) occurred in 13% (most frequently hematological) and 47% (most frequently infections or AML worsened) of pts, respectively. Rates of hematological TEAEs that led to study drug discontinuation were low in both studies (4.6% in AZA-MDS and 4.2% in AZA-AML), suggesting that these events were effectively managed with AZA dose modifications. Conclusions: The safety and tolerability of AZA in older pts with AML are consistent with the well-established safety profile of AZA in HR-MDS. Higher frequencies of grade 3-4 febrile neutropenia and pneumonia in AML pts may be due to lower baseline ANC values with more pre-existing grade 3-4 neutropenia, as well as pt- and disease-related characteristics. No new or unexpected risks were identified in AZA-treated pts with AML. Rates of common TEAEs with continued Tx in pts with MDS and AML indicate a lack of cumulative toxicity and suggest that adverse effects of AZA are attenuated over time. Clinicians can use similar approaches to managing AZA-related TEAEs in pts with MDS or AML. Disclosures Seymour: Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract includes data related to the use of azacitidine in older AML patients with 〉30% BM blasts (AZA is approved for treatment of AML with 20-30% BM blasts).. Fenaux:AMGEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Lucy:Celgene Corporation: Employment, Equity Ownership. Songer:Celgene Corporation: Employment, Equity Ownership. Dougherty:Celgene Corporation: Employment, Equity Ownership. Hinkle:Celgene Corporation: Employment, Equity Ownership. Gambini:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

Description: Abstract 443 Background: AZA is the current standard of care for IPSS int-2 and high (“higher”) risk MDS. However, most pts will experience primary or secondary treatment failure. To date, there is no published data on the outcome of those pts. Design: 565 patients from 4 independent cohorts, who had not responded to or relapsed after response to AZA, were included. The datasets included 3 prospective trials (AZA001 (n=138; Lancet Onc, 2009), J9950 (n=26; Cancer Res 2006), J0443 (n=32; NCT00101179) trials) and data from the French ATU compassionate use program (n=369). Two cohorts administered AZA as single agent (AZA001 and French ATU) while two combined AZA with a histone deacetylase inhibitor (J9950, sodium phenylbutyrate; J0443, entinostat). 339 patients had no clinical response to AZA while 226 relapsed after initial response. The influence of pre treatment variables and salvage treatment options on the outcome after AZA failure was analyzed. Survival was measured from the date of failure of AZA. Results: The cohort included 475 MDS (including 117 RAEB-T) and 90 sAML (AML secondary to MDS). Median age was 69 years and the median number of cycles of AZA before failure was 6 (range [1-41]). Patients were randomly assigned to one learning (n=377) and one validation (n=188) set stratified on the number of deaths. There was no difference in the baseline characteristics of the 2 sets. With a median follow-up of 15 months after AZA failure, the median overall survival (OS) was 6 months and the 2-year probability of OS was 15%. The multivariate model constructed with the learning set showed that age (HR 1.02/y, 95%CI [1.01-1.03], p=0.002), sex (female 7 months vs male 5.6 months HR 1.3 [1.01-1.67] p=0.04), cytogenetics (favorable 8 months vs intermediate 5.9 months HR 1.49 [1.06-2.08] p=0.02, vs high risk 4.6 months HR 2.19 [1.63-2.91] p

Description: Background: Azacitidine (Vidaza®) is an effective and safe treatment (Tx) for patients (pts) with MDS (JCO2002;20:2429) at a dosing schedule of 75 mg/m²/day SC for 7 days every 4 weeks. A dosing schedule eliminating the need for weekend administration would be more convenient to pts and clinicians. Reported here are results of the recently completed initial Tx phase (6 cycles of randomized Tx) of an ongoing study evaluating 3 alternative azacitidine dosing schedules. Methods: In this phase II multicenter, open-label trial, MDS pts were randomized to 1 of 3 regimens administered every 4 weeks for 6 cycles: AZA 5-2-2 (75 mg/m²/day x 5 days, followed by 2 days no Tx, followed by 75 mg/m²/day x 2 days); AZA 5-2-5 (50 mg/m²/day x 5 days, followed by 2 days no Tx, followed by 50 mg/m²/day x 5 days); or AZA 5 (75 mg/m²/day x 5 days). Major and minor hematologic improvements (HI) were assessed by International Working Group (IWG) criteria (Blood2000;96:3671) and pts with ≥56 Tx days were IWG evaluable. To determine whether therapeutic response is maintained after 6 cycles, a 12-month maintenance phase using the AZA-5 regimen administered every 4 or 6 weeks was added, and pts with at least stable disease were eligible to participate in that phase of the study. Results: A total of 151 pts were randomized to Tx with AZA 5-2-2 (n=50), AZA 5-2-5 (n=51), or AZA 5 (n=50). Most pts are FAB classification RA/RARS (57%) or RAEB (30%). Of the 139 pts (92%) who received ≥56 days of Tx and are IWG evaluable, 74 pts (49%) completed ≥6 Tx cycles. The median number of Tx cycles across all Tx arms was 6. Of IWG-evaluable pts, 71 (51%) experienced HI (Table). The proportions of red blood cell (RBC) transfusion-dependent pts who achieved transfusion independence were AZA 5-2-2: 55% (12/22), AZA 5-2-5: 60% (12/20), and AZA-5: 67% (16/24). In FAB low-risk (RA/RARS) transfusion-dependent pts at baseline, RBC transfusion independence was reached by 60% (9/15), 56% (5/9), and 61% (11/18), respectively. No Tx-related mortality has been reported. Most grades 3 and 4 Tx-related AEs were hematological (AZA 5-2-2: 44%, AZA 5-2-5: 33%, AZA 5: 18%). Conclusions: Independent of the alternative dosing regimen, the results of the initial 6-cycle Tx phase demonstrate a consistent response for HI, RBC transfusion independence, and safety profile across a broad range of MDS pts, including FAB low-risk pts. These results appear similar to those with the approved FDA regimen and further support the benefit of azacitidine in pts who are transfusion-dependent. Eligible pts continue to receive Tx during the ongoing 12-month maintenance phase of the study. Major Hematologic Improvement in IWG Evaluable Pts (N=139) Major HI AZA 5-2-2 (N=46) AZA 5-2-5 (N=44) AZA 5 (N=49) *Includes major and minor HI; pts counted only once for best response in an improvement category. n (%) (95% CI) n (%) (95% CI) n (%) (95% CI) Erythroid 15 (33) (20, 48) 17 (39) (24, 55) 19 (39) (25, 54) Platelet 10 (22) (11, 36) 8 (18) (8, 33) 9 (18) (9, 32) Neutrophil 3 (7) (29, 100) 4 (9) (40, 100) 4 (8) (40, 100) Any HI* 20 (44) (29, 59) 23 (52) (37, 68) 28 (57) (42, 71)

Description: Background: A previous CALGB trial (JCO2002;20:2429) showed a positive OS trend with AZA vs best supportive care (BSC) in MDS. The objective of this Phase III, international, multicenter, randomized, prospective trial was to demonstrate the superiority of AZA + BSC for prolonging OS vs CCR + BSC. Design: Higher-risk MDS patients (pts), FAB-defined as RAEB, RAEB-T, or CMML (10–29% marrow blasts) with an IPSS of Int-2 or High by central pathology/cytogenetic review, were enrolled. Before randomization, investigators preselected pts to 1 of 3 CCR: BSC only (transfusions, antibiotics, and G-CSF for neutropenic infection); low-dose ara-C (LDAC, 20 mg/m2/d x 14d, q 28d); or standard chemotherapy (Std CT: conventional induction/consolidation). Pts were stratified by FAB/IPSS and randomized to AZA (75 mg/m2/d x 7d, q 28d) or CCR. This trial did not allow erythropoietin. All analyses used the ITT population. Results: In all, 358 pts (70% male), were randomized at 79 sites to AZA (N=179) or CCR (N=179): BSC only (N=105, 59%), LDAC (N=49, 27%), or Std CT (N=25, 14%). Median age was 69 yrs (38–88) and per treatment (TX): AZA (69 yrs); BSC only (70 yrs); LDAC (71 yrs); and Std CT (65 yrs). The AZA and CCR groups were comparable for baseline (BL) parameters. At BL, 95% of pts were higher risk: RAEB (58%), RAEB-T/WHO AML (34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: Int-2 (40%), High (47%), and 13% indeterminate/other. AZA was administered for a median of 9 cycles; LDAC for 4 cycles. Median followup for the OS analysis was 21.1 months (mo). AZA demonstrated statistically superior OS vs CCR (stratified log-rank p=0.0001). AZA showed a median Kaplan-Meier (KM) OS time of 24.4 mo vs 15 mo with CCR (Figure). The hazard ratio (HR, Cox Model) was 0.58 (95% CI: 0.43, 0.77) for a 74% OS improvement. At 2 yrs, there was a 2-fold OS advantage: AZA (51%) vs CCR (26%), 95% CI: 13, 36%, p0.20). AZA was well tolerated with safety data consistent with previous reports. Conclusion: These data confirm and extend previous CALGB findings. This AZA trial is the first MDS clinical study to demonstrate a significant OS advantage, thus altering the natural disease course. AZA should now be considered first-line therapy for higher-risk MDS pts. OS Analyses per IPSS Cytogenetic Group Group % (n/N) Pts AZA Median (Months) CCR Median (Months) HR (95%CI) Log-rank p Good 46 (166/358) Not reached 17.1 0.61 (0.39, 0.96) 0.030 Intermediate 21 (76/358) 26.3 17.0 0.43 (0.21, 0.88) 0.017 Poor 28 (100/358) 17.2 6.0 0.52 (0.32, 0.87) 0.011 Figure Figure

Description: Background: Somatic gene mutations occur in the majority of MDS pts; specific mutations and high mutation frequency have prognostic relevance (Papaemmanuil et al. Blood. 2013;122:3616-27). Evaluation of somatic mutations may support the diagnosis of MDS and guide treatment (Tx) selection. The phase 3 randomized MDS-005 study compared LEN and placebo (PBO) Tx in red blood cell transfusion-dependent (RBC-TD) non-del(5q) lower-risk MDS pts ineligible for or refractory to ESAs. Deletions in chromosome 5q are associated with a high response rate to LEN in MDS pts; however, no mutations have been definitively associated with a predictable clinical response to LEN in non-del(5q) MDS. Aim:To investigate the relationship between somatic gene mutations detected by targeted next-generation sequencing (NGS) and response and overall survival (OS) in lower-risk non-del(5q) MDS pts treated with LEN in the MDS-005 study. Methods: Eligible pts were: RBC-TD (≥ 2 units packed RBCs/28 days 112 days immediately prior to randomization) with International Prognostic Scoring System defined Low-/Intermediate-1-risk non-del(5q) MDS; ineligible for ESA Tx (serum erythropoietin 〉 500 mU/mL); or unresponsive or refractory to ESAs (RBC-TD despite ESA Tx with adequate dose and duration). 239 pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40-60 mL/min) or PBO. DNA was isolated from bone marrow mononuclear cells or whole blood collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate tissue for analysis. Targeted NGS of 56 genes was performed at Munich Leukemia Laboratory; average sequencing coverage was 2,000-5,000-foldand the variant allele frequency detection cutoff was 3%. Target regions varied by gene, including all exons to hotspots. For association tests, mutant variants (heterozygous or homozygous) were scored as 1 (mutant) or 0 (wildtype) for gene-level analyses. A Fisher exact test was used to test association of mutation status with response. Median OS was calculated by the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were determined by a non-stratified Cox proportional hazards model. A log-rank test was used to test treatment effect with OS for single gene mutation status. Results: The biomarker cohort included 198 of 239 pts (83%; LEN n = 130, PBO n = 68). At least 1 mutation was detected in 30/56 (54%) genes and 173/198 (87%) pts. The most frequently mutated genes were SF3B1 (59%), TET2 (33%), ASXL1 (23%), and DNMT3A (14%); the most frequent co-mutations were SF3B1/TET2 (23%), SF3B1/DNMT3A (10%), SF3B1/ASXL1 (10%), and TET2/ASXL1 (9%) (Figure). Of 116 pts with SF3B1 mutations, 115 (99%) had ≥ 5% ring sideroblasts. The 56-day RBC transfusion-independence (RBC-TI) response rate was significantly lower in LEN-treated ASXL1 mutant pts vs wildtype pts (10% vs 32%, respectively; P = 0.031). At 168 days, the RBC-TI response rate was still lower in LEN-treated ASXL1 mutant pts vs wildtype pts (7% vs 22%); however, the difference was not significant (P = 0.101). LEN-treated DNMT3A mutant pts had a higher 56-day RBC-TI response rate vs wildtype pts (44% vs 25%); however, this difference did not reach significance (P = 0.133) due to the small sample size. RBC-TI response rate with LEN was similar regardless of total number of mutations per pt. Higher numbers of mutations were significantly associated (P = 0.0005) with worse median OS. Mutation in any of the genes associated with a negative prognosis reported by Bejar et al. (N Engl J Med. 2011;346:2496-506) was also significantly associated (P = 0.0003) with worse median OS.However, OS was not significantly different in LEN- vs PBO-treated pts based on any single gene mutation status. Conclusions: In this group of lower-risk RBC-TD non-del(5q) MDS pts, somatic mutations in genes recurrently mutated in myeloid cancers were detected in 87% of pts. SF3B1 mutations (alone or in combination) were most frequent and not associated with response to LEN. ASXL1 mutant pts had a significantly lower LEN response rate vs wildtype pts, whereas DNMT3A mutant pts had a trend for improved LEN response. Median OS was influenced by mutations, but not significantly modified by LEN. Determining predictive clinical markers for Tx response in non-del(5q) MDS pts remains challenging; nevertheless, there is a significant need to identify pt subsets who may be responsive to LEN Tx. Figure. Figure. Disclosures Santini: Novartis: Consultancy, Honoraria; Amgen: Other: advisory board; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astex: Other: advisory board. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding. Zhong:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Discitis DX: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Description: Abstract 4705 Background: One of the most important clinical features of myelodysplastic syndromes (MDS) is the presence of chronic anemia which is directly related to fatigue. Patients' experiences of fatigue associated with chronic anemia are well-documented in the literature; however, consensus on measurement of fatigue is lacking. To understand the effect that fatigue has on the health-related quality of life (HRQL) of MDS patients, and the economic burden of the disease, a qualitative interview study was completed. Methods: Following a targeted review of the existing literature, 60-minute face-to-face in-depth qualitative interviews were conducted with MDS patients (n=17) in the US. All patients interviewed had a documented diagnosis of MDS according to the World Health Organization (WHO) 2008 classification. Interviewer questions were open-ended and focused on patients' HRQL and indirect costs associated with the disease. The 12-item Short-Form Health Survey (SF-12v2®) was administered after the interview to gain further insight into the impact on patients' HRQL. Qualitative data was analyzed using a grounded theory approach that combined semi-quantitative and qualitative methods. Results: The mean age of patients interviewed was 70.8 years; 59% of patients were male. The sample included patients of each WHO 2008 classification; the most common diagnosis was refractory cytopenia with multilineage dysplasia (47%). Based on the International Prognostic Scoring System (IPSS), 59% and 41% of patients were diagnosed with low and high risk MDS, respectively, with 76% of patients currently taking treatment for their MDS. Current treatments included erythroid growth factor support (53%; not approved for MDS in the US), hypomethylating agents (18%), and lenalidomide (6%). One patient reported transfusion-dependence (≥2 transactions in the past eight weeks) – however the number of patients receiving occasional transfusions was not recoded. This qualitative study found that MDS is associated with a considerable financial impact to patients. Based on the qualitative interviews with patients, the indirect financial costs reported (i.e., decreased work activities) were equally as burdensome to patients as their direct medical cost for treatment. Seven patients (41%) discussed the impact of MDS on their ability to work, either as a result of fatigue or their constant need for treatment. Patients reported being unable to complete work activities, taking time out of work for medical appointments, and reduced productivity during working hours. Patients also reported financial impacts associated with travel to medical appointments (n=11, 65%), and caregiver assistance with daily activities that patients had difficulty completing as a result of their disease (n=5, 29%). A total of 30 HRQL concepts within 11 domains (Table 1) were spontaneously reported by patients during the interviews, with the largest HRQL impairment being physical activity (n=16, 94%) directly related to patients' fatigue. These results are consistent with findings from the SF-12v2® questionnaire, on which patients scored a mean Physical Functioning domain score of 37.5 (SD 30.28) on a scale from 0–100 where a higher score indicates a better health status. MDS patients also frequently reported the social (n=12, 71%), sleep (n=11, 65%), functional (n=10, 59%), and emotional (n=9, 53%) impacts of the disease. Conclusions: These qualitative findings provide additional insight on the HRQL and financial impact of MDS which has been considered yet not fully articulated in the literature for these patients. Specifically, in addition to decline in HRQL, fatigue and the constant need for treatment in MDS appear to impact patients' work activities as well as their productivity within society. Disclosures: Mahmoud: celgene: Employment. Hudgens:Celgene: Consultancy. Taylor:Celgene: Consultancy. Pompilus:Celgene: Consultancy. Hwang:Celgene: Consultancy. Beach:Celgene: Employment.