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.

A randomized phase II trial of azacitidine +/- epoetin- in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

“…Recent USA retrospective data reported a median OS of 16 months after HMA failure in lower-risk MDS. 22 Our study was also the first to prospectively study the impact of SNP array and mutational analysis in lower-risk MDS treated with a HMA. The frequency of mutations in this lower-risk MDS patient cohort was different from that previously published by Bejar et al, 23 with a higher frequency of SF3B1 mutations (68.6% compared to 22% for Bejar et al), explained by the high proportion of sideroblastic anemias included in our series.…”

When clinical heterogeneity exceeds genetic heterogeneity: thinking outside the genomic box in chronic myelomonocytic leukemia

“…5 However, patients sequenced at disease progression have clear changes in mutational architecture consistent with the clinical observation that postazanucleoside therapy CMML cases are chemorefractory with a survival measured in months. 40 Finally, a third approach may be to leverage single-cell sequencing to identify clonal heterogeneity obscured by conventional bulk leukemia sequencing. Although whole genome sequencing can faithfully infer clonal architecture compared with single cell sequencing, it has been hypothesized that exome and targeted panel sequencing, which represent the vast majority of sequencing experiments performed in CMML, grossly underestimate the true genetic diversity in any given sample.…”

Therapy-related myelodysplastic syndromes, or are they?

“…However most of the patients in this database were not treated with allogeneic hematopoietic cell transplantation (HCT) and it was externally validated in azacitidine-treated patients only [100]. A recent study from the MDS Clinical Research consortium compared the performance of several prognostic scores, including TPSS [101,102]. In this cohort of 370 with t-MDS, all prognostic models discriminated OS based on risk group.…”