PROGNOSTIC ROLE OF MDS GENETICS

In a study reported in The New England Journal of Medicine, Lindsley et al found that a number of mutations present in patients with myelodysplastic syndrome (MDS) were associated with poorer clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT).

Study Details

The study involved targeted mutational analysis of samples obtained before HSCT 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.

Among the 1,514 patients: 84% were aged ≥ 40 years; 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%); and the type of MDS was primary in 79% and related to therapy in 21%. The conditioning regimen for HSCT was myeloablative in 52%, reduced-intensity in 38%, and nonmyeloablative in 9%.

Mutations and Prognostic Impact

At least 1 mutation was identified in 1,196 patients (79%); the most common mutations were SXL1(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 = 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.

In multivariate analyses, only TP53 mutations were significantly associated with reduced overall survival (HR = 1.71, P < .001). Mutations associated with an 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 a 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 higher risk for death without relapse (P < .001).

Therapy-Related MDS

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 = 0.39).

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.”

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.