In a study reported in The New England Journal of Medicine, R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute, and colleagues found that a number of mutations present in patients with myelodysplastic syndromes (MDS) were associated with poorer clinical outcome after allogeneic hematopoietic stem cell transplantation.1
The study involved targeted mutational analysis of samples obtained before stem cell transplant from 1,514 MDS patients enrolled at the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. Genetic analysis included targeted sequencing of 129 genes selected for their known or suspected involvement in the pathogenesis of myeloid cancers or inherited or acquired bone marrow failure syndromes.
Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen.— R. Coleman Lindsley, MD, PhD
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Among the 1,514 patients: 84% were aged ≥ 40 years; Karnofsky performance status was 90 to 100 in 54% (missing data for 18%); Revised International Prognostic Scoring System cytogenetic risk group was good or very good in 38%, intermediate in 18%, poor in 19%, and very poor in 8%; bone marrow blasts were 0% to 2% in 25%, 3% to 5% in 18%, 6% to 9% in 16%, and 10% to 19% in 19% (missing data in 23%); platelet counts were ≥ 100, 50 to 99, and < 50 × 109/L in 36%, 23%, and 36%; and the type of MDS was primary in 79% and therapy-related in 21%. The conditioning regimen for stem cell transplant was myeloablative in 52%, reduced intensity in 38%, and nonmyeloablative in 9%. The graft type was bone marrow in 15%, peripheral blood stem cells in 74%, and cord blood in 11%.
Mutations and Prognostic Impact
At least 1 mutation was identified in 1,196 patients (79%); the most common were ASXL1 (19.6%), TP53 (19.1%), DNMT3A (15.0%), TET2 (12.2%), and RUNX1 (11.5%). Associations with outcomes were analyzed for the 32 mutations found in ≥ 20 patients. Mutations significantly associated with poorer overall survival vs absence of the mutation included TP53 (hazard ratio [HR] = 1.96, adjusted P < .001), PPM1D (5.8% of patients; HR = 1.64, adjusted P = .002), and JAK2 (2.4% of patients; HR = 1.77, adjusted P = .03). No associations of mutations with prolonged survival were found.
TP53 mutation was associated with poorer overall survival and increased risk of relapse.
RAS pathway mutations were associated with an increased risk of relapse with reduced-intensity conditioning, and JAK2 mutations were associated with an increased risk of nonrelapse mortality.
In multivariate analyses, only TP53 mutations were significantly associated with reduced overall survival (HR = 1.71, P < .001). Mutations associated with increased risk of relapse included TP53 (HR = 2.03, P < .001) and RAS pathway mutations (NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT; 0.2%–4.5% of patients; HR vs no RAS pathway mutation = 1.56, P = .002). JAK2 V617F mutations were significantly associated with greater risk of nonrelapse mortality (HR vs no JAK2 V617F mutation = 2.10, P < .001) but not a greater risk of relapse (HR = 0.68, P = 0.26).
TP53 Mutation Analyses
Among patients without TP53 mutations, survival was better in those aged < 40 vs ≥ 40 years (HR = 0.54, P < .001). Among patients with TP53 mutations, survival was similar for age < 40 vs ≥ 40 years (HR = 0.86, P = .50). Among 1,011 patients aged ≥ 40 without TP53 mutations, the presence vs absence of RAS pathway mutations was associated with poorer overall survival (median = 0.9 vs 2.2 years, P = .004) in association with a higher risk of relapse (P = .001), and the presence vs absence of JAK2 mutations was associated with poorer overall survival (median = 0.5 vs 2.3 years, P = .001) in the context of a higher risk for death without relapse (P < .001).
Patients with therapy-related MDS had poorer overall survival vs those with primary MDS (HR = 1.34, P < .001), and TP53 mutation was significantly more common among the former (38% vs 14%, adjusted P < .001), as were mutations in the TP53 regulator PPM1D (15% vs 3%, adjusted P < .001). The presence vs absence of TP53 mutations was associated with poorer survival among patients with therapy-related MDS (HR = 1.63, P < .001); among patients without TP53 mutations, survival was similar among those with therapy-related MDS vs primary MDS (HR = 1.10, P = .37). PPM1D mutation vs no mutation was not associated with poorer survival in patients with therapy-related MDS without TP53 mutations (HR = 1.26, P = .39).
Effect of Conditioning Regimen
Among patients with TP53 mutations, there was no significant difference in survival for myeloablative conditioning vs reduced-intensity conditioning (median = 7.5 vs 9.2 months, P = .19). Among patients with RAS pathway mutations vs no RAS pathway mutations, reduced-intensity conditioning was associated with a higher risk of relapse (1-year cumulative incidence = 42% vs 20%, P < .001); this difference in relapse risk was not found among patients receiving myeloablative conditioning (22% vs 15%, P = .31). The higher risk of death without relapse among patients with JAK2 mutations was similar irrespective of the intensity of the conditioning regimen.
Mutations in Younger Patients
GATA2 mutations, PIGA mutations, and compound heterozygous mutations in the Shwachman-Diamond syndrome–associated SBDS gene were more common in younger vs older patients. Whereas patients with GATA2 or PIGA mutations shared a good prognosis similar to most younger patients in the cohort, patients aged < 40 years with compound heterozygous SBDS mutations had significantly poorer survival vs those without (median = 1.2 years vs not reached, P = .009).
The investigators concluded: “Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen.” ■
Disclosure: The study was funded by the Edward P. Evans Foundation, a Harvard Catalyst KL2–CMeRIT Award, a National Marrow Donor Program Immunobiology Research Study Grant, National Institutes of Health grants, and a grant from the Leukemia and Lymphoma Society. For full disclosures of the study authors, visit www.nejm.org.
1. Lindsley RC, Saber W, Mar BG, et al: Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med 376:536-547, 2017.
Kamal Menghrajani, MD
Martin S. Tallman, MD
Although several treatment options are available for patients with myelodysplastic syndromes (MDS), hematopoietic stem cell transplantation (HSCT) remains the only curative therapy.1 The risks of complications and death from transplantation...