Exploiting <scp>ALK</scp> inhibition in anaplastic large cell lymphoma: Biological rationale and therapeutic integration

Mature T-cell lymphomas comprise a heterogeneous group of aggressive non-Hodgkin lymphomas with limited therapeutic options in the relapsed or refractory setting. Among them, anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) represents a biologically distinct subtype driven by constitutive activation of ALK fusion proteins, which promote oncogenic signalling through signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase (PI3K)/AKT Serine/Threonine Kinase 1 (AKT)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase pathways. This molecular dependency provides a strong mechanistic rationale for targeted ALK inhibition. Small-molecule ALK inhibitors, including crizotinib, have demonstrated high overall response rates (67%-88%) and complete remission rates (~60%-80%) in relapsed or refractory ALK-positive ALCL, often with rapid clinical responses. Next-generation ALK inhibitors have shown activity in patients who progress on crizotinib, supporting the concept of sequential ALK-targeted therapy to overcome acquired resistance. Resistance mechanisms include secondary ALK kinase domain mutations, such as L1196M and G1202R, as well as activation of compensatory signalling pathways, including PI3K/AKT/mTOR, underscoring the importance of molecular reassessment at relapse and the potential role of rational combination strategies. This review critically summarizes the molecular basis of ALK-driven lymphomagenesis, evaluates the clinical evidence supporting ALK-targeted therapy and discusses mechanisms of resistance. In addition, it explores emerging strategies for integrating ALK inhibitors into precision-based management of T-cell lymphomas, including combination approaches with chemotherapy, immunotherapy or antibody-drug conjugates. Collectively, these developments highlight a paradigm shift towards biology-driven, personalized therapy in ALK-positive ALCL.