Therapeutic Advances in Adult B-cell Acute Lymphoblastic Leukemia with KMT2A Rearrangements.
This review summarizes chemotherapy, allo-HSCT, antibody and cellular immunotherapies, menin inhibitors, and other emerging molecular strategies for adults with high-risk KMT2A-rearranged B-ALL, including reported resistance challenges.
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This review summarizes chemotherapy, allo-HSCT, antibody and cellular immunotherapies, menin inhibitors, and other emerging molecular strategies for adults with high-risk KMT2A-rearranged B-ALL, including reported resistance challenges.
Research significance
The supplied record supports that immunotherapies and menin inhibitors have clinical or biological rationale in adult KMT2A-rearranged B-ALL; it is reasonable but unproven from this review alone to hypothesize that rational combinations could reduce relapse or overcome lineage switch, antigen loss, and other resistance mechanisms.
Source abstract
B-cell acute lymphoblastic leukemia (ALL) with KMT2A rearrangements (KMT2Ar B-ALL) represents a distinct, high-risk subtype in adults, characterized by aggressive disease biology, high relapse rates, and inferior long-term survival. Conventional intensive chemotherapy, even when consolidated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), yields suboptimal outcomes, underscoring the need for novel therapeutic approaches. In recent years, substantial progress has been made with the introduction of antibody-based immunotherapies, cellular immunotherapies, and small molecular inhibitors, reshaping the treatment landscape for this challenging subgroup. This review provides a comprehensive overview of current and emerging therapeutic strategies for adult patients with KMT2Ar B-ALL. We summarize outcomes associated with pediatric-inspired chemotherapy and allo-HSCT, focus on clinical evidence for antibody-based immunotherapy including blinatumomab and inotuzumab ozogamicin, across frontline, consolidation, and relapsed or refractory settings. Advances in cellular immunotherapy, particularly CD19-directed chimeric antigen receptor T-cell therapy, are discussed, with a focus on unique resistance mechanisms such as antigen loss and lineage switch. In addition, we review the biological rationale, efficacy and emerging resistance mechanisms of menin inhibitors, a promising class of agents specifically targeting the epigenetic dependency of KMT2A-rearranged leukemia. Finally, other molecular approaches, including epigenetic modifiers, apoptosis pathway inhibitors, and signaling pathway inhibitors are discussed. Despite these advances, treatment resistance and disease relapse remain major obstacles. These ongoing challenges highlight the urgent need for multi-center, prospective trials to investigate rational combination strategies to improve outcomes for adults with KMT2Ar B-ALL.