Bruton Tyrosine Kinase Inhibition in Combination With Bispecific Antibodies for Richter's Syndrome: A Report of Two Cases and Mini Review.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. One feared complication of CLL is Richter's syndrome (RS), where the leukemia transforms into a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). The current standard of care aims to achieve remission with chemoimmunotherapy; however, responses are limited, prompting investigations into novel treatment options. While both pirtobrutinib and epcoritamab have demonstrated efficacy as monotherapies, their combination may represent a promising strategy with potential synergistic effects. Although it remains unclear whether the immunomodulatory effects observed with covalent Bruton's tyrosine kinase inhibitors (BTKis) will also occur with more selective, noncovalent agents such as pirtobrutinib, recent studies suggest that coadministration may potentiate bispecific antibody-mediated cytotoxicity. We discuss two cases that illustrate a management strategy incorporating combination therapy with epcoritamab and pirtobrutinib for DLBCL-RS in the relapsed or refractory setting.