Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

SIMPLE SUMMARY: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is an aggressive cutaneous lymphoma with high response rates to initial immune-polychemotherapy but with frequent relapses and disease-related death. To study the genetic profile during the disease course, 73 samples of primary/pre-treatment and relapsed/refractory disease of 57 patients with PCDLBCL-LT were molecularly characterized, including paired analysis in 16 patients. Targeted next-generation sequencing demonstrated genetic stability of the main oncogenic driver alterations of PCDLBCL-LT, especially (hotspot) mutations in MYD88/CD79B and loss of CDKN2A. As nearly all patients (95%) harboured one or more of these drivers, patients could benefit from targeted therapies addressing these alterations. Additionally, genetic stability serves as a rationale for the use of molecular-based methods for disease monitoring during follow-up, improving response evaluation and early identification and intervention of disease relapses in PCDLBCL-LT patients. ABSTRACT: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients.