Toward a Measurable Residual Disease-Based Algorithm for Selection of Allogeneic Hematopoietic Stem Cell Transplant in Acute Myeloid Leukemia

Abstract

Background: The diagnosis and management of acute myeloid leukemia (AML) have transformed in recent years with an improved understanding of leukemogenesis and improved methods of measurable residual disease (MRD) detection. Current treatment algorithms include consideration of allogeneic hematopoietic stem cell transplant (HCT) for intermediate and adverse-risk AML. MRD negativity is widely accepted as a predictive and prognostic marker for disease-free survival and overall survival. However, the clinical use of MRD status in consolidative HCT planning remains unclear. Methods: Two hundred thirty-three consecutive patients achieving complete remission (CR) as defined in ELN 2022 after receiving therapy at Massey Cancer Center were analyzed. MRD status was determined either by multiparameter flow cytometry, PCR-based sequencing, and/or next-generation sequencing. Patients were analyzed via retrospective chart review to obtain baseline characteristics, molecular and cytogenetic profiles, and survival data. Median overall survival (mOS) was calculated and compared using the Kaplan-Meier method. Continuous variables were compared using one-way ANOVA. Categorical variables were analyzed using Fisher's exact test. Results: In total,109 patients achieved MRD-negative CR and 124 patients achieved an MRD-positive CR. Of the MRD-negative patients, 42 went received HCT (39%). In the MRD-positive cohort, 44 underwent HCT (35%). Among the MRD negative group, those receiving HCT tended to be younger (52.1 y. [range: 24.8-71.7] vs 61. 8 y. (range: 27.1-82.9) p = 0.026) with fewer co-morbidities (Charlson comorbidity index [CCI] score: 3 [range: 2-9] vs 4 (range: 0-14), p = 0.322). We observed a similar trend in those who had MRD positivity at best response or at the time of transplant (age 55 y. [range: 24.5-72.2] vs 62 y. [range: 25.1-88], p = 0.142; CCI 4 [range: 2-7] vs 5 (range 2-11], p = 0.014). In the MRD-negative/no HCT group, 49.3% had ELN favorable-risk disease at initial AML diagnosis, 28.4% had intermediate risk, and 22.4% had adverse risk. In the MRD-negative/HCT group, 31% were favorable risk, 33.3% intermediate risk, and 35.7% were adverse risk. In the MRD-positive/HCT group, 46.3% favorable risk, 23.8% intermediate risk, and 29.5% were adverse risk. There were no significant differences in ELN risk between any group. MRD-positive patients who underwent HCT had a mOS of 25.7 m. vs 20.7 m. for no HCT (HR=0.68 [95% CI, 0.41-1.11], p = 0.125). The median OS was not reached for MRD-negative patients, regardless of receipt of HCT (HR=0.61 [95% CI, 0.30-1.23], p = 0.168). Patients undergoing HCT in MRD-negative CR had improved OS compared to those undergoing HCT with persistent MRD positivity (p = 0.006). Discussion: MRD positivity is a known predictor of relapse and decreased survival despite HCT. However, the use of MRD as a decision point predicting which patients will benefit from transplant a priori needs to be better understood. Our data suggest that MRD negativity has a more significant impact on overall prognosis than HCT status.Likewise, the negative impact of MRD positivity was not significantly abrogated by subsequent HCT. This highlights the need for refinement in HCT selection beyond ELN 2022 intermediate/adverse-risk patients, and new validated algorithms incorporating MRD status are warranted.