Impact of Post-Remission Intensive (IC) Consolidation Chemotherapy Cycles on Overall and Relapse Free Survival after Allogeneic Stem Cell Transplant (SCT) in Patients with Acute Myeloid Leukemia (AML) Receiving IC + Venetoclax
Authors: Marvin-Peek Jennifer , Kantarjian Hagop M. , Jen Wei-Ying , Borthakur Gautam , Daver Naval , Maiti Abhishek , Short Nicholas J. , Kornblau Steven M. , Pemmaraju Naveen , Kugler Eitan , Bazinet Alexandre , Alvarado-Valero Yesid , Abbas Hussein A. , Garcia-Manero Guillermo , Popat Uday , Shpall Elizabeth J. , Ravandi Farhad , DiNardo Courtney D. , Kadia Tapan M. 
Published: December 2024

Background: Allogeneic stem cell transplantation (SCT) is recommended for younger or fit patients with acute myeloid leukemia (AML) in first complete remission (CR1) who possess a relapse risk exceeding 35-40% (Dohner et al., 2022). The ideal number of post-remission intensive consolidation chemotherapy (IC) cycles prior to allogeneic SCT is currently unknown. With the addition of venetoclax (VEN) to high intensity regimens such as cladribine, idarubicin, and cytarabine (CLIA) and fludarabine, cytarabine, idarubicin, and filgrastim (FLAG-IDA), we sought to determine if patients who had received fewer IC + VEN cycles experienced differences in long-term outcomes post-allogeneic SCT.
Methods/Results: From January 9, 2019 to February 18, 2023, 157 patients on frontline treatment with CLIA + VEN or FLAG-IDA + VEN our institution were retrospectively reviewed. Of these, 138 patients (86.6%) achieved a CR1. Eighty-two of these patients (60.2%) underwent allogeneic SCT directly after receiving frontline IC + VEN and constituted the primary analysis population. The median age was 45 years (range: 20 - 67) and 50 (61.0%) received CLIA + VEN for induction and consolidation while the rest received FLAG-IDA + VEN (n=32, 39%). The median number of IC cycles given was 2 (range: 1 - 5), with 55 patients (67.1%) receiving ≤1 cycle of consolidation compared to 27 (32.9%) receiving ≥2 consolidation cycles. Two patients (2.4%) received only 1 cycle of IC induction prior to SCT. ELN 2022 risk was favorable for 15 (18%), intermediate for 20 (24%), and adverse for 47 patients (57%). Stem cell donor source was matched related (30, 37%), matched unrelated (MUD, 37, 46%), mis-matched unrelated (2, 3%), haploidentical (11, 14%), or syngeneic (1, 1%). A myeloablative conditioning regimen was used in 66 (80%) of patients. Measurable residual disease (MRD) negativity by flow cytometry was achieved in 71 of 77 evaluable patients (92%) prior to SCT. There was no difference in ELN risk (p=0.13), stem cell donor source (p=0.2), conditioning regimen (p=0.9), or MRD negativity (p=0.7) between patients who received ≤1 or ≥2 intensive consolidation cycles. There was a trend towards increased MUD transplants in those with ≥2 cycles of consolidation (21/55 [39%] vs 16/27 [59%], p=0.08), but the time from the start of the last IC cycle was not different between groups (59 days [range: 29 - 167] vs 66 days [range: 25 - 219], p=0.9).
Kaplan Meier curves landmarked at the time of SCT showed no difference in overall survival (OS) or relapse free survival (RFS) between patients with ≤1 or ≥2 IC consolidation cycles prior to SCT (p=0.81 and p=0.98 respectively). At a median follow up of 36 months, the median OS or median RFS has not yet been reached for either group. The 2-year estimated OS for patients receiving ≤1 IC consolidation cycle prior to SCT was 79% (95% CI: 69 - 91%) compared to 85% (95% CI: 72 - 100%) for those receiving ≥2 cycles. The cumulative incidence of relapse (CIR) did not differ between groups with a 2-year CIR risk of 12.0% (4.8 - 22.7%) in those who received ≤1 IC consolidation cycle compared to 12.2% (2.9 - 28.5%) in those who received ≥2 cycles (p=0.60).
Multivariate analysis for OS and RFS after time of SCT were constructed using age, ELN risk, MRD status, and the number of IC consolidation cycles received. The number of IC cycles was not associated with increased hazard of death (HR 0.87, 95% CI: 0.47 - 1.61, p=0.7) or relapse/death (HR 1.00, 95% CI: 0.58 - 1.72, p=0.95). Positive MRD trended towards an increased hazard of death (HR 3.04, 95% CI: 0.81 - 11.1, p=0.091) although very few patients had confirmed positive MRD at time of SCT (n=6).
Conclusions: Patients who received ≤1 IC + VEN consolidation cycle prior to allogeneic SCT did not experience worse OS or RFS post-SCT than those who received ≥2 cycles. While in clinical practice there may be delays in finding suitable donors, these results suggest that we must carefully weigh the balance between preventing relapse and avoiding excess toxicity as outcomes post-SCT may not differ with more pre-SCT IC cycles. Future prospective trials are needed to determine the ideal number of IC + VEN cycles prior to SCT.