Genetic landscapes and curative effect of CAR T-cell immunotherapy in patients with relapsed or refractory DLBCL.

As reported, 40% of patients with diffuse large B-cell lymphoma (DLBCL) still experience refractory disease or relapse after the standard R-CHOP (cyclophosphamide, doxorubicin, vincristine, and pre-dnisone+rituximab) therapy.1,2 Various salvage therapeutic strategies, including autologous hemato-poietic stem cell transplantation, have been attempted to overcome the resistance to treatment and improve overall survival (OS). Nevertheless, the disease still relapses in 30% of patients.3,4 Regarding immunochemotherapy, chimeric antigen receptor (CAR) T-cell therapy has been shown to be promising for treating patients with refractory or relapsed DLBCL (rrDLBCL). However, CD19-CAR T-cell therapy has shown only a 40% to 54% complete remission (CR) rate in patients with rrDLBCL,5-8 which may be related to the genetic heterogeneity of the rrDLBCLs. The advent of high-throughput next-generation sequencing technology has rapidly increased our knowledge of genomic alterations of DLBCL.9-11 Several reports have proposed the concept of molecular subtypes.12-16 Distinct classification describes partially overlapping features, suggesting the existence of molecular subtypes and guiding novel-targeted therapy. It is unclear whether the diverse molecular subgroups experience different efficacy of CAR T-cell therapy. To investigate, we performed targeted deep sequencing of 92 hematologic-related genes in a cohort of 105 patients with rrDLBCL, in which most of the patients underwent CAR T-cell immunotherapy after having a poor response to multiple lines of treatment. This trial is registered on the Chinese Clinical Trials Registry as #ChiCTR1900020980. One hundred five patients with rrDLBCL diagnosed from 2019 through 2020, including 6 patients with transformed follicular lymphoma, 2 with transformed mucosa-associated lymphoid tissue lymphoma, and 2 with transformed chronic lymphocytic leukemia lymphoma, were recruited for the study. Eighty-four patients (86%, 84/105) had been treated with CAR T-cell therapy before enrollment in the study. The patients were followed up until 15 April 2021. The study was approved by the Institutional Review Board of Boren Hospital. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. The baseline clinical characteristics of the 105 patients included in the study are summarized in Table 1 and supplemental Table 1. The median age of the entire cohort at initial diag-nosis was 49 (range, 13-79) years. Twenty-nine patients (27.6%) had a relatively high-risk International Prognostic Index score of 4 to 5. The median time of relapse was 12.7 months. The median number of chemotherapy cycles was 11. Among our cohort of patients, 11 with germinal center B cells (11 of 31, 35.5%) were classified as "double hit" or "triple hit" (DH/TH), harboring translocations of MYC and BCL2/BCL6, whereas only 2 patients without germinal center B-cells (GCB; 2 of 74; 2.7%) were classified as DH/TH. Most of the patients presented with advanced disease. Written informed consent was obtained from each patient, and the study was approved by the Ethics Committee at the Beijing Boren Hospital, according to guidelines of the 1975 Declaration of Helsinki.