Therapeutic Advances and Future of Therapy in Acute Myeloid Leukemia
Authors: Farhad Ravandi
Journal: American Journal of Hematology (2025)

Significant progress in the characterization of molecular pathogenic events in acute myeloid leukemia (AML) has led to better characterization of prognosis and identification of subsets that are more likely to benefit from currently available strategies. Furthermore, deciphering these molecular pathogenic events has led to the development of a number of effective molecularly targeted agents that have significantly improved our armamentarium in managing patients with AML. This has certainly provided us with opportunities for improving outcomes but at the same time has created new challenges for satisfactory patient management. Better characterization of cytogenetic and molecular subsets serves to provide long-term prognostic information but also necessitates rapid identification of subsets that may be amenable to specific therapeutic interventions. Furthermore, gaining deeper insights into the biology of disease may increase the emphasis on these pathogenic biologic events rather than morphology for disease characterization. For example, blurring the boundaries of AML and myelodysplastic syndrome (MDS), and relying more on molecular rather than morphological features for disease characterization. Although cytotoxic chemotherapy such as cytarabine and anthracyclines remain the mainstay of therapeutic regimens in AML particularly in the younger and fitter patients who are able to tolerate them, the introduction of venetoclax-based regimens has revolutionized the management of older patients with AML who constitute the vast majority of the patients. This has improved the outcomes of less fit, older patients significantly, but long-term follow-up has demonstrated that such benefit has not been universal and is also very much dependent on the molecular characteristics of the disease. Further incorporation of targeted agents in such backbones has been attempted in several subsets of AML such as FLT3 mutated, IDH mutated and KMT2A rearranged AML with significant success, yet generating the debate about whether a concomitant or sequential administration of these agents is the best strategy. Conventional wisdom that led to the development of multiagent regimens in cancer therapy suggests that the former rather than the latter would be the more effective strategy that would prevent the development of resistance and thereby would provide a more sustained response translating to longer survival and potential cure. Of course, the challenge will remain how to best develop such combinations so that the benefits are not offset by any potential toxicities. The recent development and availability of oral formulations of hypomethylating agents has allowed the development of fully oral regimens that clearly can improve the convenience of administration and adherence to therapy. Such oral regimens are not without their challenges and toxicities and their general applicability will require further assessment in ongoing clinical trials. As we have witnessed throughout the history of cancer drug therapy, the optimal dose and administration of venetoclax remains to be fully established and the available data suggests that although in some molecular subsets, especially NPM1 or IDH mutated AML, protracted administration of venetoclax may be beneficial, in other less sensitive subsets, benefits are not clear and less frequent dosing may be just as good, providing lower toxicity, particularly undesirable myelosuppression. Similar questions may apply to venetoclax when combined with more intensive chemotherapy regimens where the risk for potential toxicity is greater. Advances in technology have provided us with better assays for detecting residual leukemia after achieving morphological remission. Clearly, any detectable disease is more likely to be associated with a higher likelihood of relapse. The question then arises as to whether minute amounts of disease burden can be potentially kept in check by a relatively intact immune system in the post-remission setting or whether an absolute elimination of all leukemia cells is necessary for long-term remission and potential cure. Of course, with the latter proposition, the relevance of highly sensitive assays for the detection of any measurable residual disease (MRD) is higher than the former. Clearly, this also is partly dependent on the underlying biology of leukemia and its pathogenicity and proliferation potential. As such, the dynamics of relapse from remission is different in different subsets of AML and highly dependent on the biology. Recent developments of immune-based strategies have revolutionized the management of a number of lymphoid malignancies. Allogeneic stem cell transplant remains the ultimate immune-based therapy in AML with a significant proportion of patients gaining long-term benefit from this procedure. Further refinements to the preparative regimens, as well as better supportive strategies, have ensured continued improvement in the outcomes of patients undergoing transplants. Other forms of immune-based therapy such as monoclonal antibody-based therapy as well as cellular therapy have been investigated in AML and although challenges remain, the hope for future development of effective and safe immunotherapies in AML persists. This special issue aims to highlight the significant progress and ongoing challenges in AML research and treatment, providing a comprehensive overview of the current state and future directions in the field. The author has nothing to report. The author declares no conflicts of interest. The author has nothing to report.