AML biology matters, so should we transplant ASAP? Free

Patients with acute myeloid leukemia (AML) who are not in complete remission, because of either inadequate response to initial induction therapy or relapse, often receive reinduction chemotherapy before undergoing an allogeneic hematopoietic cell transplantation (HCT). In this issue of Blood, Stelljes et al¹ continue their efforts to determine who, if anyone, benefits from this common practice by closely examining the correlation of blast counts and cytogenetic classification with survival. Their major finding is that AML genetics are the major determinant for post-HCT survival, regardless of pre-HCT therapy.

In the previously reported ASAP trial,² the authors randomized patients to 1 of 2 approaches, namely an intensive reinduction regimen with high-dose cytarabine and mitoxantrone (the remission induction [RIST] arm) or immediate progression to allogeneic HCT without reinduction (the disease control [DisC] arm). Notably, the 4-year overall survival rates were similar between the 2 groups although patients had a high disease burden at randomization (median bone marrow blasts, >30%). In addition, those in the DisC arm spent 1 month less time hospitalized.

In this updated analysis, the authors revisited several key questions. Previous post hoc analyses showed that RIST patients who achieved remission (<5% blasts) had significantly better survival than those with chemotherapy-resistant disease. Similarly, this study found that lower blast counts immediately before transplant conditioning trended toward improved outcomes, raising an important question. If lower pretransplant blast counts are beneficial, why does reinduction chemotherapy not translate to better survival overall?

The answer seems to lie in underlying biology of AML. Genetic risk stratification, using the European LeukemiaNet 2022 classification, proved to be a dominant determinant of outcomes. Patients with adverse genetic features, especially TP53 mutations, had poor survival regardless of the treatment arm. In contrast, patients with favorable-risk mutations, such as NPM1, which are more responsive to chemotherapy,³ experienced the best outcomes. These patients may have derived sufficient benefit from the transplant conditioning regimen alone without requiring additional reinduction chemotherapy as suggested by another recent study.⁴ It should be noted, however, that the pre-HCT conditioning regimens in the ASAP trial incorporated agents such as amsacrine or chemoradiotherapy combinations that are not commonly used in some regions and thus different results might be observed with other pre-HCT conditioning therapies.

It is well established that measurable residual disease (MRD) before transplant predicts a higher risk for relapse after HCT.⁵ The MRD status before HCT was available for only a few patients in this study. However, the lack of benefit from conventional reinduction chemotherapy in this trial suggests that such treatment may not be effective in reliably achieving MRD negativity, particularly in patients with intermediate- or high-risk genetic features.

Fortunately, the treatment landscape for AML is rapidly evolving. Reinduction strategies that incorporate novel agents, like venetoclax,^6,7 or targeted therapies, such as gilteritinib⁸ or midostaurin,⁹ may increase the likelihood of achieving the desirable MRD-negative status before HCT. In addition, the emergence of effective posttransplant maintenance therapies¹⁰ could reduce the importance of achieving deep remissions before HCT. Future studies will need to define the optimal integration of these new tools to personalize treatment strategies and improve outcomes across genetic subtypes of AML.

Conflict-of-interest disclosure: The author declares no competing financial interests.