Impact of pre-transplant chemotherapy cycles on allogeneic hematopoietic cell transplant outcomes in pediatric acute myeloid leukemia Free

Introduction Allogeneic hematopoietic cell transplant (HCT) improves the outcomes of pediatric patients with high-risk acute myeloid leukemia (AML) in first complete remission (CR1). Improved cytogenetic and molecular profiling of AML and data from sequential Children's Oncology Group (COG) trials have enabled clinicians to better define and identify high-risk disease. The most recent COG phase III study in upfront AML therapy, AAML1831, recommended two cycles of induction cytarabine-based chemotherapy followed by at least one cycle of consolidative therapy prior to HCT for high-risk patients. Many patients, however, achieve a complete remission without measurable residual disease (MRD) by flow cytometry after the first or second cycle of therapy. Additional cycles of intensive chemotherapy may increase toxicity and therapy-related complications. We hypothesized that, in pediatric patients with AML who underwent HCT in CR1, the number of upfront high-intensity chemotherapy cycles would not be associated with differences in leukemia-free survival (LFS), and that transplant-related mortality (TRM) may be higher in those exposed to an increased number of cycles.

Methods This single-center retrospective study compared pediatric patients (age 0-18) who underwent HCT for AML in CR1 at the University of Minnesota between 2011-2023. Patients who were positive by flow cytometry at the time of transplant were excluded. Patients were divided into cohorts that received either 1-2 cycles or 3-4 cycles of high intensity cytarabine-based chemotherapy prior to HCT. Endpoints included 2-year LFS, overall survival (OS), and relapse incidence (RI), and 1-year TRM. Kaplan-Meier estimates of OS and LFS were made from date of HCT. Cumulative incidences of relapse and TRM were estimated using the cumulative incidence function, with the other event defined as a competing risk.

Results We identified 42 patients that met inclusion criteria. All patients were conditioned with busulfan- (n=27) or total body irradiation (TBI)-based (n=15) preparative regimens and all received a calcineurin inhibitor-based GVHD prophylaxis. 24 patients (57%) received 1-2 cycles of chemotherapy prior to HCT, 18 (43%) received 3-4 cycles. Median age was 9.2 years (Q1, Q3: 2.6, 14.1) at HCT. There were no significant differences between the two cohorts in age, sex, race/ethnicity, Karnofsky/Lansky score, gemtuzumab exposure, donor type, stem cell source, conditioning approach (busulfan vs TBI), conditioning intensity (reduced vs myeloablative), or GVHD prophylaxis. The cohorts were similar in cytogenetic mutation profile with KMT2A rearrangements in 10 (42%) patients in the 1-2 cycle cohort and 8 (44%) in the 3-4 cycle cohort. 16 (67%) of the 1-2 cycle patients had reached morphologic CR1 after one cycle of chemotherapy, 15 (63%) flow MRD negative. 10 (56%) of the 3-4 cycle patients had reached flow MRD negative remission after one cycle and 13 (72%) of the 3-4 cycle patients were flow MRD negative after 2 cycles of therapy but went on to receive further cycles. Median duration from diagnosis to transplant was 100 days (Q1, Q3: 96, 120) in the 1-2 cycle cohort, and 139 (Q1, Q3: 128, 174) in the 3-4 cycle cohort.

2-year LFS was 71% (95% CI 48-85) in the 1-2 cycle cohort and 58% (31-77) in the 3-4 cycle cohort. 2-year OS was 70% (46-84) in 1-2 cycle patients vs 77% (49-91) in 3-4 cycle patients. Cumulative incidence of relapse at 2 years was 12% (3-29) in the 1-2 cycle cohort and 42% (18-65) in the 3-4 cycle cohort. The 1-2 cycle cohort TRM was 17% (5-34) at 1 year; there was no TRM in the 3-4 cycle cohort.

Conclusions The impact of pre-transplant induction and consolidation cycles on outcomes of allogeneic HCT for pediatric AML remains a topic of deliberation. In this single center study of pediatric patients who underwent HCT for AML in flow cytometry-negative first complete remission, we found similar rates of 2-year leukemia-free survival and overall survival in patients receiving 1-2 pre-transplant chemotherapy cycles compared to those receiving 3-4 cycles. Additional cycles of consolidation therapy for patients primarily already in a flow MRD-negative state after 2 cycles did not appear to increase TRM or reduce rates of relapse. These results suggest that it may be appropriate to proceed to allogeneic HCT if in flow-MRD negative remission after 2 cycles of induction therapy without the potential toxicity of subsequent chemotherapy cycles.