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Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes.

ABSTRACT: Lenalidomide and azacitidine are active in patients with lower- and higher-risk myelodysplastic syndromes (MDS). These agents may complement each other by targeting both the bone marrow microenvironment and hypomethylating action on the malignant clone.This phase I trial explored the safety of combination therapy in patients with higher-risk MDS. Response and characterization of molecular and methylation status of responders were secondary objectives. Patients were enrolled using a 3 + 3 dose escalation. Cycles lasted 28 days, and patients received a maximum of seven cycles.Of 18 patients enrolled, median age was 68 years (range, 52 to 78 years), interval from diagnosis was 5 weeks (range, 2 to 106 weeks), and follow-up was 7 months (range, 1 to 26 months). International Prognostic Scoring System categories were intermediate 1 (n = 2), intermediate 2 (n = 10), and high (n = 6). No dose-limiting toxicities occurred, and a maximum-tolerated dose was not reached. Grades 3 to 4 nonhematologic toxicities (> 1) included febrile neutropenia (n = 5), cardiac (n = 2), and CNS hemorrhage (n = 2). Median absolute neutrophil count decrease was 26%, and platelet decrease was 1% (mean, 24%). The overall response rate was 67%: eight patients (44%) had a complete response (CR); three patients (17%) had hematologic improvement; one patient (6%) had marrow CR. Patients achieving CR were more likely to have normal cytogenetics and lower methylation levels.The combination of lenalidomide and azacitidine is well tolerated with encouraging clinical activity. The go-forward dose is azacitidine 75 mg/m(2) on days 1 through 5 and lenalidomide 10 mg on days 1 through 21.

SUBMITTER: Sekeres MA

PROVIDER: S-EPMC2860439 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes.

Sekeres Mikkael A MA List Alan F AF Cuthbertson David D Paquette Ronald R Ganetzky Rebecca R Latham Deborah D Paulic Katarina K Afable Manuel M Saba Hussain I HI Loughran Thomas P TP Maciejewski Jaroslaw P JP

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100330 13

<h4>Purpose</h4>Lenalidomide and azacitidine are active in patients with lower- and higher-risk myelodysplastic syndromes (MDS). These agents may complement each other by targeting both the bone marrow microenvironment and hypomethylating action on the malignant clone.<h4>Patients and methods</h4>This phase I trial explored the safety of combination therapy in patients with higher-risk MDS. Response and characterization of molecular and methylation status of responders were secondary objectives. ...[more]

PMID: 20354132

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Project description:Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

Project description:BackgroundThe standard of care for myelodysplastic syndromes is hypomethylating agents such as azacitidine. However, responses to azacitidine are generally temporary, and outcomes after hypomethylating agent failure are dismal. Therefore, the development of more effective treatments is crucial to improve outcomes in patients with myelodysplastic syndromes. We aimed to assess azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia.MethodsWe did this single-arm phase 1/2 study at the University of Texas MD Anderson Cancer Center, TX, USA. Patients of any age were eligible for phase 1 and 2a if they had relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome with bone marrow blasts more than 10%. For phase 2b, eligible participants were previously untreated with myelodysplastic syndrome with an International Prognostic Scoring System (IPSS) score of intermediate-1 or higher with up to 30% blasts. All participants received 75 mg/m(2) azacitidine once a day for days 1-5 for each 28 day cycle. We gave patients oral lenalidomide for 5 or 10 days starting on day 6. We assessed seven lenalidomide doses in a 3 + 3 phase 1 design (n=28). The primary endpoint in phase 1 was the maximum tolerated dose, and the primary endpoint in phase 2 was overall survival. Outcome analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01038635.FindingsBetween Dec 30, 2009, and June, 17, 2013, we enrolled 88 patients (28 in phase 1 and 60 in phase 2). One patient unexpectedly died in the phase 1 study at the highest dose level, six more patients were recruited with no further serious adverse events. We recorded no dose-limiting toxic effects, and the maximum tolerated dose of lenalidomide in combination with azacitidine in patients with acute myeloid leukaemia and myelodysplastic syndrome was initially established at 50 mg per day for 10 days. In the first 20 patients in phase 2, we noted a high rate of myelosuppression and myelosuppression-related toxic effects; therefore, we amended the lenalidomide dose to 25 mg per day for 5 days. We also adjusted the inclusion criteria to include patients with less than 30% blasts to focus mainly on patients with myelodysplastic syndromes. Median overall survival was 75 weeks (IQR 25-not reached) for the 40 patients in phase 2b. The most common grade 3-4 adverse events overall were neutropenic fever (n=27) and pneumonia (n=18).InterpretationWe have identified a safe and active sequential treatment combination of azacitidine and lenalidomide for patient with myelodysplastic syndrome and have preliminary evidence that this dose is also safe for patients with acute myeloid leukaemia.FundingMD Anderson Cancer Center and Celgene.

Project description:PurposeTreatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia.MethodsPatients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI).ResultsTwo hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L.ConclusionCC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Dataset Information

Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes.

Publications

Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes.

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