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

Summary 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.