The scientific revolution in determining the genetic basis of cancer is finally bearing fruit in hematologic neoplasms such as acute myeloid leukemia (AML), where over the past decade a number of effective new drugs have expanded our armamentarium and provided effective—and in some cases potentially curative—options for several molecular subsets. This availability of molecularly targeted agents provides effective strategies but increasingly creates questions for practicing oncologists.
Chemotherapy vs Targeted Therapy
The fundamental question is whether the field is ready to give up its historical “addiction” to traditional chemotherapy and move toward more target-directed and less toxic regimens. After all, a proportion of patients have been and are still curable with traditional chemotherapy. To use an analogy, it is clearly more desirable to target a villain hiding in a building by locating them using sophisticated surveillance techniques and selectively eliminating the risk rather than by indiscriminately targeting the building. However, the core question remains whether we are sophisticated enough to selectively identify and eliminate the leukemic cells without causing damage to the patient.
Farhad Ravandi, MD
The lower-intensity regimens initially developed for frail and elderly patients with AML have clearly been a step in the right direction, allowing treatment of even octo- or nonagenarians and providing many with meaningful, durable responses at the cost of very limited toxicity, although cure remains elusive for most, if not all.1,2 Whether these regimens can be applied to younger patients with AML remains the subject of ongoing debate and will likely be partially answered by emerging clinical trials.
The Role of MRD
My great belief as a leukemia doctor has always been that “the best time to treat AML is the first time.” That is, curing relapsed leukemia has always been, and continues to be, a challenging endeavor even in the youngest patients.3 Therefore, the goal of the initial induction and consolidation therapy should be to eradicate any leukemia cells capable of initiating and sustaining recurrence, as relapsed leukemic cells are, through the acquisition of resistance mechanisms, more challenging and less responsive to available therapies.
This is where the relevance and importance of depth of response comes to play. Although historical response assessment relying on morphologic evaluation of bone marrow specimens remains relevant, its value in predicting long-term outcomes is limited. With the development and availability of significantly more sophisticated and sensitive assays to detect persisting aberrant leukemic cells—referred to as measurable residual disease (MRD)—the field is increasingly focused on the depth of response achieved by various treatment strategies.4
The issue is lack of standardization of these assays, which limits the ability to compare data and draw definitive conclusions about whether one strategy is more effective than another. There are ongoing efforts in large datasets of patients treated in phase II and III trials with experimental agents or placebo given alongside intensive chemotherapy to establish surrogacy of MRD as a regulatory endpoint in AML drug development (as required by the U.S. Food and Drug Administration).5 If successful, such surrogate endpoints are also likely be useful in comparing intensive cytotoxic regimens with lower-intensity, target-driven regimens and, at the very least, provide a tool to assist in making such decisions.
To this end, reliance on individual MRD markers may be problematic due to the clonal diversity within each AML and the potential for clonal escape and evolution following therapy. As such, in addition to the depth of MRD response, the breadth of clonal clearance may become increasingly relevant, necessitating the development of assays that not only track the driver mutations or clonal aberrations but also detect accessory and “incidental” bystander mutations at sufficient depth.
Balancing Promise and Prudence
Clearly, the potential benefits of lower-intensity initial AML therapy—including reduced toxicity and risk of complications, shorter hospitalization, lower psychological impact, and a higher rate of patients in better clinical condition proceeding to transplant—are plausible and convincing arguments in favor of such a strategy.6
It is, however, important to remember that in certain subsets of AML, such as those with core binding factor aberrations or mutated FLT3—and perhaps other more favorable subsets—the data developed over several decades mandates a pause before moving to lower-intensity therapy until more substantial collective data are available. This is particularly true for younger patients who would traditionally be offered an allogeneic stem cell transplant in first remission but may, for a variety of reasons, be unable or unwilling to undergo transplant. In such patients, the depth of response after initial treatment is likely to be an important determinant of long-term outcome, and the comparative ability of the intensive vs lower-intensity regimens to achieve deep responses is a very important consideration.7
Exciting new developments in the management of patients with AML provide reason for optimism that, after several decades of research, we may be at the cusp of an era in which “cure” becomes a reality for most patients with this disease. However, prudence mandates that we do not prematurely abandon the gains of the past several decades outside the context of well-conducted clinical trials designed to assess the potential superiority of these regimens in all patients.
DISCLOSURE: Dr. Ravandi has received honoraria from Astellas Pharma, Quetzal, Syndax, and Taiho; has held a consulting or advisory role with Astellas Pharma, Quetzal, Syndax and Taiho; and has received research funding from Astellas Pharma, Biomea Fusion, Senti Biosciences, and Taiho.
REFERENCES
1. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.
2. Pratz KW, Jonas BA, Pullarkat V, et al: Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol 99:615-624, 2024.
3. Bataller A, Kantarjian H, Bazinet A, et al: Outcomes and genetic dynamics of acute myeloid leukemia at first relapse. Haematologica 109:3543-3556, 2024.
4. Short NJ, Zhou S, Fu C, et al: Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: A systematic review and meta-analysis. JAMA Oncol 6:1890-1899, 2020.
5. Tettero J, Eric S, Freeman S, et al: Validation of measurable residual disease as a surrogate endpoint in acute myeloid leukemia: A HARMONY Alliance study of European randomized trials. 2025 ASH Annual Meeting & Exposition. Abstract 343. Presented December 6, 2025.
6. Fathi A, Perl A, Fell G, et al: Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. 2025 ASH Annual Meeting & Exposition. Abstract 6. Presented December 7, 2025.
7. Bazinet A, Kadia T, Short NJ, et al: Undetectable measurable residual disease is associated with improved outcomes in AML irrespective of treatment intensity. Blood Adv 7:3284-3296, 2023.
Dr. Ravandi is the Dallas/Fort Worth Living Legend Chair for Cancer Research III and Professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston.
