Combination Treatment Strategies in Acute Myeloid Leukemia: A Literature Review

Abstract

Introduction: Acute Myeloid Leukemia is a hematologic malignancy with high relapse rates and poor long‐term survival, largely due to the persistence of leukemic stem cells that resist conventional treatments. This study reviews combination treatment strategies aimed at targeting these stem cells to improve patient outcomes.

Methods: A comprehensive literature search was performed using major scientific databases to identify peer-reviewed articles, clinical trials, and preclinical studies published between January 2010 and January 2025. Titles and abstracts were screened for relevance, followed by full-text review by both authors. The search focused on studies evaluating combination therapies (the use of ≥2 therapeutic modalities with the intent of synergistic efficacy in AML) in AML patients involving targeted agents, such as inhibitors of FLT3 and BCL-2, and other treatment modalities, including hypomethylating agents, chemotherapy, metabolic inhibitors, and immunotherapeutic approaches. Both clinical outcomes and mechanistic insights were analyzed to assess the efficacy of strategies that simultaneously target leukemic blasts and stem cells and are reported in this review

Results: Findings indicate that combination therapies yield significant improvements over single-agent approaches. FLT3 inhibitors combined with chemotherapy or hypomethylating agents have demonstrated enhanced remission rates and survival in patients with FLT3-mutated disease. Similarly, regimens incorporating BCL-2 inhibitors with low-intensity agents have shown promising results, particularly in older or unfit patients. Emerging data also suggest that targeting metabolic dependencies and employing immunotherapy can further sensitize resistant leukemic stem cells (LSCs), leading to more durable remissions.

Discussion: The analysis underscores that the dual targeting of proliferating leukemic cells and quiescent stem cells is crucial for overcoming resistance and reducing relapse. Despite the advances observed with targeted combination regimens, challenges such as treatment resistance, metabolic plasticity, and toxicity remain. These issues highlight the need for continued investigation into multi-faceted therapeutic approaches.

Conclusion: This review supports the clinical potential of combination treatment strategies in Acute Myeloid Leukemia, advocating for personalized regimens that address disease heterogeneity and resistance mechanisms. Future research should focus on refining these approaches to enhance efficacy while minimizing adverse effects, ultimately paving the way for improved long-term outcomes.