Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status

Abstract

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.

Figure 1.

Transplant outcomes for patients with therapy-related (solid line) and de novo myelodysplastic syndrome (dotted line) following allogeneic hematopoietic cell transplantation. (A) Overall survival, (B) relapse free survival, (C) cumulative incidence of relapse and non-relapse mortality (NRM).

Figure 2.

The distribution and frequency of mutations detected by next-generation sequencing in 43 out of 60 patients with therapy-related myelodysplastic syndrome with detected mutation(s).

Figure 3.

Transplant outcomes for patients with therapy-related myelodysplastic syndrome with (dashed line) and without (solid line) TP53 mutation who underwent allogeneic hematopoietic cell transplantation. (A) Overall survival, and (B) relapse-free survival.

Figure 4.

Transplant outcomes for patients with therapy-related myelodysplastic syndrome with (dashed line) and without (solid line) one of high-risk mutations who underwent allogeneic hematopoietic cell transplantation. (A) Overall survival, and (B) relapse-free survival.