Azacitidine Arm Research Articles

Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy.

7009Background: Venetoclax (VEN) is a potent, orally bioavailable BCL-2 inhibitor with single-agent activity in relapsed/refractory acute myeloid leukemia (AML) patients (pts), displaying synergistic activity with hypomethylating agents in preclinical studies. This trial evaluates VEN plus decitabine (DEC) or azacitidine (AZA) in treatment (Tx)-naive AML pts ≥ 65 y (NCT02203773). Methods: Tx-naive pts (ECOG PS ≤ 2, ≥ 65 y, intermediate- or poor-risk karyotype) not eligible for standard induction therapy received DEC (Arm A: 20 mg/m2 iv) daily on days (D) 1−5 or AZA (Arm B: 75 mg/m2; subcutaneous or iv) daily on D 1−7 of each 28-D cycle in combination with once-daily continuous oral VEN. VEN dose escalation follows a 3+3 design; 1200 mg is the final dose level. Objectives include safety, preliminary efficacy, and biomarker evaluations. Results: As of 11/28/15, 39 pts (49% male; median age 74 y [65–85 y]) have been enrolled in Arm A (n = 20) and Arm B (n = 19). Median time on study is111 D (6−375 D); 16 pts...

Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study

Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study

Intensive Treatment Versus Azacitidine for Acute Myeloid Leukemia in Elderly: Retrospective Evaluation

Backround: Most of patients with acute myeloid leukaemia (AML) are elderly and older age is an negative prognostic factor for AML. There is no consensus about treatment of elderly patients with AML. In this study, we evaluated intensive treatment with cytosine arabinoside and idarubicine versus azacitidine treatment. Primary objectives were evaluation of disease free (DFS) and overall survival (OS), the rate of complete remission and the remission duration. Methods: 45 patients with AML were evaluated retrospectively. We examined peripheral blood smear, bone marrow aspirate and trephine, immunophenotyping and cytogenetic analysis, biochemical evaluation of renal and liver function and coagulation profile in pre-treatment period. Intensive treatment consisted of cytosine arabinoside 200 mg/m2/day for 7 days and idarubicin 12 mg/m2/ for 3 days. Bone marrow examination was done between 14-28 days for intensive treatment and 2-6 cyclus for azacitidine treatment. Consolidation treatment (1-3) was done after intensive treatment if the patients were remission. All patients were ≤ECOG 2. Growth factors were not routinely administered before, during or after chemotherapy. Statistical analyses, differences in baseline characteristics between groups were analyzed using the Student's t-test for continuous variables and differences in OS between groups were then analyzed using the likelihood ratio or log-rank tests. Table 1. The main properties of patients with elderly AML Treatment arm Mean age Sex M/F Leucocyte mean Hb gr/dl FAB (n) MDS history(n) LDH Complete remission Total 73±9 26/19 34.029 ±6870 8.53±1,2 M0:15, M1:6, M2:15,M4:4,M5:2 Yes:21 No:24 276±151 15 Intensive 72±7 18/10 44.176±12390 6.91±2 M0:6, M1:4, M2:12, M4:3, M5:1 yes: 14 299±101 13 Azacitidine 74±8 8/9 31.289±4013 8,95±1.6 M0:9, M1:2, M2:3, M4:1, M5:1 yes:7 256±72 2 Results: Total patient number were 45 and they were ≥ 65 years (yrs). Male/female ratio was 29/16. Two patients rejected leukemia treatment. One patient were not evaluated for treatment response. Intensive arm consisted of 26 patients and azacitidine arm 16 patients. Disease free survival and overall survival for intensive arm and azacitidine arm were 12,1±9,4, 16,7±22,4, respectively. The most importance factors were leucocyte counts, hb level. Picture 1-2: Disease free survival and overall survival for intensive arm and azacitidine arm Conclusions: These results showed that intensive treatment is more effective than azacitidine in elderly AML patients with ECOC≤2. There is need for large studies which include higher number of patients with AML in order to evaluate efficiency of intensive treatment. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Azacitidine Followed By Intensive Induction/Consolidation Chemotherapy in Older Patients with Acute Myeloid Leukemia (AML): Results from the Randomized AML-AZA Trial of the Study Alliance Leukemias (SAL)

▪IntroductionAberrant DNA methylation is a common feature of acute myeloid leukemia (AML) and increases with age. DNMT inhibitors such as Azacitidine (AZA) can induce meaningful responses and remissions in AML as monotherapy. The combination of AZA with standard chemotherapy (7+3) has not been tested in a randomized trial.Patients and study designThe AML-AZA trial compared AZA directly followed by standard induction therapy, AZA followed by standard consolidation, and further Azacitdine maintenance with standard induction and consolidation without AZA in older patients with AML. All patients received standard Cytarabine (100 mg/sqm) and Daunorubicin (60 mg/sqm) induction (“7+3”) and up to two cycles of intermediate dose Cytarabine (1 g/sqm q12hr days 1, 3, 5) as consolidation therapy. AZA (75 mg/sqm for 5 days) preceded each therapy cycle in the AZA arm. In addition, AZA maintenance for up to 1 year was also scheduled for patients in the AZA arm. 105 patients were randomized to receive AZA plus Cytarabine plus Daunorubicin as induction therapy (AZA + 7+3) and 109 patients to receive 7+3 only (control group). Median age was 70 years in both treatment arms. Patient cohorts were well balanced with regard to blast counts in bone marrow, secondary versus de novo AML and molecular genetics risk group. More patients in the AZA + 7+3 arm (39/105; 37.1%) than in the control group (25/109; 22.9%) showed high risk cytogenetics (p=0.057). Event free survival (EFS) was the primary end point. Secondary endpoints were overall survival (OS), complete remission (CR) rate, toxicity and different treatment response according to molecular markers.ResultsOverall, 214 of 216 planned patients were enrolled into the AML-AZA trial. Due to a higher number of severe adverse events (SAE), AZA administration was stopped after recruitment of 214 patients whereas chemotherapy was continued as planned. Percentages of patients in the AZA arm with AZA doses as initially planned were as follows: 99% for first induction cycle, 72% for the second induction cycle. AZA as maintenance therapy for at least one cycle was delivered to 18% of patients in the AZA group. At least one SAE occurred in 51% of AZA + 7+3 patients compared to 31% of 7+3 patients (p=0.005). Cardiac disorders with CTCAE grade 3-5 occurred more frequently in the AZA + 7+3 arm (n = 15) than in the 7+3 arm (n = 6) (not significant). Leukopenia was prolonged by one day (median 23 vs 22 days) in the AZA + 7+3 group (p=0.043), whereas time of thrombocytopenia was not different. The early death rates at 30, 60 and 90 days did not differ significantly between treatment groups. Efficacy analyses were performed on an intention-to-treat basis. Median EFS as the primary endpoint was 6 months in both treatment arms (p=0.96). Median OS was 16 months for patients treated with AZA + 7+3 and 21 months for 7+3 (p=0.35). Median relapse free survival was 12 months in both treatment arms (p=0.95). 48 of 100 patients (48%) in the AZA + 7+3 arm achieved complete remission (CR) after induction therapy versus 57 of 109 patients (52%) in the 7+3 arm (p=0.58). DNMT3A exon 23 mutations were detected in 30 out of 162 analyzed patients. Exploratory analyses were performed to detect a potential interaction between AZA + 7+3 response and DNMT3A mutation status. Trends for improved EFS and OS were noted for AZA + 7+3 treatment in DNMT3A mutated patients.ConclusionAZA as addition prior to standard induction and consolidation chemotherapy does not prolong EFS and OS in unselected older AML patients and it is more toxic. However, a trend towards better efficacy in patients with DNMT3A mutation was observed and should be further explored. DisclosuresMüller-Tidow:Celgene: Honoraria, Research Funding. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other. Kiehl:Roche: Membership on an entity’s Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ehninger:GEMoaB GmbH: Consultancy, Patents & Royalties.

Initial Results of a Randomized Phase II Study of Low Dose Decitabine (DAC) Versus Low Dose Azacitidine (AZA) in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS)

▪Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS.Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS.Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Chi-square test and independent t-test were performed to evaluate differences of patients’ characteristics. OS was estimated with the Kaplan-Meier method. A log-rank test was used for statistical analysis, and p<0.05 was considered statistically significant.Results: Between 11/2012 and 4/2014, 68 patients were enrolled. Eleven patients have not been on-study long enough for response assessment. Fifty-seven patients are currently evaluable in this study; 28 patients received DAC, and 29 patients received AZA. Median duration of follow-up is 9 months (range, 0-18+). Median age at enrollment was 71 years (33-85). Median time from diagnosis to therapy was 1.5 months (range, 0.2-63.4). Baseline patient demographic and clinical characteristics did not differ significantly between groups. Of the 28 patients in the DAC arm, 13 (46%) had diploidy, and 2 (7%) had complex karyotypes; 3 (11%) were low-risk and 25 (89%) were intermediate-1-risk by IPSS. Of the 29 patients in the AZA arm, 17 (59%) had diploidy, and 1 (3%) had complex karyotype; 5 (17%) were low-risk and 24 (83%) were intermediate-1-risk by IPSS (2006). Six (21%) patients in the DAC arm and 7 (24%) in the AZA arm received growth factor support prior to therapy.Overall, 19 (33%) patients achieved CR, 2 (4%) CRp, 6 (11%) mCR, and 5 (9%) HI. In the DAC arm, 15 (54%) achieved OIR, 10 (36%) CR, 1 (4%) CRp, 3 (11%) mCR, and 1 (4%) HI. In the AZA arm, 16 (56%) achieved OIR, 9 (31%) CR, 1 (3%) CRp, 3 (10%) mCR, and 3 (10%) HI. Median response duration is 13 months (range, 0-16+). In the DAC group, 1 (8%) out of 12 initially RBC-dependent patients became RBC independent, 3 of 5 RBC/platelet-dependent patients became RBC/platelet-independent, and 1 (7%) of 14 transfusion-independent patients became RBC-dependent. In the AZA group, 3 (27%) of 11 initially RBC-dependent patients became RBC-independent, and 1 (7%) of 14 transfusion-independent patients became dependent. The median number of courses is 7 (range, 2-17+). Treatment has been well tolerated, and only 3 (5%) patients had dose reduction due to grade 3-4 myelosuppression. No death is observed during therapy but 9 deaths in total (16%) were observed after HMA failure; 3 (10%) in AZA and 1 (3%) in DAC in patients who failed to respond and discontinued therapy before death; 2 (7%) in AZA and 3 (11%) in DAC in patients who progressed to higher grade of MDS and changed therapy before death. The 1-year survival rates for the DAC and AZA were 80% and 67%, respectively (p=0.478). Median OS has not been reached, and no difference was noted between groups. Analyzing survival by the MDA lower-risk scoring system (Leukemia. 2008;22:538-543), the median survival was not reached for patients with low-risk disease, not reached for patients with intermediate-risk disease, and 272 days for patients for high-risk disease. The 1-year survival rates were 100%, 82%, and 64% for patients with low-, intermediate-, and high-risk disease, respectively.Conclusion: Low-dose HMA shows promising results in patients with low- or intermediate-1- risk MDS, with an OIR of 53%. The study continues to accrue patients, and results will continue to be updated as they are analyzed. DisclosuresNo relevant conflicts of interest to declare.

Azacitidine (AZA) Versus Conventional Care Regimens (CCR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (>30% Bone Marrow Blasts) with Morphologic Dysplastic Changes: A Subgroup Analysis of the AZA-AML-001 Trial

Azacitidine (AZA) Versus Conventional Care Regimens (CCR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (>30% Bone Marrow Blasts) with Morphologic Dysplastic Changes: A Subgroup Analysis of the AZA-AML-001 Trial

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown.Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%.Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA).Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. [Display omitted] [Display omitted] DisclosuresSekeres:Boehringer-Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Bone Marrow Hypocellularity Does Not Impair the Tolerability or Efficacy of Azacitidine (AZA) in Patients with Higher-Risk Myelodysplastic Syndromes Treated in the AZA-001 Study

AbstractAbstract 3808 Background:Approximately 10–15% of patients with myelodysplastic syndromes (MDS) have a hypocellular bone marrow (BM) at diagnosis. Some studies have suggested hypocellular MDS may have an adverse prognostic impact, but this is controversial. In the Phase 3 randomized AZA-001 study, AZA prolonged overall survival (OS) in patients with higher-risk MDS compared with conventional care regimens (CCR) (Lancet Oncol, 2009). However, the efficacy and tolerability of AZA in the subset of patients with hypocellular MDS has not been determined. Purpose:This post hoc analysis was conducted to determine whether the prolongation of OS observed with AZA compared with CCR in the AZA-001 study is influenced by baseline BM cellularity. We also sought to explore the tolerability of AZA treatment in patients with higher-risk MDS and hypocellular BM. Methods:Study design of AZA-001 is reported elsewhere (Lancet Oncol, 2009). Briefly, patients with higher-risk MDS (FAB: RAEB, RAEB-t, or CMML, and IPSS Int-2 or High risk disease) were randomized to AZA (75 mg/m2/d SC × 7d q 28d) or to CCR (supportive care, low-dose Ara-C [LDAC], or intensive chemotherapy [IC]). In the current analysis, patients were divided into 2 groups based on centrally reviewed baseline BM biopsy samples which confirmed the diagnosis of MDS (J. Bennett): a hypocellular (≤30%) group and a non-hypocellular (>30%) group. OS was assessed using Kaplan-Meier methods and treatments were compared by log-rank analysis. Results:Of 358 patients in AZA-001 (AZA n=179, CCR n=179), BM cellularity data were available for 299 patients (AZA n=154, CCR n=145). At baseline, 87% of patients (n=260) had non-hypocellular BM and 13% of patients (n=39) had hypocellular BM. Of patients with hypocellular BM in the CCR group (n=18), 7 patients (39%) received supportive care, 9 (50%) LDAC, and 2 (11%) IC. In general, baseline characteristics were similar between the hypocellular and non-hypocellular BM groups. Similarly, age, % BM blasts, cytogenetics, cytopenias, and transfusion dependence, were generally balanced across treatments within the 2 cellularity groups (Table). Median (range) duration of AZA treatment cycles in hypocellular patients was 35.5 (28–54) days and in non-hypocellular patients was 33.0 (15–75) days. Response (complete or partial response [CR+PR]) rates in hypocellular patients treated with AZA were 0% and with CCR were 5.6% (p=0.4615); and hematologic improvement (HI) rates were 52% and 41%, respectively (p=0.532). In non-hypocellular patients treated with AZA or CCR, rates of CR+PR were 7.5% and 0.8%, respectively (p=0.010); and HI rates were 48% and 28% (p=0.001), respectively. The improvement in OS in AZA-treated patients was more pronounced in the hypocellular group than the non-hypocellular group, whereas OS in CCR-treated patients was similar regardless of BM cellularity (Figure). Median OS was significantly prolonged with AZA vs. CCR in both the hypocellular and non-hypocellular groups. In patients with hypocellular BM, at 33 months median OS was not reached (NR; 95% CI: 19.2, NR) in the AZA arm vs. 16.9 months (95% CI: 11.1, 19.3) in the CCR arm (p=0.001). In patients with non-hypocellular BM, median OS in the AZA arm was 21.1 months (95% CI: 16.2, 34.7) vs. 15.3 months (95% CI: 9.3, 17.6) in the CCR arm (p=0.012). Safety and tolerability in the two BM cellularity groups were similar to that seen in the overall AZA-001 study (Lancet Oncol, 2009). Frequencies of grade 3–4 hematologic AEs in AZA-treated patients in the hypocellular and non-hypocellular groups were similar: anemia (9.5% vs 14.7%, respectively), febrile neutropenia (9.5% vs 11.6%), leukopenia (14.3% vs 13.2%), neutropenia (61.9% vs 60.5%), and thrombocytopenia (61.9% vs 58.1%). Conclusions:In this post hoc analysis, the prevalence of patients with hypocellular MDS was 13%, consistent with the reported prevalence in the general MDS population (Bennett, 2009). The survival advantage with AZA vs. CCR in both baseline BM cellularity groups observed in this analysis was consistent with the overall OS advantage with AZA shown in AZA-001. These findings suggest AZA is a safe and effective treatment option for patients with BM hypocellularity. [Display omitted] [Display omitted] Disclosures:Seymour:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau, Travel support Other. Bennett:Celgene Corporation: Consultancy. List:Celgene Corporation: Consultancy. Mufti:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Fenaux:Celgene: Honoraria, Research Funding. Hetzer:Celgene Corporation: Employment, Equity Ownership. Songer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

Results of a phase II trial of azacitidine (AZA) with or without epoetin beta (EPO) in lower-risk MDS.

6523 Background: Although anemia of IPSS low and int-1 (LR) MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients (pts), response is generally transient. Anemia recurrence with RBC cell transfusion dependency (RBC-TD) is an indicator of poor prognosis, even in absence of progression to higher risk MDS. AZA leads to RBC transfusion independence (RBC-TI) in 30–40% of LR-MDS (Lyons, JCO, 2009), but it has not been prospectively tested in LR-MDS patients resistant to ESA. It also remains unknown if the addition of ESA to AZA would be useful in such pts. Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), the Groupe Francophone des Myélodysplasies (GFM) compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus EPO 60000U/week (AZA+EPO arm). Inclusion criteria were LR-MDS resistant to at least 12 weeks of ESA, with RBC-TD ≥ 4 RBC units in the previous 8 weeks. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was RBC-TI (HI-E major using IWG 2000 criteria) after 6 courses. Results: Between 2009 and 2010, the 98 planned pts were included: M/F 65/28; median age 71y (41-84); 5 pts were excluded (one consent withdrawal, 2 early unrelated events and 2 with exclusion criteria). In the remaining 93 pts, IPSS risk was low in 69 and int-1 in 23 pts, with no imbalance between arms. Five pts received &lt; 4 cycles and 16 received only 4 or 5 cycles, mainly due to toxicity or progression. RBC-TI after 6 courses was observed in 16.7% (8/48) in the AZA arm and 18 % (8/45) in the AZA+EPO arm (P=1), and in 19.5% (8/41) and 26 % (8/31) respectively, in the 72 pts who received ≥ 6 cycles (P=.57). Overall best response rate (at least HI-E minor using IWG 2000 criteria) was 35 and 33% in the AZA and AZA+EPO arms, respectively (P=0.99). Of note, only 9 pts in the AZA+EPO arm required at least one hospitalization for a SAE, compared to 22 pts in the AZA arm (P=0.015). Conclusions: Erythroid response to AZA, in LR MDS with demonstrated ESA resistance, appears lower than expected, with no improved outcome when combined with an ESA. The latter may however improve tolerance of AZA in LR MDS.

Interim Results of A Randomized Phase II Trial of Azacitidine (AZA) +/− Epo In Lower Risk Myelodysplastic Syndrome (MDS) Resistant to An Erythropoietic Stimulating Agent (ESA) Alone

AbstractAbstract 1880 Background:Red blood cell (RBC) cell transfusion dependency (TD) is an indicator of poor prognosis in IPSS low and int-1 (lower risk) MDS. In addition, median response duration to ESAs is only about 2 years (Park, Blood, 2008). AZA can lead to RBC transfusion independence (RBC-TI) in 30–40% of lower risk MDS (Lyons, JCO, 2009), but it has not been systematically evaluated in ESA-resistant lower risk MDS and it remains unknown if the combination of AZA and ESA would be useful in such patients (pts). Methods:In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), we compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus epoetin beta 60000 U/week (AZA+EPO arm) in lower risk MDS. Inclusion criteria were: IPSS low or int-1 MDS resistant to ESA (i.e having received at least 12 weeks of EPO ≥60000 U/w or darbepoetin ≥250 μg/w or having relapsed after response to ESA), and with RBC-TD of at least 4 RBC units in the 8 weeks prior to enrollment. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was major erythroid responses (HI-E major) after 6 courses, according to IWG 2000 criteria. Secondary endpoints included overall IWG 2000 HI-E, including major and minor, after 4 and 6 courses, response duration, IPSS progression, survival and toxicity. An interim analysis was planned after 49 of 98 planned patients were evaluable for response after 6 courses. Results:From Feb 09 to first of Jul 10, 96 pts were included (M/F=2:1); median age 72y (45-85); 3 pts did not receive any study drug and were excluded from the analysis (one consent withdrawal, one pancreatic cancer and one fatal cardiac event); 93 pts are the subject of this analysis (RARS=40, RCMD-RS=16, RCMD=12, RA=5, RAEB1=12, CMML=7, Unclassified=1). IPSS cytogenetics was favorable in 73, intermediate in 18, adverse in 1 (this pt was not excluded from the present analysis) and failed in 1 cases, with no imbalance for all these characteristics between arms. Overall, 68% of the pts were resistant to ESAs and 32% had lost response to ESA (after a median response duration of 32 weeks, range: 4–120). Median RBC-TD was 6 units (range: 4–16) in the 8 weeks prior to enrollment. Fifteen pts were too early for evaluation of response, 78 were evaluable for toxicity and 72 and 52 pts were evaluable for response after 4 and 6 courses, respectively, as 6 and 22 patients went off-study before 4 and 6 courses, respectively, due to toxicity or progression. Although overall HI-E rates were similar in the AZA and AZA+EPO arms, (40 and 36.5 % respectively, P=0.51), there was a trend for more frequent HI-E major after 6 courses (ie the primary endpoint of the study), in the AZA+EPO arm (7/22,32%), compared to the AZA arm (4/30,13%, P=0.17). Furthermore, in responding patients, the proportion of HI-E major was significantly greater in the AZA+EPO arm (87.5%) compared to the AZA arm (30%, P=0.03). Finally, a significant increase in HI-E major between 4 and 6 cycles was noted only in the AZA+EPO arm (P=0.016). Seventeen responding patients entered the maintenance phase. Of the 78 pts evaluable for toxicity, 22 (28%) had to be hospitalized at least once for an anemia-related event (N=6) and/or a clinical infection/febrile neutropenia (N= 16). Interestingly, only 6 pts had to be hospitalized in the AZA+EPO arm, compared to 16 in the AZA arm, (P=0.o4). Conclusions:In this first randomized study comparing AZA and AZA+ EPO in highly transfusion-dependent lower-risk MDS, this planned interim analysis shows a promising trend for more major HI-E in the AZA+EPO arm, suggesting that addition of EPO to AZA increases the frequency of major erythroid responses in those patients, and may also significantly decrease the hospitalization rate due to infectious and non-infectious complications, allowing more patients to receive prolonged treatment with azacitidine. Updated results will be presented at the meeting. Disclosures:Récher:Celgene: Consultancy, Honoraria, Research Funding. Vey:Celgene: Consultancy, Honoraria, Research Funding. Fenaux:Celgene: Consultancy, Honoraria, Research Funding. Gardin:Celgene: Consultancy, Honoraria, Research Funding.

Treatment of high-risk MDS patients (pts) with -7/del(7q) with azacitidine (AZA) versus conventional care regimens (CCR): Effects on overall survival (OS)

7033 Background: -7/del(7q) is associated with poor prognosis in MDS. In a recent phase III, randomized trial, AZA significantly prolonged OS in pts with high-risk MDS (Fenaux, Blood 2007;110,817). This analysis assessed the effect of AZA on OS in this subgroup of high- risk MDS pts with -7/del(7q). Methods: Primary inclusion criterion for the Phase III study was high-risk MDS (FAB RAEB, RAEB-T, or CMMoL and IPSS Int-2 or High). Pts were randomized to AZA (75 mg/m2/d x 7d, q28d) or CCR. CCR comprised 3 treatments: BSC only (transfusions, antibiotics, G-CSF for neutropenic infection); low-dose ara-C (20 mg/m2/d x 14d, q28d); or induction chemotherapy (7+3 regimen). No erythropoietin was allowed. Results: At baseline (BL), 57 (30 AZA, 27 CCR) of 358 pts in the total population had -7/del(7q), 35% had -7/del(7q) alone and 65% had -7del(7q) as part of complex karyotype. BL characteristics were balanced in the 2 arms: 70% male; median age, 69 years. The median Kaplan Meier difference in OS for AZA vs CCR was 8.4 months, a significant improvement (3-fold) over CCR (Table). The hazard ratio (HR) was 0.33 (95% CI: 0.16–0.68) indicating a 67% reduced risk of death in the AZA arm; this compares with an HR of 0.58 for the OS improvement with AZA vs CCR with all cytogenetic subtypes in the phase III trial. At 2 years, a 4-fold OS advantage was observed in the AZA arm with 33% of pts alive vs 8% in the CCR arm (p=0.03). Secondary endpoints support the OS advantage (Table). Significantly higher IWG 2000 response rates (CR+PR) were seen in pts with -7/del(7q) alone (64% vs 11%; p=0.03) or complex (21% vs 0; p=0.02) with AZA vs CCR, and compared favorably to the overall AZA group with IPSS good and intermediate cytogenetics. AZA was generally well tolerated. Conclusion: This phase III subgroup analysis indicates the disease modifying effect of AZA extends to unfavorable cytogenetic patterns that include -7/del(7q), and suggests AZA may represent the treatment of choice for this otherwise poor prognosis subset. OS, CR, PR, HI, and transfusion independence (TI) in RBC-dependent -7/del(7q) pts at BL (n/N,%) OS (mos) CR+PR CR RBC TI HI-E HI-P AZA 13.1 13/30, 43 8/30, 27 12/21, 57 13/26, 50 10/20, 50 CCR 4.6 1/27, 4 1/27, 4 0/19, 0 0/24, 0 2/25, 8 P value 0.003 0.0005 0.03 <0.0001 <0.0001 0.002 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Amgen, Celgene, Pharmion Corporation Pharmion Amgen, Celgene, Cephalon, Johnson & Johnson, Novartis, Pharmion, Roche Pharmion Corporation

FDA Drug Approval Summary: Azacitidine (5-azacytidine, Vidaza™) for Injectable Suspension

On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.