Imatinib-induced complete and long-term sustained remission in chemotherapy-resistant systemic ALK-positive anaplastic large cell lymphoma

Background: Platelet-derived growth factor receptor (PDGFR) is expressed in nucleophosmin–anaplastic lymphoma kinase (NPM-ALK) positive anaplastic large cell lymphomas (ALCL ALK+). Our previous preclinical research suggested that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib could be an effective treatment strategy for ALCL ALK+. A young indicator patient whose ALCL cells expressed PDGFR and who failed three treatment lines (including autologous stem cell transplantation) achieved complete remission (CR) with imatinib. Methods: We report imatinib treatment of 6 relapsed/refractory (r/r) ALK-positive ALCL patients, 4 of which were treated in a prospective clinical trial (EudraCT No.: 2013-003505-26). Median follow-up was 40 months (160 weeks, range 4–428). Patients were characterized by whole exome sequencing, bisulfite sequencing, and immunological prnofiling. Whole exome sequencing data were integrated and compared to 25 additional ALK+ ALCL patients (Larose et al. Haematologica, 2021). Results: 4 out of 6 patients achieved a CR that was maintained throughout the follow-up of 3.3–8.9 years. 5-year progression-free survival (PFS) was 67%. Lymphoma cells of the two non-responding patients did not express PDGFRA/B. Cytoplasmic co-expression of both ALK and PDGFRA/B in ALCL tumor cells was associated with imatinib response in ALCL ALK+ patients. Methylation profiling confirmed a differentially activated PDGFR axis between responders and non-responders and identified a specific protein kinase profile that included a significant upregulation of HGFAC, VEGFa, and TNFa. Additionally, non-responders were characterized by an exclusive mutational signature of genes linked to vesicular endocytosis and signaling as a resistance mechanism to pan-kinase inhibitors. EA - Encore Abstract: Regional or national meeting (≤1'000 attendees) Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.