{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:54:27Z","timestamp":1788965667191,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>Mature T\u2010cell lymphomas comprise a heterogeneous group of aggressive non\u2010Hodgkin lymphomas with limited therapeutic options in the relapsed or refractory setting. Among them, anaplastic lymphoma kinase (ALK)\u2010positive 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\u2010kinase (PI3K)\/AKT Serine\/Threonine Kinase 1 (AKT)\/mammalian target of rapamycin (mTOR) and mitogen\u2010activated protein kinase pathways. This molecular dependency provides a strong mechanistic rationale for targeted ALK inhibition. Small\u2010molecule ALK inhibitors, including crizotinib, have demonstrated high overall response rates (67%\u201388%) and complete remission rates (~60%\u201380%) in relapsed or refractory ALK\u2010positive ALCL, often with rapid clinical responses. Next\u2010generation ALK inhibitors have shown activity in patients who progress on crizotinib, supporting the concept of sequential ALK\u2010targeted 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\u2010driven lymphomagenesis, evaluates the clinical evidence supporting ALK\u2010targeted therapy and discusses mechanisms of resistance. In addition, it explores emerging strategies for integrating ALK inhibitors into precision\u2010based management of T\u2010cell lymphomas, including combination approaches with chemotherapy, immunotherapy or antibody\u2013drug conjugates. Collectively, these developments highlight a paradigm shift towards biology\u2010driven, personalized therapy in ALK\u2010positive ALCL.<\/jats:p>","DOI":"10.1111\/bjh.70458","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T01:14:33Z","timestamp":1774833273000},"page":"1525-1534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploiting\n                    <scp>ALK<\/scp>\n                    inhibition in anaplastic large cell lymphoma: Biological rationale and therapeutic integration"],"prefix":"10.1111","volume":"208","author":[{"given":"Santino","family":"Caserta","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology AO of Cosenza  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of 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