Intensive chemotherapy bridging to allogeneic hematopoietic cell transplant in relapsed or refractory Acute Myeloid Leukemia Free

Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have poor outcomes. Allogeneic hematopoietic cell transplant (HCT) remains the only potentially curable treatment. Disease status prior to HCT has a direct impact on outcome, moreover, it is not uncommon for R/R AML patients to achieve inadequate responses to salvage therapies. Novel transplantation strategies are needed such as HCT in aplasia after intensive chemotherapy (IC) (Stolzel et al. Leukemia 2013) or sequential conditioning regimens for patients with active disease. In the ASAP trial, immediate HCT was compared to salvage chemotherapy and immediate HCT was shown to be an attractive option for long term disease control (Stelljes et al. Lancet Haem 2024). However, these studies were done in the pre-venetoclax (ven) era. Here, we describe the feasibility and outcomes of patients with R/R AML undergoing intensive chemotherapy (IC) followed by HCT.

Methods This retrospective analysis included adult patients aged 18 years or older with R/R AML who were treated at City of Hope (COH) and received a course of IC prior to HCT within 60 days. Response criteria for complete remission (CR)/CR without hematological recovery (CRi) were per standard International Working Group (IWG) criteria. Morphologic Leukemia-Free State (MLFS) is defined as absence of both bone marrow blasts <5% and extramedullary disease with no hematologic recovery required. Other endpoints were overall survival (OS), progression-free survival (PFS), cumulative incidence (CI) of relapse (CIR), and non-relapse mortality (NRM) from HCT. Safety was assessed according to the Common Terminology Criteria for Adverse Events, version 5 of the National Cancer Institute. Measurable residual disease (MRD) was obtained by flow cytometry performed by the University of Washington with sensitivity of 0.1%. A threshold of p-value = 0.05 was considered statistically significant (RStudio, version 3, Boston, MA).

Results Thirty consecutive patients met the inclusion criteria for analysis. The median age for the whole cohort was 52 years (range 19-74), and the majority were males (56.7%), non-Hispanic whites (63.3%), and ELN 2022 Adverse Risk (70%). TP53 (23.3%), BCOR (16.7%), and RUNX1 (13.3) were frequently detected aberrations by next generation sequencing. The median (range) lines of therapy were 2 (1-6), and 46.7% of patients had 3 or more lines of therapy. Most patients were previously exposed to ven (86.7%) and 13.3% of patients failed prior HCT. FLAG +/- Idarubicin (or Etoposide) +/- Ven based intensive chemotherapy (83.3%) were the most frequently delivered IC regimens.

The CR/CRi/MLFS rate prior to HCT was 63.3% (CR/CRi = 10%) and MRD negativity rate amongst responders was (52.6%). The median time to neutrophil and platelet recovery for the bridging therapy was 27 and 26.5 days, respectively. Febrile neutropenia (83.3%) was common; however, rates of grade 3 or higher treatment emergent adverse events were infrequent (gastrointestinal bleeding; 2(6.7%), pancreatitis 1(3.3%)). The median time to HCT was 43.5 (range= 21-60). Conditioning with TMLI-based (63.3%) or Fludarabine/Melphalan (26.7%), and Tacrolimus and Sirolimus (T/S) (80%) based GVHD prophylaxis regimens were common. Median OS and PFS from HCT were 12.7 (range= 4.8-17.7); and 8.1 (range= 2.2-16.6), respectively. Post-HCT, CIR and NRM were (34.4% and 20.6%) at 12 months and 47.6% and 29.7% at 24 months respectively.

For the transplant, median time to neutrophil and platelet engraftment was 16 (range= 15-19) and 22 (range=18-33) days, respectively. The CI of acute GVHD (II-IV) and III/IV at 100 days was 28.6% and 17.9%. Moderate to severe cGvHD by 1 year was 29.4%. A univariate analysis for OS showed ANC recovery (>500) at the time of conditioning was associated with improved 1-year OS (HR=0.22, 95% CI: 0.05-0.92; p=0.019).

Conclusions IC bridging with ven prior to HCT was feasible in pts with R/R AML. The observed engraftment, non-relapse mortality, and rates of GVHD were within acceptable ranges, supporting the safety of this approach. Notably, most patients had ELN 2022 adverse-risk disease and were heavily pretreated, contributing to a high post-transplant relapse rate. These findings underscore the need for future strategies that are aimed at enhancing disease control, which include optimizing conditioning intensity and incorporating post-transplant maintenance therapies.