Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma.

Although CD20xCD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in CNS lymphoma is unknown. Here, we report the CD20xCD3 bispecific, glofitamab, penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces responses in CNS lymphoma.

Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2.

BACKGROUND: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. METHODS: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. RESULTS: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. CONCLUSIONS: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.

CD5 Gene Signature Identifies Diffuse Large B-Cell Lymphomas Sensitive to Bruton's Tyrosine Kinase Inhibition.

PURPOSE: A genetic classifier termed LymphGen accurately identifies diffuse large B-cell lymphoma (DLBCL) subtypes vulnerable to Bruton's tyrosine kinase inhibitors (BTKis), but is challenging to implement in the clinic and fails to capture all DLBCLs that benefit from BTKi-based therapy. Here, we developed a novel CD5 gene expression signature as a biomarker of response to BTKi-based therapy in DLBCL. METHODS: CD5 immunohistochemistry (IHC) was performed on 404 DLBCLs to identify CD5 IHC+ and CD5 IHC- cases, which were subsequently characterized at the molecular level through mutational and transcriptional analyses. A 60-gene CD5 gene expression signature (CD5sig) was constructed using genes differentially expressed between CD5 IHC+ and CD5 IHC- non-germinal center B-cell-like (non-GCB DLBCL) DLBCLs. This CD5sig was applied to external DLBCL data sets, including pretreatment biopsies from patients enrolled in the PHOENIX study (n = 584) to define the extent to which the CD5sig could identify non-GCB DLBCLs that benefited from the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). RESULTS: CD5 expression was observed in 12% of non-GCB DLBCLs. CD5+ DLBCLs displayed transcriptional features of B-cell receptor (BCR) activation and were enriched for BCR-activating mutations known to correlate with BTKi sensitivity. However, most CD5+ DLBCLs lacked canonical BCR-activating mutations or were LymphGen-unclassifiable (LymphGen-Other). The CD5sig recapitulated these findings in multiple independent data sets, indicating its utility in identifying DLBCLs with genetic and nongenetic bases for BCR dependence. Supporting this notion, CD5sig+ DLBCLs derived a selective survival advantage from the addition of ibrutinib to R-CHOP in the PHOENIX study, independent of LymphGen classification. CONCLUSION: CD5sig is a useful biomarker to identify DLBCLs vulnerable to BTKi-based therapies and complements current biomarker approaches by identifying DLBCLs with genetic and nongenetic bases for BTKi sensitivity.

Integrative genomic analysis identifies unique immune environments associated with immunotherapy response in diffuse large B cell lymphoma.

Most diffuse large B-cell lymphoma (DLBCL) patients treated with bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was employed to characterize DLBCL immune environments, which effectively segregated DLBCLs into four quadrants - termed DLBCL-immune quadrants (IQ) - defined by cell-of-origin and immune-related gene set expression scores. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute to orchestrating unique DLBCL immune environments. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with the CD20 x CD3 BsAb, mosunetuzumab, but not with CD19-directed CAR T cells. DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and uncovers the differential impact of the endogenous immune environment on outcomes to BsAb and CAR T cell treatment.