ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.
Subject(s)
Antibodies, Bispecific , Lymphoma, Large B-Cell, Diffuse , Humans , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Drug Resistance, Neoplasm/immunology , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/drug therapy , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsSubject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Humans , Neoplasm Recurrence, Local/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Central Nervous System Neoplasms/prevention & control , Central Nervous System/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Methotrexate/therapeutic use , Rituximab/therapeutic use , Cyclophosphamide/therapeutic use , Prednisone/therapeutic useABSTRACT
The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL.
