The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

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Allogeneic bone marrow transplantation (BMT) is the only curative therapy available for patients with myelodysplastic syndrome (MDS). In an attempt to identify prognostic factors influencing outcome, we collected data retrospectively on 60 consecutive adult patients who had undergone BMT at our center for primary MDS or acute myelogenous leukemia evolving from preexisting primary MDS (sAML). Patients were divided into subgroups according to cytogenetic abnormalities based on a recently described International MDS Workshop categorization system. The 7-year actuarial event-free survival (EFS), relapse rate, and nonrelapse mortality (NRM) for all patients were 29% (95% confidence interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI, 37% to 64%), respectively. The EFS for the good-, intermediate-, and poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI, 16% to 63%), and 6% (CI, 0% to 24%), respectively (P= .003). The corresponding actuarial relapse rates were 19% (CI, 6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%), respectively (P = .002) with no difference in NRM between the subgroups. Univariate analysis showed cytogenetic category, French-American-British (FAB) subtype, and graft-versus-host disease (GVHD) prophylaxis used to be predictive of relapse and EFS. In multivariate analysis, only the cytogenetic category was predictive of EFS, with the relative risk of treatment failure for the good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = .004). For adults with primary MDS and sAML, even after BMT, poor-risk cytogenetics are predictive of an unfavorable outcome; novel treatment strategies will be required to improve results with allogeneic BMT in this patient population. © 1998 by The American Society of Hematology.