Overcoming Brigatinib Resistance with Lorlatinib in Pediatric ALK Positive Anaplastic Large Cell Lymphoma with Acquired ALK p.F1174V Mutation – a Case Report

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) among children is rare, and the cause is generally unknown. We describe a pediatric patient with relapsed/refractory ALK+ ALCL and available whole genome and transcriptome data. Germline genome sequencing showed two inherited FANCM variants of potential clinical significance for childhood lymphoma predisposition. While our patient did not experience excessive treatment toxicity, nor showed other signs of Fanconi anemia, the role of these variants was deemed unclear. The lymphoma developed resistance to several lines of therapy. While on the second-generation ALK inhibitor brigatinib, the lymphoma initially responded with near-complete remission but progressed after 2 months of therapy. Tumor sequencing revealed multiple structural variants, homozygous deletion of TP53, and a point mutation in ALK: c.3520T>G, all of which were not present in the diagnostic lymphoma sample. This point mutation results in an amino-acid residue substitution in the ALK protein, p.F1174V, which may explain the acquired brigatinib resistance. Complete disease remission was achieved using the third-generation ALK inhibitor lorlatinib. We conclude that if progression of ALK+ ALCL is experienced while treating with an ALK inhibitor, ALK sequencing should be conducted and a later-generation ALK inhibitor considered to overcome the acquired resistance.