Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study

Abstract

Purpose: Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.

Methods: We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53^multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).

Results: The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53^single versus TP53^multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001).

Conclusion: HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.

Trial registration: ClinicalTrials.gov NCT02016781.

FIG 1.

Patients included in this study. BMT CTN, Blood and Marrow Transplant Clinical Trials Network.

FIG 2.

Spectrum of myeloid driver mutations in the BMT CTN 1102 study. A comutation plot shows mutations in individual genes per study arm as labeled on the top. Mutations are depicted by colored bars and each column represents one of the 309 patients. ^aSignificant with P < .05 (Fisher's exact test). ^bSelection of patients with de novo MDS with IPSS intermediate-2 or high risk age 50-75 years from a matched retrospective cohort. BMT CTN, Blood and Marrow Transplant Clinical Trials Network; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome.

FIG 3.

Clinical outcomes by TP53 allelic state. (A) OS by TP53 allelic state. (B) Cumulative incidence of MDS relapse or progression to AML by TP53 allelic state, with death considered as a competing event. Time is measured from consent. MDS, myelodysplastic syndrome; OS, overall survival.

FIG 4.

Forest plots of the multivariable analysis. Forest plot of subgroup analyses showing the HR for death and 95% CI in (A) the multivariable analysis of the donor versus no donor comparison and (B) the multivariable time-dependent analysis where HCT was considered as a time-dependent variable. Multivariable Cox regression analysis was used, with adjustment for treatment arm (A) or HCT (B), TP53 allelic state, DDX41 mutation, KMT2A^PTD, complex karyotype, duration of disease, IPSS score, sex, age, and performance score. ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplantation; HR, hazard ratio; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival.

FIG 5.

Forest plot of the multivariable analysis in patients with mutated TP53. (A) Forest plot of subgroup analyses in patients with mutated TP53 showing the HR for death and 95% CI in the multivariable time-dependent analysis where HCT was considered as a time-dependent variable. Multivariable Cox regression analysis was used, with adjustment for HCT, TP53 allelic state, DDX41 mutation, KMT2A^PTD, complex karyotype, duration of disease, IPSS score, sex, age, and performance score. (B) OS in patients with TP53 mutations in which HCT is considered as a time-dependent covariate according to a Simon-Makuch plot. Time is measured from consent and patients switch from the no HCT to the HCT at the time of HCT if they received HCT. (C) Serial analysis of enrollment and pre-HCT TP53 samples (n = 35). Patients with pre-HCT TP53 VAF ≥5% (left) and pre-HCT TP53 VAF <5% (right) are shown. (D) OS in patients with TP53 mutations by pre-HCT TP53 VAF cutoff of 5%. Time is measured from transplantation. ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplantation; HR, hazard ratio; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival; VAF, variant allele fraction.

FIG 6.

Outcome based on IPSS-M risk classification. (A) Forest plot of subgroup analyses showing the hazard ratio for death and 95% CI in the intention-to-treat analysis of donor versus no donor. Multivariable Cox regression analysis was used, with adjustment for treatment arm, IPSS-M score, duration of disease, age, and performance score. (B) A comutation plot shows mutations in individual genes in patients with IPSS-M very high risk per TP53 mutation status as labeled on the top. Mutations, cytogenetic abnormalities, hemoglobin, platelet count, and bone marrow blasts are depicted by colored bars and each column represents one of the 69 patients. For hemoglobin, platelet count, and bone marrow blast, the color scheme ranges from red (high-risk value) to blue (low-risk value). (C) OS (left) and cumulative incidence of MDS relapse or progression to AML (right) by donor versus no donor comparison in patients with IPSS-M very high risk with a TP53 mutation. (D) OS (left) and cumulative incidence of MDS relapse or progression to AML (right) by donor versus no donor comparison in patients with IPSS-M very high risk without a TP53 mutation. Time is measured from consent. ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IPSS-M, molecular International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival.