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.

Prognostic factors influencing survival after allogeneic transplantation for AML/MDS patients with TP53 mutations

“…[1][2][3][4] The TP53 gene is located in the 17p13 chromosomal region and is 1 of the major tumor suppressor genes, often inactivated by deletion and/or mutation in many tumors, including hematologic malignancies. [5][6][7][8] TP53 mutations in AML and MDS are associated with significantly lower responses to standard chemotherapy and have emerged as a strong negative prognostic marker with poor treatment outcomes, 6,[8][9][10][11][12][13][14][15] including with ASCT. 3,4,8,[12][13][14] Here we hypothesized that outcomes of patients with TP53mutated AML/MDS are not uniformly poor and aimed to identify prognostic factors for survival in patients with TP53-mutated AML/MDS undergoing ASCT.…”

“…Several studies have shown the ability of graft vs leukemia effect to overcome the poor prognosis in these patients after ASCT in CR1. 3,4,7 A recent European Society for Blood and Marrow Transplantation analysis showed that ASCT for patients in CR1 with 17P abnormality led to a 2-year OS of 28% and leukemiafree survival of 24%. The 2-year NRM was 15%, and the 2-year relapse incidence was 61%.…”

Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia

“…The role of allogeneic transplant remains controversial for TP53 -mutated leukemia [ 140 , 141 ]. Practices vary dramatically among transplant centers—some do not recommend transplant to any patients with mutated TP53 , some recommend transplant only if a complete remission (CR) is achieved, and others recommend transplant in the absence of another viable alternative.…”

TP53 in Myelodysplastic Syndromes

“…This suggests that the escalation of the intensity of the conditioning regimen is ineffective in improving the outcomes of TP53 -mutated MDS patients [ 69 ]. However, controversial results were also reported, in which no significant difference in prognosis was found after transplantation between the MDS with or without TP53 mutations [ 71 ]. Yoshizato et al compared the prognosis of TP53 -mutant MDS in combination with complex karyotypes to patients with TP53 mutations but without complex karyotypes, and showed that the TP53 mutation-alone patients had a significantly better OS compared to those with both TP53 mutation and complex karyotypes [ 72 ].…”