Novel Genomic Biomarkers Improve Post-Hematopoietic Cell Transplantation Relapse Risk Stratification for Patients With Myelodysplastic Syndromes.

Abstract

Hematopoietic cell transplantation (HCT) is considered the only curative treatment for patients with myelodysplastic syndrome (MDS), with disease relapse (REL) as the major cause of post-HCT failure. We aimed to conduct a comprehensive genomic screening of prognostic biomarkers associated with post-HCT disease relapse. In this retrospective, cohort study, we analyzed whole-genome sequencing data from 494 non-Hispanic White patients with MDS who received HCT in the Center for International Blood and Marrow Transplant Research network. Genomic prognostic biomarkers were determined by cause-specific Cox regression multivariable models, with additional sensitivity analyses on unrelated transplant subcohorts and different competing outcomes. Their clinical significance on post-HCT risk stratifications was further evaluated via random survival forest models with optimism-bias adjusted bootstrap procedure. Ten novel genomic biomarkers associated with relapse were identified, including somatic mutations in two genes (<i>HNRNPA3</i> and <i>TENM2</i>), one locus (<i>HSPC324</i>) with a burden of rare germline single-nucleotide variants (SNVs), six loci harboring common SNVs, and one region harboring a structural variant (SV). For prognostic performance comparisons, the combined model that included these novel genomic biomarkers showed significant improvement of concordance indices (0.747 [95% CI, 0.705 to 0.786]) for predicting post-HCT disease relapse, compared with 0.547 (95% CI, 0.503 to 0.595) in the baseline model (Revised International Prognostic Scoring System [IPSS-R] + hypomethylating agents + graft-versus-host disease prophylaxis). Especially, the combined model showed superior risk stratifications for low or intermediate IPSS-R MDS patients with divergent post-HCT outcomes. Our results suggest that SNVs and SVs beyond recurrent somatic mutations and cytogenetic abnormalities may play important roles in determining post-HCT relapse risk stratification in patients with MDS.