Mutations of the B-cell receptor pathway confer chemoresistance in primary cutaneous diffuse large B-cell lymphoma leg-type

Abstract Primary cutaneous diffuse large B-cell lymphoma leg-type (PCLBCL-LT) preferentially involves the lower limb in elderly subjects. A combination of poly-chemotherapy with Rituximab has improved prognosis. However, about 50% of patients will experience progression or relapse without any predictive biologic marker of therapeutic response. The mutational profile of PLCBCL-LT has highlighted mutations contributing to constitutive NF-κB and B-cell receptor (BCR) signaling pathways but has not demonstrated clinical utility. Therefore, the mutational status of 32 PCLBCL-LT, 14 patients with complete durable response and 18 with relapsing/refractory disease was determined with a dedicated lymphopanel. Tumors pairs at diagnosis and relapse or progression were analyzed in 14 relapsing/refractory patients. PCLBCL-LT patients harboring one mutation that targets one of the following BCR signaling genes ( CD79A/B or CARD11 ) displayed a reduced progression-free survival and specific survival (median 18 months, P =0.002 and 51 months, P =0.03 respectively, whereas median duration in wild type group was not reached) and were associated with therapeutic resistance ( P =0.0006). Longitudinal analyses revealed that MYD88 and CD79B were the earliest and among the most mutated genes. Our data suggest that evaluating BCR mutations in patients with PCLBCL-LT may help to predict first-line therapeutic response and to select targeted therapies.