Alk‐positive anaplastic large cell lymphoma with variant alk‐fusion partner: a population‐based analyses of the nhl‐bfm study group

Introduction: ALK-positive anaplastic large cell lymphomas (ALCL) are characterized by rearrangements involving the ALK gene on chromosome 2. The translocation t(2;5) (p23;q35) resulting in the NPM1::ALK gene fusion is detected in the majority of ALCL. In 10%–20% of ALCL, ALK is fused to various other partner genes. Compared to NPM1::ALK, variant ALK-fusion proteins are not expressed in the nucleus. The frequency, distribution, and possible prognostic significance of the different variant ALK partner genes have not been analyzed in population-based studies so far. We investigated all patients with ALK-positive ALCL with exclusive cytoplasmic ALK-expression diagnosed in a uniformly treated cohort of ALCL patients in the NHL-BFM study group. Patients and Methods: Between 2000 and 2017, 312 children and adolescents were diagnosed with an ALK-positive ALCL in Austria, Germany, Switzerland and the Czech Republic, and included in the ALCL 99 trial or the NHL-BFM registry 2012. Reference pathology demonstrated exclusive cytoplasmic ALK-staining in 49 tumors. Formalin-fixed-paraffin-embedded or frozen tumors of 43/49 patients were available for molecular analyses. Tumor-DNA was analyzed by an ALK-specific genomic capture high throughput sequencing assay. ALK-partner gene-specific RT-PCR assays were used to identify the respective partner genes when tumor cDNA was available. Results: 41 of 43 available tumors with exclusive cytoplasmic ALK-staining could be analyzed. 13 were NPM1::ALK positive and 28 tumors had a variant ALK partner. TPM3::ALK (n = 9, 32%) and ATIC::ALK (n = 8, 29%) were the most common variant partner genes. XPOI could be identified as a novel ALK fusion partner. The patients´ characteristics of ALCL expressing Variant::ALK were comparable to those with NPM1::ALK fusions. The five-year event-free survival (EFS) and overall survival were comparable between the 284 NPM1::ALK and the group of 28 different Variant::ALK-expressing patients. However, none of the 9 patients with TPM3::ALK positive ALCL relapsed, compared to 5 relapses among 8 patients with ATIC::ALK positive ALCL. Conclusions: In our population-based cohort of ALK-positive ALCL-patients, less than 10% carried variant ALK-fusion partners, 60% of which were TPM3 or ATIC. In patients with exclusive cytoplasmic ALK staining patterns, NPM1::ALK positivity should be excluded by molecular analysis. The tendency of a different relapse risk between ATIC::ALK and TPM3::ALK -positive ALCL-patients suggests that the fusion partner might confer tumor aggressiveness or drug resistance. The research was funded by: KNACK DEN KREBS Fördergemeinschaft Kinderkrebs-Zentrum Hamburg e.V. and HAMBURGER STIFTUNG ZUR FÖRDERUNG DER KREBSBEKÄMPFUNG Keyword: diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.