Ranging in severity from readily curable to aggressive and rapidly fatal, acute myeloid leukemia (AML) is a heterogeneous malignancy. These outcomes are governed by its underlying genomic landscape. A comprehensive understanding of the cytogenetic and molecular abnormalities that drive leukemogenesis is paramount to selecting optimal treatment strategies.

AML harboring t(8;21)(q22;q22,1) and inv(16)(q13.1;q22) is collectively referred to as core binding factor AML (CBF-AML). It accounts for about 15% of all newly diagnosed AML cases and is regarded as favorable risk with complete remission (CR) rates of over 90% and median time to disease progression of 5 years following intensive induction therapy with cytarabine-containing regimens [1].

The mechanisms behind CBF-AML’s chemosensitivity remain unclear. However, it is likely due to favorable cytarabine metabolism and a lower burden of high-risk molecular and cytogenetic clones. Currently, the 2022 European LeukemiaNet (ELN) guidelines recommend reserving allogeneic stem cell transplant (allo-SCT) for patients with relapsed or refractory CBF-AML [2]. Nevertheless, despite an excellent rate of initial response, 40–50% of patients with CBF-AML still relapse [3]. For such patients, allo-SCT remains the only chance for long term leukemia-free survival.

A recent study by Tarantino et al., published in Bone Marrow Transplant, challenges the traditional view on remission before allo-SCT. Through a retrospective analysis of data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT), the authors propose that intense salvage chemotherapy to induce remission prior to allo-SCT may be unnecessary in CBF-AML. Notably, the study underscores heterogeneity within CBF-AML, highlighting those patients with t(8;21) rearrangement, monosomal karyotype, and relapsed status tend to have worse outcomes. These findings are thought-provoking and warrant further investigation to refine the optimal therapeutic strategy for relapsed or refractory CBF-AML.

The outcomes of patients undergoing allo-SCT with active disease, either primary refractory or relapsed, have been evaluated across multiple studies [4,5,6,7,8]. However, these reports encompass heterogenous patient populations, including patients with primary refractory AML, as well as those with first and second relapses. The proportion of patients with CBF-AML in these studies is inconsistently reported and averages less than 10%. Previously published report by Poiani et al. on behalf of ALWP of EBMT has demonstrated that patients with CBF-AML fare significantly better than those with intermediate or high-risk disease with respect to achieving CR on day 100 (79% vs. 69% vs. 61%, respectively) as well as leukemia free survival (34% vs. 27% and 18%, respectively) [9]. These results again reinforce that disease biology rather than disease burden determines the success of allo-SCT.

Recently published by Stelljes et al., an open-label, randomized trial, assessed the utility of salvage chemotherapy with cytarabine and mitoxantrone (HAM) before allo-SCT (remission induction cohort) compared to immediate allo-SCT using sequential conditioning (disease control cohort) [10]. This study included 65% of patients with primary induction failure, however only 10% of patients had favorable risk disease per ELN 2022. The rate of CR at Day +100 (83% disease control vs. 79% remission induction) as well as 4-year OS (46% disease control vs. 49% remission induction) were comparable between the study cohorts. However, since patients in the disease control arm were permitted to receive cytoreductive therapy and underwent sequential conditioning, these findings may not be generalizable to patients who would typically be conditioned with more traditional regimens. Furthermore, with the widespread availability and use of the less toxic induction strategies, such a azacitidine and venetoclax combination, the patients may be spared morbidity and mortality associated with intensive chemotherapy induction prior to undergoing allo-SCT [11].

The decision to proceed with allo-SCT in AML is a complex, multifaceted process. It requires a careful balance between the risks associated with allo-SCT and the risk of relapse without it. In CBF-AML, pre-transplant disease burden even at measurable residual disease (MRD) level correlates with post-transplant outcomes. This has been demonstrated by Yalniz et al. where 3-year post-transplant OS and LFS were 69.3% and 66.3% vs. 100% and 100% for MRD positive and negative patients respectively [12]. Therefore, traditionally, maximal efforts are made to achieve complete remission, preferably with undetectable MRD, prior to proceeding with allo-SCT. However, Tarantino et al.’s findings suggest that CBF-AML’s unique biology may mitigate this risk.

While potentially offering better long-term outcomes, remission reinduction therapy carries the risk of increased morbidity, including worsening organ function, heightened infection risk, allo-immunization from transfusions, clonal evolution, and deterioration of performance status. Consequently, complications associated with an attempt to achieve second remission can preclude the patient from undergoing allo-SCT altogether. Yet, for patients who are not candidates for re-induction chemotherapy, allo-SCT in active disease may be the only chance for long term disease control. In such situations pre-transplant conditioning therapy serves to reduce leukemia burden and subsequent graft versus leukemia (GVL) effect helps with subsequent control of chemo-resistant clones.

Oftentimes, reasons other than leukemia burden necessitate therapy prior to allo-SCT. For instance, patients who do not have readily available donors may need to receive systemic therapy to control the disease while processes of donor identification and recipient evaluation are underway. With advances in the safety of haploidentical transplants, the time required for donor identification and collection has significantly decreased, allowing for possibility of proceeding with allo-SCT without delay. Furthermore, now with the evidence of efficacy shown by Tarantino et al., there is a conflict between balancing the risks of remission induction therapy against proceeding directly to transplant with active disease remains a key challenge.

Allo-SCT in patients with active primary refractory or relapsed AML remains a controversial approach yet has been shown to be feasible and should be considered on a case-by-case basis. Relapsed or refractory CBF-AML is rare and thus Tarantino et al. are providing invaluable insight, suggesting that the inherent chemosensitivity of CBF-AML may allow this patient group to benefit from allo-SCT without prior salvage therapy. Key factors supporting early allo-SCT despite active disease include chemotherapy-refractory status, high anticipated toxicity from salvage chemotherapy, and the availability of a suitable donor.