Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium

Abstract

Background: The hypomethylating agents (HMAs) azacitidine and decitabine are most commonly used to treat patients with higher-risk myelodysplastic syndromes (MDS). To the authors' knowledge, the prognosis of patients with low-risk and intermediate-1-risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure has not been explored comprehensively.

Methods: The clinical characteristics and treatment outcome of 438 patients with low-risk and intermediate-1-risk MDS who were treated with HMAs were retrospectively analyzed.

Results: Using the International Working Group response criteria, the overall objective response to HMA was 35% with a median of 6 cycles of HMA administered, and the median response duration was 7 months. Only 7% of patients had disease that transformed into acute myeloid leukemia while receiving therapy. Of the 290 patients who were evaluable at the time of HMA failure, 77% remained in the lower-risk disease categories. On multivariate analysis, baseline neutropenia, intermediate-risk and poor-risk baseline karyotype, and lack of response to HMA were found to be independently associated with a higher risk of disease progression. With a median follow-up of 16 months, the median transformation-free survival and overall survival (OS) after HMA failure were 15 months and 17 months, respectively. On multivariate analysis, only The University of Texas MD Anderson Global Scoring System was found to be independently predictive of outcome, with patients with higher-risk categories having poor transformation-free survival (hazards ratio [HR], 1.5; P = .003) and OS (HR, 1.8; P = .002). The administration of salvage therapy was independently associated with better OS only (HR, 0.8; P = .01).

Conclusions: Outcomes of patients with lower-risk MDS after HMA failure are poor and the treatment of these patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population.

Keywords: hypomethylating agent failure; low-risk; myelodysplastic syndrome; survival.

Conflict of interest statement

Conflict of Interest Disclosures: Dr. Jabbour has received a grant from GlaxoSmithKline for work performed outside of the current study. Dr. Padron has received a grant from the Edward P. Evans Foundation for work performed as part of the current study. Dr. Lancet has acted as a paid consultant for and received research support from Celgene for work performed outside of the current study. Dr. Steensma has acted as a paid consultant for Celgene and Incyte. He also owns stock equity in ARIAD Pharmaceuticals and has been a paid member of the Data Safety Monitoring Board for Amgen and Novartis for work performed outside of the current study. Dr. Sekeres has acted as a paid member of the advisory boards for Celgene, Amgen, and Boehringer Ingelheim for work performed outside of the current study. Dr. Gore has received a grant and personal fees from Celgene for work performed outside of the current study. Dr. List has acted as a paid consultant for Celgene for work performed outside of the current study.

© 2014 American Cancer Society.

Figures

Figure 1

Outcome is shown. (A) Overall survival (OS) and transformation-free survival (TFS) are shown for the 290 evaluable patients. (B) OS and TFS are shown for the entire patient population (438 patients). (C) OS is shown by The University of Texas MD Anderson Cancer Center Global Scoring System (MDGSS) (4 categories). (D) OS is shown by the MDGSS (2 categories). (E) TFS is shown by the MDGSS (4 categories). (F) TFS is shown by the MDGSS (2 categories). (G) OS is shown by salvage therapy received. int-I indicates intermediate-1 risk; int-II, intermediate-2 risk; SCT, stem cell transplantation.