Background:Chronic anemia is most often the presenting symptom and major issue for patients (pts) with low-risk myelodysplastic syndrome (LR-MDS). Erythropoietic stimulating agents (ESAs) are the initial therapy for many LR-MDS pts and can predictably yield benefit in pts with low transfusion burden and a low erythropoietin (EPO) level. (Hellstrom-Lindberg, 2013). However, only about 40-50% of pts respond to erythropoietin (ESAs). We posit that improvement of the predictive algorithm for response to ESA therapy might be optimized with inclusion of molecular mutation informatics. If validated, the model could inform those pts with risk of ESA treatment failure and thus favor alternative approaches such as hypomethylating therapy (Thus, sparing unnecessary pt exposure, cost and time to an ineffective agent, as well as delay to delivery of a possibly more effective therapy). Furthermore, the impact of EPO stimulation/treatment on the clonal dynamics of LR-MDS is not yet well understood nor described. Thus, we analyzed molecular profiles of LR-MDS pts in order to identify mutations associated with ESA failure and the subsequent clonal alterations post ESA exposure.

Methods:Of 394 pts who had LR-MDS based on International Prognostic Scoring System (IPSS) criteria, and were treated at Cleveland Clinic from 2002-2015, we studied 49 primary cases with clinical and mutational data. Next generation targeted deep sequencing was performed for a panel of 60 genes that are known to be commonly mutated in myeloid malignancies. ESA response was assessed in the first 8 weeks of treatment according to International Working Group (IWG) criteria (Cheson, 2006). We further studied clonal alterations upon ESA treatment in a small subset of patients who had sequential samples during the course of treatment.

Results: Median age of 50 pts was 76 yrs (range, 45-87) and 56% were male. 28% had MDS with single lineage dysplasia, 21% had MDS with ringed sideroblasts, 38% had MDS with multilineage dysplasia, 6% had isolated del(5q), and 7% had MDS-unclassifiable. 65% had normal cytogenetics at diagnosis and 44% had low EPO level at baseline. 43% of pts responded to ESA therapy. Mutations commonly found in our cohort included SF3B1 (25% in responders vs 22% in non-responders), U2AF1 and DNMT3A (15% in responders vs 11% in non-responders), ASXL1 (10% in responders vs 15% in non-responders), and TET2 (10% in responders vs 11% in non-responders). In 20 responders, 2 cases had CBL2 mutation, while 2 other cases harbored JAK2 mutation, which were not detected in non-responders. In 27 non-responders, NGS identified EZH2, ETV6, and RUNX1 mutations in 2 individual cases while one case harbored both ETV6 and RUNX1 mutations. None of these mutations were found in responders. Of interest, among 8 patients who had low baseline EPO level without response to ESA, 3 patients harbored RUNX1 mutation. Serial analysis of eight cases revealed genomic diversity that may give insight to prognostic models for EPO response. For example, we found in one case who had a U2AF1, CBL mutations prior to starting ESA, at the time of evolution to AML this pt had acquired additional mutations involving RUNX1, IDH1, and GPR98. Additional cases with high risk mutations at presentation including EZH2, ASXL1, DNMT3A, U2AF1did not respond and evolved to secondary acute myeloid leukemia (sAML).

Conclusions: Evaluation of the mutational spectrum in LR-MDS patient, revealed insight into clonal dynamics that may be determinants of EPO responsiveness. We found in our cohort that LR-MDS individuals harboring RUNX1 and ETV6 mutations did not respond to ESA directed therapy and were noted to evolve to high risk MDS or sAML. Notably, pts with SF3B1 mutations can respond to ESA therapy but not all pts appear to reliably do so. These mutational data will inform a future algorithm to help predict ESA responsive patients in LR-MDS that will require prospective validation.


Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.

Author notes


Asterisk with author names denotes non-ASH members.

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