Acquired L1196M ALK mutation in anaplastic lymphoma kinase‐positive anaplastic large cell lymphoma during alectinib administration

RNA sequencing analysis revealed that the large-sized tumour cells of the pulmonary tumour had acquired L1196M mutation in the ALK gene (Table 1). TABLE 1 SNPs of the ALK gene of each tumour sample by RNA sequence analysis Sample Mutation of ALK gene ClinVar Nucleotide change rs number Small-sized tumour cells at onset D1529E Benign c.4587C > G rs1881421 K1491R Benign c.4472A > G rs1881420 I1461V Benign c.4381A > G rs1670283 Large-sized tumour cells at onset D1529E Benign c.4587C > G rs1881421 K1491R Benign c.4472A > G rs1881420 I1461V Benign c.4381A > G rs1670283 Small-sized tumour cells at the first relapse D1529E Benign c.4587C > G rs1881421 K1491R Benign c.4472A > G rs1881420 I1461V Benign c.4381A > G rs1670283 Large-sized tumour cells of the pulmonary tumour at the second relapse L1196M Likely pathogenic c.3586C > A rs1057519784 D1529E Benign c.4587C > G rs1881421 K1491R Benign c.4472A > G rs1881420 I1461V Benign c.4381A > G rs1670283 Note: Large tumour cells of the pulmonary tumour at the second relapse acquired an L1196M mutation in the ALK gene. [...]L1196M ALK mutation was detected only in the pulmonary lymphoma sample and not in any of the blood samples, including the sample at the second relapse. [...]we concluded that the acquired L1196M ALK mutation induced alectinib resistance. In a previous study that investigated the susceptibility of EML4-ALK expressing cells with various ALK mutations to each ALK inhibitor, cells with L1196M ALK mutation were found to be more susceptible to alectinib than crizotinib but cells with L1196M ALK mutation were less susceptible to alectinib than cells with wild-type ALK [ 10]. [...]reduced alectinib susceptibility by acquired L1196M ALK mutation could contribute to a second relapse during alectinib therapy in our patient. [...]EML4-ALK expressing cells with various ALK mutations including L1196M show higher susceptibility to other ALK inhibitors such as ceritinib, brigatinib and lorlatinib, which are off-label for ALK+ALCL, than alectinib[ 10]. [...]they may become alternative candidates as salvage therapy for refractory ALK+ALCL cases.