Lorlatinib therapy in relapsed/refractory ALK+ lymphomas previously treated with tyrosine kinase inhibitors.

7054 Background: ALK+ Lymphomas are aggressive diseases with poor prognosis when chemoimmunotherapy (CIT) and Crizotinib fail. Lorlatinib is a 3rd-generation tyrosine kinase inhibitor (TKI), that inhibits all reported ALK kinase domain mutations responsible for resistance to Crizotinib. Methods: From 2019 to 2024, we enrolled 8 patients (pts) in a phase 2 open label monocentric study with Lorlatinib in relapse/refractory (r/r) ALK+ lymphomas previously treated with other TKI (EudraCT2016-003970-41). Overall response rate (ORR), the primary endpoint, was evaluated using 18F-FDG PET/CT scans and ALK RT-PCR on peripheral blood and bone marrow samples. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) from the start of Lorlatinib to relapse and/or death. Side effects were classified according to CTCAEv4.03. Our cohort included 4 ALK+ Large B Cell Lymphoma (LBCL) with Clathrin-ALK (CLTC::ALK) rearrangement, 2 ALK+ Anaplastic Large Cell Lymphoma (ALCL) with ATIC::ALK fusion, 1 ALK+ ALCL Lymphoma with NPM::ALK translocation and 1 ALK+ histiocytosis with EML4::ALK rearrangement. Results: The median follow-up (fup) was 23 months (1,3- 62), the median age at diagnosis was 23 years (19-57); all pts were in stage IV Ann Arbor and treated with CIT and Crizotinib. 2 pts also received other TKIs (Alectinib and Ceritinib). Lorlatinib was administered daily at a dose of 100 mg. The ORR at one month (M1) was 100% (95% CI: 72-100%): 5 CR and 3 PR. 3 pts (2 ALCL [ATIC::ALK], 1 ALCL [NPM::ALK]), underwent Allogeneic Stem Cell Transplant (ASCT) while in CR and resumed Lorlatinib post-transplant. Due to hepatic GVHD and memory impairment, their Lorlatinib dosage was reduced from 100 mg to 75-50 mg/day. All of them are in CR. 2 pts (LBCL with CLTC::ALK) refused ASCT, maintained CR from M1 through their last fup at 15 and 65 months respectively, continuing with Lorlatinib at 100 mg/day. 2 ALK+ LBCL pts (CLTC::ALK) achieved PR at M1 but relapsed within 3 months and did not benefit from ASCT or salvage treatments. The pt with ALK+ histiocytosis was in PR at M1 and then obtained CR at M3 with Lorlatinib; surgical resection of a residual necrotic lung mass was performed. She has been in CR for >40 months. PFS rate at 3 months was 75%, with no additional events reported. OS was 87% at 3 and 12 months, and 72% at 24 months and stabilized thereafter. All ALK+ lymphoma pts in CR at M1 maintained a durable response, whereas those in PR died of disease progression. The type of lymphoma or of ALK translocation did not correlate with outcome. Main adverse effects (all grade I/II) included hyperlipidaemia, weight gain, muscle cramps, gastrointestinal symptoms, thrombocytopenia and memory difficulty. Conclusions: Our analysis confirms Lorlatinib's efficacy and safety as salvage therapy. Achieving a CR at M1 was found to be the most important prognostic factor for survival. Adverse events are manageable with dose adjustments. Clinical trial information: EudraCT2016-003970-41 .