Impact of diagnostic genetics on remission MRD and transplantation outcomes in older patients with AML

Abstract

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (VAF≥2%) on diagnostic samples from 295 AML patients age 60 or older who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at the time of remission in 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS 85%), intermediate (55%), high (35%), and very high risk (7%). Prior to HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 mutations (DT) and 61.4% with other mutations (MRDpositive). In univariable analysis, MRD-positivity was associated with increased relapse and inferior LFS compared with DT and MRDnegative patients. However, in a multivariable model accounting for baseline risk, MRD-positivity had no independent impact on LFS, likely due to its significant association with diagnostic genetic characteristics including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In conclusion, molecular associations with MRD positivity and transplant outcomes in older AML patients are driven primarily by baseline genetics, and not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are required.

Maintenance therapy for AML after allogeneic HCT

“…In addition, serial MRD measurements can be used to monitor treatment response while on therapy and potentially serve as surrogate endpoints. However, pitfalls of overutilizing MRD presently include heterogeneity of mutations, some of which do not represent leukemia driving mutations, and the fact that certain MRD measures have not been definitively proven to imply imminent relapse ( 60 ). Maintenance therapy trials that prospectively plan to follow MRD status between intervention and control arms will be invaluable to determine the clinical utility of MRD.…”

Survival, response rates, and post-transplant outcomes in patients with Acute Myeloid Leukemia aged 60-75 treated with high intensity chemotherapy vs. lower intensity targeted therapy

“…Pre-transplant MRD negativity by MFC, PCR, or NGS has also been shown to be predictive of superior post-transplant outcomes including improved OS, improved leukemia free survival (LFS), and reduced incidence of relapse in patients of all ages ( 22 , 23 ). However, findings from recent studies have also suggested that pre-transplant MRD status by flow or NGS may not be independently predictive of post-transplant LFS or OS in patients older than 60, particularly in patients who are treated with lower intensity therapy for remission induction ( 24 , 25 ). The impact of treatment intensity on achievement of MRD negativity in this patient population will be an important question for future studies to address, as will the impact of MRD negativity on post-transplant outcomes for patients treated with intensive vs. targeted therapies.…”

The Cup Runneth Over: Treatment Strategies for Newly Diagnosed Acute Myeloid Leukemia

“…73 Molecular characteristics at diagnosis in patients 60 years or older with AML who undergo allo-HCT in CR1 are predictive of leukemia-free survival and persistence of MRD. 74 These data should, therefore, be integrated into the transplant decision.…”