In next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring, the use of non-DNMT3A, TET2, or ASXL1 (non-DTA) mutations may predict relapse and survival following allogeneic hematopoietic cell transplantation (alloHCT) for patients with acute myeloid leukemia (AML), according to findings published in Blood Advances.
While alloHCT represents an optimal consolidation therapy and standard treatment for patients with high-risk or relapsed AML, the relapse rate following transplant remains high. The prognostic strategy identified in this study may offer clinicians an opportunity to detect molecular relapse before a clinical relapse occurs and implement earlier interventions to improve outcomes, the authors, led by Michael Heuser, MD, of the Hannover Medical School in Germany, wrote.
The study included 138 patients with AML and at least one molecular MRD marker who could be analyzed using NGS-MRD. Dr. Heuser and colleagues assessed the prognostic role of DTA mutations versus non-DTA mutations for MRD monitoring after alloHCT to refine selection of MRD markers. Mutations in DNMT3A, TET2, and ASXL1 are associated with clonal hematopoiesis and may be unsuitable markers for MRD in patients with AML prior to or without transplant, they noted.
Patients were retrospectively assessed by amplicon-based error-corrected NGS on day 90 and/or day 180 following alloHCT. A total of 34 patients had MRD detected on day 90 and/or day 180. The median age of patients who had an MRD marker was 53 years (range = 19-74). Most of these patients underwent alloHCT in first or second complete remission (CR)/CR with incomplete hematologic recovery (CRi; 80%).
Of the 81 patients in CR/CRi at time of alloHCT, 42 patients were deemed MRD positive (52%).
When researchers evaluated the prognostic impact of DTA and non-DTA MRD positivity, they found that nine of the 51 patients with DTA mutations (17.6%) were MRD positive. The mutations identified included: DNMT3A (n=5); TET2 (n=3); and ASXL1 (n=1). The remaining 42 patients were MRD negative.
When DTA mutations were considered, the investigators found similar rates of cumulative incidence of relapse (CIR; p=0.828), relapse-free survival (RFS; p=0.448), and overall survival (OS; p=0.625) between MRD-positive and MRD-negative patients.
A separate analysis evaluated outcomes in the 131 patients with non-DTA mutations. In this group, 26 patients were MRD positive and the non-DTA mutation–based MRD marker was significantly predictive of CIR (p<0.001), RFS (p<0.001), and OS (p=0.001). Additional outcomes are presented in the TABLE.
The investigators also assessed the role of post-alloHCT MRD according to pre-transplant MRD status in 77 patients with evaluable data. “Patients who were MRD negative before alloHCT had an excellent prognosis independent of post-alloHCT MRD,” the authors reported. “Patients who were MRD positive before alloHCT and who became negative after alloHCT had an intermediate prognosis, whereas patients who were MRD positive before and after alloHCT had the worst prognosis.”
Limitations of this study include its retrospective nature, small cohort, and inclusion of patients conditioned for alloHCT with regimens of varying intensities. The investigators also noted that the patient population may not fully represent the average patient with AML, as the study’s selection criteria excluded relapse before day 90 and mandated availability of at least one year of survival follow-up data.
Heuser M, Heida B, Büttner K, et al. Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations. Blood Adv. 2021;5(9):2294-2304.