The Impact of Molecular Lesions in Post-Transplant Acute Myeloid Leukemia (AML) in Correlation with Cytogenetic Abnormalities,

Abstract 4137

Relapse remains the most common cause of treatment failure in allogeneic hematopoietic stem cell transplantation (AlloHCT) for AML. Several risk factors (i.e. older age, persistent disease at transplant, adverse cytogenetics, secondary AML, non-myeloablative conditioning regimen) have been identified as predictors for post-transplant AML recurrence. In addition, the adverse prognostic influence of specific mutations (DNMT3, ASXL1, IDH1/2, RUNX1, TET2, TP53 etc.) has been identified in both de novo and secondary AML treated with standard chemotherapy regimens. The impact of these mutations on clinical outcomes following AlloSCT, however, remains largely unexplored. Consequently, we conducted this study to investigate the prognostic role of molecular lesions including metaphase (MC) and SNP array (SNP-A) cytogenetic defects and somatic mutations in patients undergoing AlloHCT.

A total of 186 patients were identified who received myeloablative AlloHCT for AML (2000–2010) and had pre-transplant diagnostic leukemic sample available for testing. We performed SNP-A karyotyping and sequencing for RUNX1, DNMT3, TP53, ASXL1, CBL, IDH1/2, NPM1, FLT3ITD and TET2 gene mutations and correlated the results with clinical outcomes following AlloHCT. SNP-A based karyotyping helped to upstage the cytogenetics by inclusion of previously undetected cryptic abnormalities.Cox proportional hazards analysis was used to identify prognostic factors for relapse, relapse free (RFS) and overall survival (OS). Analysis was based on 103 patients (55%) who had data on cytogenetics. Of these 103 patients, 42 (41%) had disease relapse following transplantation and 58 (56%) died within the median follow up of 39 months (range, 8–133) following their myeloablative AlloSCT. The frequencies of mutations were estimated; for example, FLT3, NPM1, DNMT3, ASXL1, IDH1/2, CBL, RUNX1 and TP53 were detected in 18%, 13%, 14%, 9%, 9%, 4%, 2% and 2% of the cases, respectively. Overall, mutations were present in 35% of AML cases, and were exclusive to those with intermediate or favorable risk cytogenetics. Various combinations were encountered, however in those with 2 concomitant mutations, NPM1 was present in all cases. In patients with intermediate risk cytogenetics (n=83) and those with mutational abnormalities the leukemia relapse rate was 40% and 38%, respectively. In particular, among patients harboring NPM1 mutation relapses occurred in those who were positive for either DNMT3 or FLT3ITD. Lower rate of relapse (25%) was observed in patients with ASLX1 and IDH1/2 mutations. In one case of aggressiveTP53 mutation the patient was alive and leukemia free 3 years after her AlloHCT. In multivariable analysis, complex cytogenetics was an independent predictor for inferior RFS (HR=1.97, 95% CI, 1.04–3.7) and OS (HR=1.96, 95% CI, 1.04–3.7).Older age at transplant (per 10 yr increase, HR=1.24, 95% CI, 1.01–1.5) was associated with poorer OS, whereas higher comorbidity score (HR=1.86, 95% CI, 1.04–3.3) was associated with poorer RFS. There was no significant difference in post-transplant outcomes between patients in intermediate risk cytogenetics with detected genetic mutations (excluding isolated NPM1) and those with no detectable mutations.

Our preliminary results suggest that myeloablative AlloHCT could minimize the prognostic impact of adverse molecular markers in AML. These mutations potentially serve as important biomarkers in determining the management of AML. Further studies designed to determine their precise role are planned.