Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the uncontrolled clonal expansion of immature myeloid progenitor cells (blasts), which disrupts normal hematopoiesis and ultimately results in bone marrow failure (Dohner et al., 2015, Short et al., 2018). AML is the most frequently diagnosed acute leukemia in adults, with a median onset age of 68 years, and its incidence is expected to increase as the global population ages (Shallis et al., 2019). According to recent data from the American Cancer Society, approximately 20,800 new AML cases and 11,220 related deaths are projected for 2024 (Siegel et al., 2024). Data from the Surveillance, Epidemiology, and End Results (SEER) program covering 2014–2020 indicate a 5-year overall survival (OS) rate of about 30 % (SEER, 2022). However, survival rates vary by age group – reaching 40–50 % in individuals under 60 but dropping to 10–20 % in older patients (Sasaki et al., 2021). This disparity is largely attributed to more frequent complex genetic mutations in the elderly, along with reduced tolerance to intensive chemotherapy regimens (De Kouchkovsky and Abdul-Hay, 2016). Despite considerable advances in our understanding of AML biology and genomics, the primary therapeutic approach continues to rely on intensive induction chemotherapy, most commonly the “7 + 3” regimen combining cytarabine and anthracyclines. Unfortunately, treatment resistance and relapse continue to present formidable clinical obstacles (Dohner et al., 2015, Winer and Stone, 2019). As a result, there is an urgent need for the development of more effective, targeted treatment strategies to enhance outcomes in AML.

Advances in next-generation sequencing technologies over the past two decades have revolutionized our understanding of AML pathogenesis, particularly in elucidating intracellular signaling pathways essential for blast cell proliferation and survival. These advancements have enabled the identification of critical therapeutic targets including FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 (BCL-2), isocitrate dehydrogenase 1/2 (IDH1/2), CD33, CD47, and others (Kayser and Levis, 2022). Compared to conventional chemotherapy, targeted therapies demonstrate superior short-term efficacy and reduced toxicity (Wei and Tiong, 2017). Several phase III clinical trials of second-generation FLT3 inhibitors, gilteritinib and quizartinib, demonstrated improvements in median OS by 3.7 and 1.5 months, respectively, versus intensive chemotherapy (Daver et al., 2021). However, the clinical benefits of these targeted therapies remain constrained in relapsed/refractory (R/R) AML due to the rapid development of secondary mutations and acquired drug resistance (Antar et al., 2020, Bewersdorf et al., 2020). Although FLT3 inhibitors exemplify the promise of precision medicine, similar challenges persist across other targeted agents, underscoring the need for innovative strategies to overcome resistance mechanisms in AML therapy.

Resistance to targeted therapies in AML arises through multiple mechanisms, including on-target mutations that disrupt drug-target interactions, activation of compensatory signaling pathways, and changes in cell surface antigen expression. While these resistance pathways have been partially elucidated, their full prognostic implications remain under investigation. Recent studies are increasingly focused on combination regimens and adaptive therapeutic strategies designed to mitigate resistance and prolong remission. In this review, we examine the current landscape of targeted treatments in AML, the biological mechanisms driving therapeutic resistance, and emerging approaches aimed at overcoming these barriers. Our goal is to provide a comprehensive analysis that informs the development of more durable and effective treatment modalities for patients with R/R AML.

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