Treatment outcomes of cohesin complex-mutant myelodysplastic syndrome and acute myeloid leukemia.

Abstract

e19007 Background: Mutations in the genes STAG1, STAG2, SMC1A, SMC3, and RAD21 which are part of the cohesin complex are recurrent in myelodysplastic syndrome and acute myeloid leukemia. The cohesin complex is involved in sister chromatid attachment during cell division and in DNA loop formation bringing enhancers and genes together. Prognosis and treatment efficacy for this subgroup has not been well studied in MDS or AML. We evaluated the treatment outcomes of a subgroup with cohesin mutations from a database of MDS and AML patients at the University of Massachusetts. Methods: We performed a retrospective analysis of adult patients with a new diagnosis of AML and/or MDS from 2015-2019 in the University of Massachusetts Leukemia Registry. Fisher’s exact test was used to compare initial response to treatment via induction chemotherapy or hypomethylating agents. Kaplan-Meier curves for overall survival were compared using the log-rank test. We considered < 5% blasts by morphology to be complete remission (regardless of hematologic recovery). Four patients who did not undergo treatment were excluded from treatment and survival analysis. Results: A total of 19 patients had mutations in a cohesin complex gene with one patient having mutations in both STAG2 and SMC1A. The cohesin complex mutation frequency was 9.95% (19 out of 191 patients) with STAG2 representing 70% of the mutations. First-line induction chemotherapy resulted in an improved rate of complete remission 83.3% compared to hypomethylating agents 0% (p = 0.002). For AML patients alone, there was improvement in complete response rate for induction chemotherapy vs. hypomethylating agents (p = 0.048). There was no overall survival benefit for induction chemotherapy compared to hypomethylating agents (44.4% vs 41.7% probability of survival at 2 years) with p = 0.87. Excluding the MDS patients, there was still no difference in overall survival with p = 0.63. Conclusions: In this retrospective analysis of cohesin complex-mutant MDS and AML, induction chemotherapy resulted in significantly improved complete remission rates compared to hypomethylating agents. There was no overall survival benefit. We also found one patient with simultaneous mutations in two cohesin genes while cohesin mutations were previously reported to be mutually exclusive. Further work looking at additional samples may be able to show induction chemotherapy is the treatment of choice for cohesin mutant AML.[Table: see text]