Azacitidine Maintenance Research Articles

Response-Adapted Sequential Azacitidine and Induction Chemotherapy in Patients > 60 Years Old with Newly Diagnosed AML Eligible for Chemotherapy (RAS-AZIC): First Data of the Interim Analysis of the DRKS00004519 Study of the East German Study Group (OSHO)

The prognosis of AML in patients (pts) >60 years (y) is poor and there is no universally accepted standard approach. After induction chemotherapy (IC), a complete remission (CR+CRi) rate of 56.4% and a mortality of 21% at day (d) 90 are expected (Niederwieser et al, ASH 2012). Azacitidine (AZA) yields a one-year survival (OS) rate of 46.5% in pts >65 y and >30% marrow (BM) blasts (Dombret et al, Blood 2015). Yet, AZA and IC are not mutually exclusive. First results of the interim analysis of the DRKS00004519 (RAS-AZIC) study which evaluates priming with AZA followed by AZA or IC in pts >60 y with AML are presented.Patients and methods: Major inclusion criteria are newly diagnosed AML with marrow blasts >20% by aspiration or biopsy irrespective of WBC count, age >60 y, and eligibility for IC. Secondary AML from an antecedent hematologic disorder and therapy-related AML are not excluded.In the phase I part of the trial, safety of priming with AZA (75 mg/m2/day s.c) for 7 d followed by IC (Mitoxantrone 10 mg/ m2/day d 1-3 and cytarabine 1 g/m2/BID d 1, 3, 5, 7) on d 17 was established through a 3+3 design. In the multicenter phase II part (figure), priming was sequentially followed by AZA or IC based on d 15 BM blasts and d 56 response which were identified as early predictors for long-term response to AZA in AML (Al-Ali et al., Leuk Lymph 2012). The primary objective is overall response (OR) which includes CR, CRi, and PR at d 90 according to the International Working Group criteria (Cheson et al, J Clin Oncol 2003). Safety, OS, and mortality were secondary end points. According to the optimal two-stage design (Simon, Control Clin Trials 1989), an expected OR of 61% at the end of trial was estimated. Thus in a first stage analysis, < 19 of consecutive 40 (47.5%) pts not achieving the primary objective would be considered an indication for inferiority of the protocol treatment compared to standard IC. Hence, an interim analysis of the first stage was planned per protocol while accrual continues to include the first 40 pts who received the maximal tolerated priming dose of AZA. The trial is supervised by an independent Data Monitoring Committee. Adverse events (AEs) are reported according to the NCI CTCAE 4.03. All pts gave written informed consent.Results: Patient characteristics are shown in table 1. Median age is 69 y and median blast count 39%. All pts received priming with AZA. Median BM blasts at d 15 was 27% (range 2.4-88%). To date, data on subsequent therapies are captured in 33 (82.5%) pts. Except for one (withdrew consent on d 27), all pts received protocol assigned treatment based on BM blasts on d 15 [17/32 (53%) continued with AZA, 15/32 (47%) received IC]. Likewise, 26/32 (81%) pts ([2x data not yet available, 2x death (d 34; d 53), and 2x physician's choice] received response-adapted treatment on d 56 [12/26 (46%) started AZA maintenance and 14/26 (55%) received IC]. OR at d 90 for the 26 as yet evaluable pts is 80.7% [CR (61.5%, n=16); CRi (11.5%, n=3); PR (7.7%, n=2). No additional mortality till d 90 was reported. For the entire cohort, 85% of pts are alive after a median follow-up of 6 months. AEs were consistent with the known safety profile of AZA and IC. AEs > grade 3 were reported 83x in 20 (50%) pts being mainly infectious and respiratory complications (60%). As expected, the majority (57%) were reported under IC, followed by 19% and 17% under priming and the 2. AZA cycle respectively. AEs led to postponement of the planned therapy in 6 pts (3x IC on d 17, 2x 2. AZA, 1x IC on d 56). The final assessment of the interim analysis is set in the near future.Conclusions: These data imply that in a heterogeneous disease like AML, integrating epigenetic therapy with chemotherapy in elderly pts in an individualized response-based approach is feasible, induces responses at least comparable to those seen after IC, and is associated with a remarkable low mortality. The definitive response rate and the impact of such an approach on survival will be answered at the end of the trial.Table 1Patient characteristics (n=40)Median age, range (years)69 ( 61 - 82)Male/Female (%)55 / 45Baseline ECOG (%)0/1/221 / 63 / 16Type of AMLDo novo/secondary (%)61 /39Median WBC (range) x 109/L6.7 (0.7 - 81.8 )Median bone marrow blasts (aspiration) (range) (%)39 (13 - 90)Cytogenetics (n=35)Normal/intermediate/unfavourable (%)54 /23 / 23FLT3+ (n=34) (%)9NPM1 + (n=34) (%)9 [Display omitted] DisclosuresAl-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine is not approved for the use in patients with AML and blasts > 30% outside clinical trials.

Advances of azacitidine in myelodysplastic syndromes

In recent years, researches on the mechanisms of methylation and demethylation treatment strategies have brought new ideas for treatment of myelodysplastic syndrome (MDS) . Azacitidine and decitabine were approved by United States Food and Drug Administration(FDA) for the treatment of MDS. Chinese researchers have a preliminary understanding of the clinical applications of decitabine after 5 years exploration. Azacitidine can improve the quality of life of high-risk patients with MDS, and prolong overall survival (OS) and the median time of acute myeloid leukemia(AML) transformation, especially in high-risk MDS patients over 65 years old compared with decitabine. Azacitidine maintenance therapy after hematopoietic stem cell transplantation(HSCT) can delay the recurrence. In addition, application of low-dose azacitidine for low-risk MDS patients is still in exploring. Azacitidine has been combined with other novel agents such as histone deacetylase(HDAC) inhibitors, lenalidomide and infliximab monoclonal antibody are very promising in clinical researches. However, azacitidine has not been approved by China Food and Drug Administration (CFDA) and lacks clinical experience. This article reviews literatures on exploring optimal dose, efficacy of different subtypes of MDS and prospects of azacitidine combination therapy. Key words: Azacitidine; Myelodysplastic syndromes; Drug therapy

CC-486 (Oral Azacitidine) Following Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in Patients with Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

Background: Disease relapse and graft vs host disease (GvHD) following alloHSCT are major causes of treatment (Tx) failure in patients (pts) with MDS and AML (Paietta, 2012). Studies of parenteral azacitidine, an epigenetic modifier, have shown efficacy in preventing post-transplant relapse in MDS and AML pts, and possibly reducing GvHD severity (Platzbecker, 2012; de Lima, 2010). Azacitidine maintenance after alloHSCT may enhance graft vs leukemia (GvL) effects and reduce GvHD by expansion of regulatory T cells (Goodyear, 2010, 2012). CC-486 is a novel oral formulation of azacitidine which, as well as potentially allowing easier administration over extended schedules, could increase the duration of drug exposure to residual malignant cells. We now report preliminary results from a prospective phase I/II dose-finding study of CC-486 as maintenance Tx after alloHSCT in pts with MDS or AML.Objective: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and safety outcomes of CC-486 following alloHSCT in pts with MDS or AML.Methods: Pts with WHO-defined MDS or AML who have undergone alloHSCT with myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens and who had sibling or unrelated donors with ≤1 antigen mismatch at the HLA-A, -B, -C, -DRB1 or -DQB1 locus, are enrolled. CC-486 Tx is initiated between days (d) 42 and 84 after alloHSCT. Pts receive prophylactic Tx for GvHD and infections per institutional standard. A standard 3x3 MTD design is being used to evaluate 4 dosing schedules: CC-486 200 mg or 300 mg QD, administered for 7 d (Cohorts 1 and 2) or 14 d (Cohorts 3 and 4) of repeated 28d Tx cycles. MTD determination is based on DLT that occur during the first 2 Tx cycles (pts are not evaluable if unable to complete 2 Tx cycles for reasons other than a DLT). Adverse events (AEs) are graded using NCI-CTCAE v4.0. Pts are followed for safety, incidence of acute and chronic GvHD, and relapse. PK of azacitidine after CC-486 administration, alone or with standard concomitant medications, are evaluated on d 1 of CC-486 Tx cycles 1 and 2.Results: At data cut-off (7/17/2014), outcome data were available for 7 pts enrolled in the first 2 cohorts (Table): 1 pt had IPSS Int-2 MDS and 6 had AML with high-risk features. Stem cell source was from bone marrow (n=2) or peripheral blood (n=5) from unrelated (n=5) or sibling (n=2) donors. Two pts had 1 antigen mismatch and 5 had a full match.Conditioning included MAC (n=3) and RIC (n=4) regimens. One pt in Cohort 2 was not evaluable for DLT or PK assessments due to early discontinuation (AML relapse) during the first CC-486 Tx cycle. Of the 6 evaluable pts, 4 completed ≥6 CC-486 Tx cycles and 2 ongoing pts had not reached 6 cycles on-study at data cut-off (Table). One pt who had GvHD before CC-486 Tx subsequently withdrew from the study after developing febrile neutropenia and diarrhea related to GvHD of the bowel; 1 pt withdrew for personal reasons; and 1 pt discontinued after 6 Tx cycles due to relapse. At data cut-off, 3 pts remained on-study, all with continued CR (Table). No pt in Cohort 2 developed GvHD. For all pts, most AEs were grade 1-2. Grade 3-4 AEs were reported for 2 pts: both had nausea and vomiting, which were controlled with antiemetic agents upon onset; 1 also had device-related infection and dyspnea, and 1 also had febrile neutropenia and rash. No DLT emerged with these CC-486 regimens and no pt experienced secondary graft failure. Overall azacitidine plasma concentration profiles (Figure) and PK parameters were similar following CC-486 given alone or with concomitant medications, and were within range of values observed following similar CC-486 doses in pts with MDS, CMML, and AML (Garcia-Manero, 2011). The AUC range for oral CC-486 is ~10% of that seen with subcutaneous azacitidine administered at 75 mg/m2 (Garcia-Manero, 2011).Conclusion: Preliminary data from this analysis suggest that CC-486 administered at doses of 200 or 300 mg QD for 7 days every 4 weeks is safe and well tolerated in the post-transplant setting. Overall, azacitidine plasma concentration profiles and PK parameters were not affected by use of concomitant medications. No DLT and a low rate of GvHD support the ongoing evaluation of 14d extended CC-486 dosing regimens in this ongoing study, as a preliminary to a prospective, randomized trial of this new agent post-transplant. [Display omitted] [Display omitted] Disclosuresde Lima:Celgene: Consultancy. Champlin:Celgene: Consultancy. Giralt:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Scott:Celgene: Consultancy, Honoraria, Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Craddock:Celgene: Honoraria, Research Funding.

Azacitidine Maintenance after Allogeneic Stem Cell Transplantation Is Feasible in Patients with Acute Myeloid Leukemia and Myelodysplasia

Background: 5-Azacidine (5-AZA) is a DNA hypomethylating agent with proven clinical activity in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A recent non-randomized study reported promising results with the use of lower doses of 5-AZA as maintenance therapy after hematopoietic stem cell transplantation (HSCT). It is important to note that 5-AZA has an immunomodulatory effect and might enhance the graft-versus-leukemia (GVL) effect. Here, we report the successful use of 5-AZA maintenance following allogeneic HSCT in patients with high risk AML and MDS.Patients and methods: Nine patients (M=6, F=3; median age=49 (36-65) years ) with high-risk AML (n=6 including 2 abnormal karyotypes) or MDS (n=3 including 1 abnormal karyotype) received 5-AZA as post-transplant maintenance at a dose of 32mg/m2 daily for 5 days every 4 weeks starting at a median time of 100 (30-210) days post-transplant. All patients were in complete remission at initiation of 5-AZA. A median of 12 cycles (1-18) were delivered. Patients’ characteristics, treatment details, response and side effects are summarized in Table I.Results: After a median follow-up of 19 months post HSCT and 15 months after starting 5-AZA treatment, five patients with normal karyotype are still in CR. Conversely, all three patients with abnormal karyotype rapidly developed disease recurrence while they were receiving 5-AZA after a median of 3 months. Overall, the actuarial 1-year progression free and overall survival rates were 65% and 90%, respectively. 5-AZA was generally well tolerated with only mild thrombocytopenia observed in 2 patients. No clinically evident graft-versus-host disease exacerbation was observed.Conclusion: These results suggest that Low-dose 5-AZA is an effective maintenance therapy post- allogeneic SCT in high-risk AML and MDS particularly when a normal diploid karyotype is present. The relative lack of efficacy in the presence of an abnormal karyotype is intriguing and questions whether these subjects might benefit from higher doses of 5-AZA or other novel therapies within the context of a well-designed clinical trial. Prospective clinical trials and longer follow-up are needed to confirm these observations. Abstract 5884 TABLE IPatients characteristics and Outcomes After Azacitidine maintenanceSubject #123456789Age at transplant655848433649495851genderMMFMFMFMMDiseaseAMLAMLAMLAMLSecondary AMLSecondary AMLMPD/MDSMDS (RAEB-2)MDS (RAEB-2)cytogeneticnormalnormalT(6,9)normalDel 5normalnormalnormalHypoploidy(43-45)Molecular abnormalityNoneNoneNoneFLT3 ITDNoneNoneNoneNoneNoneDisease status at HSCTCR2CR3CR1CR1RefractoryCR1PRPRCR1Donor typeMRDMRDMRDMRDMUDMRDMRDMRDMRDConditioningFB2+ATGFB3+ATGFB3+ATGFB4+ATGFB3+ATG+ TBI (4Gy)FB4+ATGFB4+ATGFB3+ATGFB2+ATGGVHD prophylaxisCSACSACSACSACSACSACSACSACSA, mycophenolate mofetilTime from HSCT to 5-AZA (days)37701001503021010055104Disease status at 5-AZACRCRCRCRCRCRCRCRCRnb of cycles12131241218129ToxicityNoneNoneNoneNoneGrade II thrombocytopeniaGrade II thrombocytopeniaNoneNoneNoneGVHD after 5-AZANoNoYesYesYesNoYesNoNoDisease recurrencenonoyesnoyesnononoyesSalvage therapy if recurrenceN/AN/AChemotherapy followed by DLIN/ANoneN/AN/AN/AChemotherapy followed by DLIProgression free survival, months13+24+124+319+21+18+10Status at last follow upCRCRCRCRdiedCRCRCRCRSurvival, months13+24+18+24+519+21+18+34+Stem cell source for all patients: peripheral blood; CR: complete remission; PR: partial remission; CSA: cyclosporine A; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; CCR: continuous complete remission; FB4: 5 days fludarabine plus 4 days busulfan (130 mg/m2/day); FB3: 5 days fludarabine plus 3 days busulfan (130 mg/m2/day); FB2: 5 days fludarabine plus 2 days busulfan (130 mg/m2/day) ATG: anti-thymoglobuline; DLI: donor lymphocyte infusion. DisclosuresOff Label Use: Azacitidine maitenance post HSCT.

Response-Adapted Sequential Azacitidine and Induction Chemotherapy in Patients > 60 Years Old with Newly Diagnosed AML Eligible for Chemotherapy (RAS-AZIC): Results of the Phase I of the DRKS00004519 Study

Survival (OS) in elderly patients with AML is poor. Azacitidine (AZA) prolongs OS in elderly patients even with >30% marrow (BM) blasts (Dombret, EHA, 2014). Remarkably, a hematologic response to AZA, not only complete remission (CR), correlates with a survival advantage. Yet, AZA and induction chemotherapy (IC), which could induce a 50% response in patients > 60 years, are not mutually exclusive. Identifying biomarkers for response to AZA such as BM blasts > 45% on day (d)15 of the first cycle, and response at d56 might identify patients early who are less likely to have a long-term benefit from AZA and for whom IC might be an option (Al-Ali et al, Leuk Lymph, 2012). Indeed, in vitro data suggest a possible synergistic effect of cytarabine and AZA when AZA is administered before cytarabine (Neil et al, Cancer Res, 1976; Kong et al, Mol Pharmacol, 1991). Results of the phase I of the DRKS00004519 (RAS-AZIC) study are presented where the feasibility of priming with AZA prior to IC was determined.Patients and methods: RAS-AZIC is a prospective, multicentric, phase I/II trial evaluating the efficacy of priming with AZA followed by a sequential, and response-adapted therapy on d17, d56, and d90 with AZA or IC in eligible patients > 60 years with newly diagnosed AML (phase II). AZA is continued on d28 if d15 BM blasts are < 45%, or else, IC on d17 is given. If response at d56 is CR/CRi, maintenance with AZA is continued/started. Otherwise, IC is given followed by AZA maintenance on d90 in patients who achieve CR/CRi/partial remission. Patients in CR could be assigned to allogeneic stem cell transplantation.In the monocentric phase I part, the safety and dose level of priming with AZA 75 mg/m2/day s.c. for 5 (dose level 1) or 7 days (dose level 2) followed by IC on d17 (Mitoxantrone 10 mg/ m2/day d 1-3 and cytarabine 1 g/ m2/BID d1, 3, 5, 7) needed to be established through a 3+3 design. Six to 12 patients were required with at least 3 patients treated at dose level 1 (figure 1). The level at which not more than one of 6 patients experienced a dose limiting toxicity (DLT) would be used in the phase II. DLT was defined as a medical event, at least possibly related to trial therapy, occurring within 56 days, and fulfilling one of the following: Grade ≥ 3 liver or renal toxicity (NCI CTCAE 4.03), or delay in WBC regeneration (≥ 1x109/L) beyond d45 after IC. After each cohort, a safety evaluation by an independent Data Monitoring Committee (DMC) was performed. All pts gave written informed consent.Results: The first 3 patients were enrolled at dose level 1. No DLT was encountered. Again, at dose level 2, no DLT occurred in cohort 1 and 2 (0/6 patients). Thus, phase I was completed after enrolling 9 patients. Median age was 71 (range 63-76) years, 5 patients (56%) were female. Secondary/therapy-related AML, and unfavorable cytogenetics were present in 56%, and 33% of patients respectively. Baseline median WBC and marrow blasts were 4.1 x109/L and 44% respectively (Table). AZA priming was given as out-patient therapy in 67% of patients. In 8 (89%) patients, IC was started as per protocol. In patient #9, IC was delayed and given on d26 because of viral pneumonia. Median WBC regeneration ≥ 1 x109/L following IC occurred after 24 (range 7-35) days. No early death on d90 ensued. CR/CRi on d56 in the entire phase I, and dose level 2 was 78%, and 100% respectively. BM blasts > 45% on d15 were documented in two patients at dose level 1, and one patient at dose level 2 (Figure 2). To date and after a median follow-up of 13 (range 6-19.5) months, median survival time is 12 (range 4-19) months with a survival rate of 67% . Priming with AZA 75 mg/m2/day s.c. for 7 days was considered safe and feasible by the DMC and ethic board. Phase II has now been initiated.Conclusions: Priming with AZA followed by induction chemotherapy is feasible in elderly pts with newly diagnosed AML. Results of the phase I are very encouraging in terms of safety and efficacy. It is unlikely that a single agent alone could accomplish the goal of attaining rapid responses and translating them into long-term survival in all pts because of the heterogeneity of the disease. Integrating AZA epigenetic therapy with chemotherapy in well-designed trials might further optimize outcome in elderly patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresAl-Ali:Celgene: Honoraria, Research Funding. Off Label Use: azacitidine priming prior to chemotherapy in AML within a clinical trial.

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.

A New Strategy Of MDS Treatment With Azacitidine (AZA): Induction With AZA Combined With Low Dose AraC Followed By Maintenance Therapy With AZA

IntroductionAzacitidine (AZA) is a promising agent for higher risk myelodysplastic syndrome (MDS), but it does not prevent disease progression as a single agent in most cases of AML. MDS is a heterogeneous disease not only pathologically but also clinically. Some cases have progressive clinical stages and disease-related symptoms (fever, edema and effusion), so called aggressive MDS (aMDS). Since some aMDS cases failed single agent AZA treatment, we considered combination chemotherapy with AZA for aMDS. Here we report the use of low dose of AraC followed by AZA for aggressive MDS in a pilot study. MethodWe evaluated eligible 37 MDS, CMML, overt AML and de novo AML patients from March, 2011 to June, 2013. All MDS and CMML patients had disease-related symptoms or disease progression in the previous 3 months. Twenty-two patients (median age 73 years, range 55-87) were treated with single agent AZA (sAZA) 75 mg/m2/day i.v. 1∼5, 8, 9 days every four weeks. For low dose AraC combination therapy, AraC 10mg/m2xtwice/day s.c. for 1∼5 days and Aclarubicin Hydrochloride (Aclacinon) 20 mg/m2/day i.v. for 1, 2days (CA therapy) was followed by AZA 75 mg/m2/day iv for 7 days (8∼12, 15, 16). Fifteen patients (median age 74 years, range 62∼85) received sAZA after 1 cycle of CA followed by AZA (CA-AZA). Responses were scored according to IWG 2006 criteria for MDS. ResultsDiagnosis was RCMD n=3, RAEB1 n=4, RAEB2 n=10, CMML n=1, overt AML n=3, de novo AML n=1 for sAZA-treated group and RCMD n=1, RAEB1 n=2, RAEB2 n=6, CMML n=2, overt AML n=4 for CA-AZA-treated group. IPSS-R risk category was intermediate n=6, high n=2, very high n=8 for sAZA-treated group and intermediate n=1, high n=1, very high n=7 for CA-AZA-treated group. Overall response rate was 27.2% and 80% for sAZA- and CA-AZA-treated groups, respectively. 50% of progressive disease and 9% (n=2) of failure (death) were observed in sAZA group at 1 to 3 courses of AZA. One year overall survival (1yOS) was 38.1% and 90.9% in sAZA- and CA-AZA-treated groups, respectively, without significant difference (P=0.11). In overt AML, CA-AZA treatment resulted in a significant difference in 1yOS (0% vs. 100%, P=0.02). In the higher risk groups (High, Very high and overt AML) and the poor and very poor karyotype groups, CA-AZA treatment showed a trend towards improved 1yOS (P=0.07, P=0.11) compared with sAZA. Adverse events were similar between two treatment groups. ConclusionsFor aMDS, sAZA therapy was not sufficient to control disease progression. To suppress disease progression and to improve the efficacy of AZA, we used CA prior to AZA maintenance therapy. In one case with overt AML and in two cases of aggressive type CMML, CA with AZA maintenance successfully prevented disease progression for almost two years. These three cases are now being treated every two or three months with sAZA as maintenance therapy. AZA combination therapy with AraC have been examined in in vitro and in vivo studies (R.L. Momparler Cancer Res. 1975;35, G.L. Neil Cancer Res. 1976;36). Our low dose and short term chemotherapy (CA) was safely and effectively combined with AZA for older aMDS patients. We are planning a clinical study to further evaluate CA-AZA therapy in a larger cohort of patients. Disclosures:Hirai:NIPPON SHINYAKU CO.,LTD: Speakers Bureau. Hino:NIPPON SHINYAKU CO.,LTD: Research Funding.

Low Dose Azacitidine Maintenance Therapy Following Allogeneic Stem Cell Transplantation for MDS/AML Does Not Interact with Tacrolimus Dosing or Serum Levels

AbstractAbstract 4209 Background:Recurrence of disease remains a significant cause of morbidity and mortality in patients who undergo allogeneic SCT for AML and MDS. Low-dose azacitidine is currently under investigation in the post-transplant setting with the goal of prolonging disease-free survival and decreasing relapse rates. It is unclear if there is potential pharmacologic interaction between azacitidine and dose-adjusted tacrolimus used to prevent post-transplant graft-versus-host disease (GVHD), a clinically relevant question since any resultant tacrolimus under- or over-dosing may lead to increased risk of GVHD or drug toxicity, respectively. We hypothesized that azacitidine does not significantly interact with tacrolimus levels and performed a retrospective analysis to test this hypothesis. Patients and Methods:We reviewed tacrolimus daily doses and serum drug levels of 62 AML and MDS patients who received azacitidine maintenance therapy (n=30) or no maintenance therapy (n=32) following allogeneic stem cell transplantation at MD Anderson Cancer Center between 2008–2012. Patient characteristics are summarized in the Table. Patients in the maintenance cohort received subcutaneous azacitidine at 32 mg/m2 on days 1–5 repeated every 28 days starting at a median time of post-transplant day +65 (range 43–100). Tacrolimus doses and serum levels were averaged for 28 days for each patient before and after initiation of azacitidine maintenance and at day +66 in the non-maintenance cohort. Differences between the two cohorts in their mean change of tacrolimus doses and serum drug levels were assessed using a Student’s t-test. Results:Mean (SD) oral tacrolimus doses pre- and post-maintenance therapy were 2.61 (2.13) mg daily and 2.44 (2.15) mg daily in the azacitidine group and 2.54 (1.86) mg and 2.23 (1.39) mg daily in the non-azacitidine cohort. This resulted in a mean change in tacrolimus dosing of -0.17 (1.16) mg daily in the azacitidine patients and -0.31 (1.10) mg daily in the non-maintenance group (p=0.62). Mean (SD) serum tacrolimus levels pre- and post-maintenance therapy were 8.07 (1.16) ng/mL and 7.58 (2.32) ng/mL in the azacitidine group and 8.23 (1.49) ng/mL and 7.10 (1.69) ng/mL in patients on no maintenance therapy. This resulted in a mean change in serum tacrolimus levels of -0.49 (2.75) ng/mL in the azacitidine cohort and -1.13 (2.04) ng/mL in the non-maintenance group (p=0.30). Conclusion:Maintenance azacitidine therapy following allo-SCT for AML and MDS does not appear to affect concurrent tacrolimus dosing or serum drug levels.TablePatient CharacteristicsAZA (N=30)No AZA (N=32)p-valueGender, n (%)Male17 (56.7)22 (68.8)0.43aFemale13 (43.3)10 (31.3)Age at transplant (years)Mean (SD)51.2 (14.5)52.5 (14.3)0.74bMedian (range)54 (19–72)57 (20–70)Diagnosis, n (%)AML26 (86.7)26 (81.3)0.73aMDS4 (13.3)6 (18.8)Donor type, n (%)Match unrelated donor10 (33.3)15 (46.9)0.69aMatch related16 (53.3)12 (37.5)Mismatch unrelated3 (10.0)4 (12.5)Haploidentical1 (3.3)1 (3.1)Stem cell source, n (%)Peripheral blood19 (63.3)22 (68.8)0.68aBone Marrow10 (33.3)8 (25.0)Cord1 (3.3)2 (6.3)Conditioning regimen, n (%)Fludarabine/Busulfan15 (50.0)15 (46.9)1.00aFludarabine/Melphalan11 (36.7)12 (37.5)Other4 (13.3)5 (15.6)GVHD prophylaxis, n (%)Tacrolimus/Methotrexate27 (90.0)27 (84.4)0.71aTacrolimus/Cyclophosphamide/MMF1 (3.3)3 (9.4)Tacrolimus/MMF1 (3.3)2 (6.3)Tacrolimus/Cyclophosphamide1 (3.3)0 (0.0)aFisher's exact test,bStudent's t-test Disclosures:Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML. Champlin:Otsuka: Research Funding. De Lima:Celgene: Research Funding.

Azacitidine-Containing Induction Regimens Followed by Azacitidine Maintenance Therapy in High Risk Acute Myeloid Leukemia: First Results of the Randomized Phase-II AMLSG 12-09 Study (ClinicalTrials.gov No. NCT01180322)

AbstractAbstract 412 Background:A large proportion of patients are currently not eligible for genotype-adapted strategies in acute myeloid leukemia (AML), in particular those lacking specific genetic aberrations such as PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 or activating FLT3 mutations. This subgroup of patients accounts for about one-third of all AML patients and mainly includes the large group of AML with myelodysplasia-related changes, AML with recurrent cytogenetic abnormalities [inv(3) or t(3;3), t(9;11), t(v;11q23)] and cytogenetically normal AML (CN-AML) with wild-type NPM1 and FLT3. Prognosis in this subgroup of patients is generally poor. Azacitidine has been shown to be active in AML with low blast counts frequently observed in AML with myelodysplasia-related changes and in CN-AML in the absence of specific gene mutations. Aims:To evaluate clinical efficacy of azacitidine in combination with intensive induction chemotherapy and in maintenance for two years as single agent in patients with AML who are not candidates for genotype-adapted treatment approaches. Methods:Patients with AML in the absence of specific genetic aberrations (PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 mutation, activating FLT3 mutations) who are fit for intensive chemotherapy were eligible. Patients were up-front randomized for induction therapy into one standard arm and three experimental arms; i) ICE (standard arm), idarubicin (12 mg/m2/day, iv, days 1,3,5), cytarabine (100 mg/m2/day, cont. infusion, days 1–7), etoposide (100 mg/m2/day, iv, days 1,2,3); ii) AZA-prior, azacitidine (100 mg/m2/day, sc, days 1–5), idarubicin (12 mg/m2/day, iv, days 6, 8, 10), etoposide 100 mg/m2/day, iv, days 6,7,8); iii) AZA-concurrent, azacitidine (100 mg/m2/day, sc, days 1–5), idarubicin (12 mg/m2/day, iv, days 1,3,5), etoposide 100 mg/m2/day, iv, days 1,2,3); iv) AZA-after, idarubicin (12 mg/m2/day, iv, days 1,3,5), etoposide 100 mg/m2/day, iv, days 1,2,3), azacitidine (100 mg/m2/day, sc, days 4–8). After two induction cycles for patients achieving complete remission (CR), consolidation therapy was prioritized; first priority) allogeneic hematopoietic blood stem cell transplantation (HSCT) from matched related as well as unrelated donors, second priority) 3 courses of high-dose cytarabine followed by two-year maintenance therapy with azacitidine as single agent (50 mg/m2/day, sc, days 1–5, every 4 weeks) in patients initially randomized to experimental treatment. The primary endpoint was achievement of CR. The statistical design of the study was based on the Simon’s optimal two-stage design applied for each arm separately. The null hypothesis was CR-rate equal or below 0.40 whereas the alternative hypothesis was a CR rate of at least 0.55 with a power of 80% and a level of significance of 5%. Thus, in each arm at least 12 of 26 patients with response to induction therapy were necessary after the first to proceed to the second stage. Results:During the first stage of the study 104 patients were randomized; median age was 62.5 years (range 18–82), 46% were female. Data on cytogenetics showed intermediate risk karyotype in 67% (n=50) including CN-AML (n=31) and high-risk karyotype in 33% (n=25). The most frequent serious adverse events were grade 3/4 infection with an overall incidence of 25% and ranging from 20 to 34% in the different treatment arms. The number of responding patients in the treatment arms AZA-prior and AZA-concurrent after the first stage of the study were 11 of 26 (42%) and 10 of 26 (38%)Both arms, AZA-prior and were terminated accordingly. In contrast, the treatment arms ICE and AZA-after were carried forward to the second stage of patient recruitment since responding patients at that time were 14 of 26 (54%) in both arms. In total, 100 patients each have been enrolled in both treatment arms, ICE and AZA-after, with CR-rates of 59% and 52%, respectively (p=0.39). To date, 60 patients received an allogeneic HSCT (n=36 matched unrelated donors, n=23 matched related donors, n=1 haploidentical family donor). Maintenance treatment was started in 12 patients. Conclusion:Induction therapy with ICE or idarubicin, etoposide followed by azacitidine (AZA-after) appears equally effective in producing CR in patients with AML who are not candidates for genotype-adapted treatment approaches. An amendment perpetuating the treatment arms ICE and AZA-after within a phase-III concept is planned. Disclosures:Schlenk:Celgene: Research Funding. Off Label Use: Azacitidine combined with intensive chemotherapy.

A Phase 1b Dose Escalation Safety Analysis of Lenalidomide and Azacitidine Maintenance Therapy for Poor Risk AML,

Abstract 3625 Background:Despite achieving remission after intensive chemotherapy for AML, the majority of patients will relapse. Maintenance therapy is an attractive option, with the goal of eradicating residual disease and prolonging disease remission. The hypomethylating agent azacitidine and the immunomodulatory drug lenalidomide have been shown to be active in high risk MDS, especially in combination (Sekeres et al, Journal of Clinical Oncology 2010; 2253). Azacitidine maintenance therapy has been examined after intensive induction chemotherapy for high risk MDS and MDS progressing to AML (Grövdal et al, British Journ of Haem 2010; 293). In this study, an azacitidine dose of 75 mg/m2 resulted in excessive neutropenic toxicity. An amended dose of azacitidine 60 mg/m2 for 5 days each cycle was found to be deliverable, with acceptable hematopoietic toxicity. The goal of this study was to determine the optimal maintenance dosing schedule of azacitidine in combination with lenalidomide after intensive chemotherapy for AML in complete remission (CR) and a high risk of relapse. Methods:A phase Ib/II open label dose escalation study enrolled patients with high risk AML in CR/CRi and high risk features (age > 60, adverse risk karyotype, FLT3-ITD+ or CR2). Patients were treated with azacitidine subcutaneously on days 1–5 of each 28-day cycle combined with lenalidomide orally on days 5–25 for a maximum of 12 cycles. A 3×3 dose escalation schema to identify the maximum tolerated dose was conducted. Cohort A (Table 1) assessed the safety of azacitidine 50 mg/m2 alone. Cohorts B-H planned to investigate azacitidine 50–75 mg/m2 in combination with lenalidomide 5–25mg.Table 1CohortNPoor riskMedian RFSGrade 3/4 non-hematologic toxicityStatusA (Aza 50)3Age>60 (n=3)164 daysNilRelapse (n=2); off study for allo-SCT (n=1)B (Aza 50, Len 5)3Age>60 (n=3); CR2 (n=1)231 daysNilAllo-SCT (n=1); relapse (n=1); non-relapse death (n=1)C (Aza 60, Len 5)7Age>60 (n=5); CR2 (n=1); Adverse risk karyotype (n=1)219 daysALT elevation (known hepatitis C) (n=1)CR (n=4); relapse (n=3); allo-SCT (n=1)D (Aza 60, Len 10)3Age>60 (n=1); CR2 (n=1); FLT3-ITD+ (n=1)Not reachedNilCR (n=3) Results:We report herein the analysis of the first 16 patients (M 8, F 8), median age 65 years (43–73) recruited to the study. Patients were at high-risk for relapse, based on age >60 years (n=11), CR2 (n=3), adverse risk karyotype (n=1) or FLT3-ITD+ (n=1). Neutrophil (Figure 1) and platelet (Figure 2) toxicity was modest during cycle 1. A summary of outcomes is shown in table 1. After a median follow-up of 301 days, 6/16 patients have relapsed with a median relapse-free survival (RFS) of 219 days (17–546) and median overall survival (OS) of 443 days (86–546). Dose-escalation is ongoing. [Display omitted] Conclusion:The combination of azacitidine with lenalidomide as maintenance therapy after intensive chemotherapy for high-risk AML is well tolerated. The clinical efficacy of this regimen and the maximum tolerated dose remains to be determined. Disclosures:Wei:Celgene: Honoraria, Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:Celgene: Honoraria.

A Phase 1 Study of Concomitant High Dose Lenalidomide and 5-Azacytidine Induction in the Treatment of Acute Myeloid Leukemia,

Abstract 3616Novel therapies for elderly and relapsed AML are needed. We recently published an institutional phase 2 trial using high dose (50mg/day × 28 days) single agent lenalidomide (HDL) followed by maintenance of 10 mg daily for 12 months in responders in elderly untreated AML patients (≥ 60 years) showing a complete remission (CR)/complete remission with incomplete blood count recovery (CRi) of 30% (Fehniger et al, Blood, 2011). Azacitidine (AZA) given IV or SC has also shown significant response in patients with MDS and AML. Recently Pollyea et al (JCO 29: 2011 (suppl; abstr #6505) reported on a phase 1 trial combining AZA and escalating doses of lenalidomide repeated sequentially in 6 week cycles in patients with untreated AML. Here, we report on a phase 1 single institutional study to evaluate the toxicities and feasibility of combining HDL and AZA concurrently as induction followed by a less intensive lenalidomide and AZA maintenance schedule in untreated elderly AML (≥60 years) or relapsed/refractory AML ≥18 years. Treatment schedule: 2 cycles of induction (each 28 days) of lenalidomide 50 mg PO days 1–28 and AZA at 3 dose cohorts 25 mg/m2 (cohort 1), 50 mg/m2 (cohort 2) and 75 mg/m2 (cohort 3) given IV days 1–5. Thereafter patients were given maintenance cycles (every 28 days) with lenalidomide 10 mg PO days 1–28 and AZA 75 mg/m2 days 1–5 for a total of 12 cycles. The median age was 74 (range 63–81); 7 males, 8 females; 6 with newly diagnosed elderly AML and 9 with relapsed or refractory AML. The median WBC count was 2600 (range 300–13100). The median bone marrow blast percentage was 22% (range 2–90%),with normal cytogenetics in 7 (63.6%), monosomy 7 in 3 (20%), trisomy 8 in 1 (6.7%), and other in 4 (26.6%). 8 patients were enrolled in cohort 1, 4 patients in cohort 2 and 3 patients in cohort 3. 2 patients in cohort 1 and 1 patient in cohort 2 who received less than 1 induction cycle (2 withdrew consent and 1 had progressive disease) were replaced. 11 (73.3%) of patients completed 1 induction cycle and 7 (46.7%) of patients completed 2 induction cycles and 5 (30%) patients went on to maintenance therapy. Patients remained on therapy for a median of 2 months (range 0.5–13 months). Dose limiting toxicities (DLT) observed included grade 3 rash in cohort 1 leading to expansion of the cohort to include 3 additional patients. To date grade 3/4 non-DLT hematological toxicity was seen in 6/11 (54.1%) patients. The most common 3/4 non-DLT non-hematological toxicity was neutropenic fever seen in 5/11 (45.4%). The most common grade 1/2 toxicity was fatigue in 7/11 (63.6%). 40% (6/15) of patients died, all due to progressive disease. Of the 11 evaluable patients 7 (63.6%) responded to treatment with CR/CRi in 3 (27.3%) and partial remission (PR) in 4 (36.4%) with the median duration of response of 3 months (range 0.5–11 months). In summary combination of lenalidomide with AZA appears to be a feasible regimen with acceptable toxicities. A phase 2 multicenter extension of this study with untreated elderly AML at the maximum tolerated dose of AZA and HDL will be initiated soon. Disclosures:Off Label Use: Here we discuss the use of lenalidomide and azacytidine in relapsed refractory or elderly AML. Stockerl-Goldstein:Celgene: Speakers Bureau. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau.

A Phase II Study of Post–Remission Therapy with Azacitidine (AZA) in Patients with AML Post-MDS and High-Risk MDS: A GFM Group Study.

Abstract 844 Introduction: intensive chemotherapy (IC) in AML post-MDS ( here AML) or High Risk-MDS ( here MDS) is associated with lower CR rate, shorter response duration and poor overall survival compared to de novo AML. Upfront treatment of MDS with AZA delays time to AML evolution and prolongs overall survival (OS). The low toxicity profile of AZA should also allow its use in IC responders in an outpatient setting. Preliminary results with this approach by the Nordic MDS group in 23 pts (ASH 2008, abstr n°223) showed its feasibility. We used it in AML or MDS patients (pts), who had achieved response after IC. Methods: Inclusion criteria were: (1) de novo MDS patients and IPSS int-2 or high risk (including CMML if WBC 2 /d for 5 days, every 28 days for the first two cycles. In the absence of grade ≥ 3 toxicities, dosing of subsequent cycles could be increased to 75mg/m 2 /d. Dosing of AZA had to be reduced in case of grade ≥3 toxicities, persistent cytopenias beyond day 42 of each cycle, or if cytopenias were associated with re-hospitalization. AZA post-remission therapy was to be continued until relapse (according to IWG-AML and MDS criteria) or toxicity. Results: From July 06 to June 09, 51 pts (M31/F20) were included but 5 were not evaluable (2 IWG failures upon review, 1 protocol violation, 1 therapy-related MDS, 1 patient too early). The 46 evaluable pts had achieved CR (n=33), CRi (n=11) and PR (n=2) before study entry. Median age was 66y (55-78). Diagnosis at IC onset was MDS (N=13) and AML (N=33), IPSS cytogenetics was normal (N= 28), intermediate (N=10), high (N= 6), and failed (N=2). Median time from diagnosis of MDS to IC was 8 months (0.5-101). Median number of AZA maintenance cycles was 5.5 (0-32+)in CR pts (>23 cycles in 4 of them) and 2 (0-11) in CRi or PR pts. Median follow-up was 24 months (m). Median DFS was 6.5 m and 18-m DFS was 20% (95% CI 9-35); median and 18 month OS from response were 15 m and 43% (95% CI 27-58), respectively. 18-m-DFS and OS were 30 % (95% CI 13-48) and 56% (95% CI 35-72), in the 33 CR pts (median OS 24m), compared to O% and 17% (95% CI 3-41), in the 11 PR/CRi pts, ( P= .0001 and .04, respectively) . 21 of the 33 CR pts had relapsed and 3 had CR duration >24 months. None of the pts in CRi/PR after IC improved their response with AZA. Only initial response to IC (ie CR vs CRi/PR), but not cytogenetics (normal vs. others), diagnosis at IC onset (MDS vs AML), % bone marrow blasts (using 20 or 30 % cut-off), age or time from MDS diagnosis to treatment, significantly predicted DFS or OS in this cohort. AZA dosing in CR patients was escalated in 9 pts but had to be reduced in 6 other pts, due to GI tract intolerance (n=1) and cytopenias (n=5). Only 2/33 CR pts, developed severe infection or febrile neutropenia while in persistent response, compared to 4/11 pts in CRi or PR (including 1 fatal case). We finally compared outcome of the 22 AML study pts in CR to that of 46 similar AML post MDS pts from our ALFA group elderly AML 9803 study ( Gardin, Blood 2007 ), in which pts in CR received DNR/IDA–AraC post-remission therapy. Cumulative incidence of relapse did not differ between the present AZA cohort in AML patients and the ALFA cohort (18-m CIR at 41% (95% CI 18-63) and 25% (95% CI 13-40), respectively; P=0.92). OS from CR was also identical between the 2 cohorts (18-m OS of 56% (95% CI 31-76) and 54% (95% CI 37-69), respectively; P=0.84) Conclusion: In this study, post–CR therapy with AZA alone was associated with a 30% DFS rate and 56% OS at 18m and a median OS of 24m, while pts in CRi or PR did not benefit from AZA. Although selection biases may exist between cohorts, DFS and OS of AML post MDS in CR were identical to those observed in similar pts treated after CR by anthracyclin and AraC consolidation. Hematological toxicity of AZA, however, was minimal. Combinations of AZA with other drugs may be of further interest in those patients at high–risk of relapse. Disclosures: Gardin: Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: azacitidine as post-remission therapy in AML patients. Dombret: Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.