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Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications.

ABSTRACT: The MDS-IWG and NCCN currently endorse both FAB and WHO classifications of MDS and AML, thus allowing patients with 20-30 % bone marrow blasts (AML20-30, formerly MDS-RAEB-t) to be categorised and treated as either MDS or AML. In addition, an artificial distinction between AML20-30 and AML30+ was made by regulatory agencies by initially restricting approval of azacitidine to AML20-30. Thus, uncertainty prevails regarding the diagnosis, prognosis and optimal treatment timing and strategy for patients with AML20-30. Here, we aim to provide clarification for patients treated with azacitidine front-line.The Austrian Azacitidine Registry is a multicentre database (ClinicalTrials.gov: NCT01595295). For this analysis, we selected 339 patients treated with azacitidine front-line. According to the WHO classification 53, 96 and 190 patients had MDS-RAEB-I, MDS-RAEB-II and AML (AML20-30: n?=?79; AML30+: n?=?111), respectively. According to the FAB classification, 131, 101 and 111 patients had MDS-RAEB, MDS-RAEB-t and AML, respectively.The median ages of patients with MDS and AML were 72 (range 37-87) and 77 (range 23-93) years, respectively. Overall, 80 % of classifiable patients (?30 % bone marrow blasts) had intermediate-2 or high-risk IPSS scores. Most other baseline, treatment and response characteristics were similar between patients diagnosed with MDS or AML. WHO-classified patients with AML20-30 had significantly worse OS than patients with MDS-RAEB-II (13.1 vs 18.9 months; p?=?0.010), but similar OS to patients with AML30+ (10.9 vs 13.1 months; p?=?0.238). AML patients that showed MDS-related features did not have worse outcomes compared with patients who did not (13.2 vs 8.9 months; p?=?0.104). FAB-classified patients with MDS-RAEB-t had similar survival to patients with AML30+ (12.8 vs 10.9 months; p?=?0.376), but significantly worse OS than patients with MDS-RAEB (10.9 vs 24.4 months; p?

SUBMITTER: Pleyer L

PROVIDER: S-EPMC4833933 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications.

Pleyer Lisa L Burgstaller Sonja S Stauder Reinhard R Girschikofsky Michael M Sill Heinz H Schlick Konstantin K Thaler Josef J Halter Britta B Machherndl-Spandl Sigrid S Zebisch Armin A Pichler Angelika A Pfeilstöcker Michael M Autzinger Eva-Maria EM Lang Alois A Geissler Klaus K Voskova Daniela D Geissler Dietmar D Sperr Wolfgang R WR Hojas Sabine S Rogulj Inga M IM Andel Johannes J Greil Richard R

Journal of hematology & oncology 20160416

<h4>Background</h4>The MDS-IWG and NCCN currently endorse both FAB and WHO classifications of MDS and AML, thus allowing patients with 20-30 % bone marrow blasts (AML20-30, formerly MDS-RAEB-t) to be categorised and treated as either MDS or AML. In addition, an artificial distinction between AML20-30 and AML30+ was made by regulatory agencies by initially restricting approval of azacitidine to AML20-30. Thus, uncertainty prevails regarding the diagnosis, prognosis and optimal treatment timing an ...[more]

PMID: 27084507

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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.

Dataset Information

Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications.

Publications

Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications.

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