Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation

Abstract

Key Points• TP53 and RAS-pathway mutations predict very poor survival, when seen with CK and MDS/MPNs, respectively. • For patients with mutated TP53 or CK alone, long-term survival could be obtained with stem cell transplantation.Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.

Induction chemotherapy followed by allogeneic HCT versus upfront allogeneic HCT for advanced myelodysplastic syndrome: A propensity score matched analysis

“…Recent studies showed that mutations in TP53 and Ras-pathway were associated with relapse and surivival after HCT. 30,31 These mutations might also affect the relapse incidences after HCT. Thus, the proportion of blast and molecular profiles need to be included for analyzing the propensity score matching in the future study.…”

Implications ofTP53Allelic State for Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

“…Allele specific copy-number profiles were generated from NGS data using CNACS 9 . CBA data were available for 2,931 (88%) patients.…”

“…We assessed chromosomal alterations based on NGS sequencing data using CNACS 9 . CNACS enables the detection of arm level and focal copy-numbers changes as well as regions of cnLOH.…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Besides known risk factors such as remission state or karyotype knowledge about specific somatic mutations will also be incorporated into such stratification algorithms. Potential candidates for this seem to be TP53 mutations, as several analyses indicated a dismal prognosis for MDS patients after allo-SCT [65][66][67][68]. The goal is to identify a patient population with an extraordinary high relapse risk for further studies to test innovative prophylactic strategies after transplant.…”