Transplantation-Specific Cytogenetics Grouping Scheme for Patients with Myelodysplastic Syndromes: A Multicenter Validation Study

Abstract Cytogenetics are an important prognostic factor for patients with myelodysplastic syndromes (MDS). However, the most commonly employed cytogenetics grouping scheme, as used in the IPSS, was derived from a cohort of patients who primarily received supportive care. This scheme may therefore not be optimal for stratifying patients undergoing aggressive therapy such as allogeneic stem cell transplantation (SCT). We previously proposed an SCT-specific cytogenetics grouping scheme for patients with MDS and AML arising from MDS (mAML), based on single-institution data. That scheme allowed for better prognostic stratification than the IPSS scheme. We undertook the present retrospective multicenter study to validate those results. Included were 546 patients with MDS or mAML from the Fred Hutchinson Cancer Center, the M.D. Anderson Cancer Center, and Princess Margaret Hospital. The median age was 53 years (range 18–74). 27% of patients had high-risk MDS (RAEB 1 or 2), and 43% had mAML; 17% had therapy-related disease. Overall 61% of patients were untreated at the time of SCT, while 12% were in CR following treatment. 68% received a conventional intensity conditioning regimen, and 65% were transplanted with peripheral blood stem cells. Donors were matched related (46%), matched unrelated (36%), or mismatched (18%). Cytogenetics were available for 86% of patients. Of those, 47% had favorable, 25% intermediate, and 28% adverse cytogenetics, when grouped by IPSS category. With a median follow-up of 48 months, 4-year relapse-free and overall survivals were 36% and 40%, respectively. In multivariate analyses, variables significantly associated with overall survival were cytogenetics, disease type and stage, patient age, donor match, and year of transplantation. Notably, therapy-related disease was not associated with increased mortality in this model. The optimal cytogenetics grouping scheme comprised two groups, with abnormalities of chromosome 7 and complex karyotype being adverse, and all other abnormalities (including normal karyotype, del(5q), and del(20q)) being standard risk. Adverse cytogenetics was the strongest prognostic factor for SCT outcome in this cohort, with a hazard ratio for mortality of 2.1 (p<0.0001). Four-year relapse-free and overall survivals were 42% and 46%, respectively, in the standard risk group, versus 21% and 23% in the adverse group (p<0.0001 for both comparisons). These differences were solely due to an increased risk of relapse in the adverse group (with a 4-year cumulative relapse incidence of 41%, versus 24% in the standard risk group (p<0.0001)), while non-relapse mortality was the same for both groups (38% and 38%, p=0.6). This grouping scheme retained its prognostic significance irrespective of patient age, disease type (low-risk versus high-risk MDS versus mAML), therapy-related or de novo disease, and conditioning intensity. Based on this multicenter validation, we propose that this SCT-specific cytogenetics grouping scheme be used for patients with MDS or mAML who are considering or undergoing SCT, for prognostication, patient selection, outcome reporting, or clinical trial stratification purposes.

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