CAR T Outcomes Not Significantly Affected by rrDLBCL Subgroup

Researchers have characterized 4 genetically distinct subsets of tumors in patients with relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL), finding that genetic classification showed little impact on outcomes of chimeric antigen receptor (CAR) T-cell therapy.

With 40% of patients with DLBCL experiencing relapsed or refractory disease, the researchers highlighted the promise of CAR T-cell therapy for these patients. However, just under half of patients achieve a complete response (CR), which the researchers note may be attributed to the heterogeneity of the disease.

“The advent of high throughput next-generation sequencing technologies has rapidly increased our knowledge of genomic alterations of DLBCL. Several reports have proposed the concept of molecular subtypes,” wrote the researchers in Blood Advances. “Distinct classification conclusions describe partially overlapping features, suggesting the existence of molecular subtypes and guiding novel targeted therapy. It is unclear if the diverse molecular subgroups [affect the efficacy of] the CAR T-cell therapy.”

For their study, the researchers performed deep sequencing on 92 hematologic-related genes from 105 patients with rrDLBCL. Of the patients, 86% received CAR T-cell therapy, which resulted in a CR rate of 42.8% and an overall response rate of 58.3% in the 3 months following infusion. With a median follow-up of 13.63 months, median progression-free survival was 6.23 months and median overall survival (OS) was 16.2 months. Across the 4 subtypes, there were no statistically significant differences in the CR rate or in OS.

However, among patients who whose tumors were described as EZB-like, those who received CAR T-cell treatment had favorable OS compared with those who did not receive the treatment. Most of the 34 tumors in this subtype harbored a double hit (DH)—BCL2 translocation and MYC break—and tended to have mutations in the chromatin modifiers KMT2D, CREBBP, and EZH2. They also frequently harbored DDX3X mutation with nonsynonymous single nucleotide variant and stop-gain mutations. These tumors occurred in most transformed follicular lymphoma cases and were strongly enriched in patients with DH GCB-type DLBCL.

The researchers also described 52 MCD-like tumors, 33% of which had mutations in MYD88 and 21% in CD79B. These mutations have previously been associated with ABC-type DLBCL. Other alterations, also associated with ABC-type DLBCL, included alterations in IRF4 and ETV6, as well inactivation of PRMD1. Among these patients, those who received CAR T-cell treatment had favorable OS compared with those who did not receive the treatment.

There were 12 tumors the researchers described as N1-like, which harbored gain-of-function NOTCH1 mutations. According to the researchers, a somatic KIT p.M541L mutation in these tumors strengthens the ability of KIT to activate PI3K-AKT-MTOR and MAPK signal transduction and allows for the proliferation of tumor cells.

The fourth group of tumors, ST2-like, had mutations in JAK/STAT pathways members and immune escape. Half of the 7 tumors had mediastinal involvement, which the researchers said indicates some biological similarity with primary mediastinal large B-cell lymphoma.

Among the patients receiving CAR T-cell treatment, the researchers also examined whether other genetic factors influenced response to treatment. They found that, “Among tumor genetic factors, only TP53-alterations were predictive of inferior rate of CR in univariable logistic regression. No association with CR rate was observed with other cytogenetic features. The patients carrying mutations in TP53 and DDX3X had inferior OS after CAR T-cell immunotherapy vs the WT group. In these patients with TP53 mutation, CAR T-cell immunotherapy can improve the survival.”

Reference

Shi H, Zheng P, Liu R, et al. Genetic landscapes and curative effect of CAR T-cell immunotherapy in relapse and refractory DLBCL patients. Blood Adv. Published online July 28, 2022. doi:10.1182/bloodadvances.2021006845