<p>Chronic lymphocytic leukemia (CLL) that changes into an aggressive lymphoma (typically diffuse large B-cell lymphoma [DLBCL]) through Richter transformation (RT) has a dismal prognosis. It is typically refractory to conventional chemoimmunotherapy, and novel therapeutics are a significant unmet need.</p>

Several groups have recently published studies comparing CLL tissue with RT tissue using genetics, epigenetics, and other techniques. No single genetic alteration has been identified as a cause of RT. A number of genetic alterations are common, and they include TP53 aberrancy and NOTCH1 mutations, among many others. There have been attempts to predict RT risk at the time of CLL diagnosis, or months to years prior to RT, by looking for the presence of RT cell clones in the blood, but this is still an open research question. In addition, although RT most commonly occurs in patients with CLL who have received multiple lines of therapy, it has also been described in patients who have not received any treatments for CLL. These individuals may have slightly better outcomes than those who received multiple lines of therapy for CLL before developing RT.

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One of our standard treatment regimens for RT is chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Researchers at Dana-Farber Cancer Institute and other institutions are also evaluating venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) for newly diagnosed RT. VR-EPOCH seems to have some efficacy, as an initial analysis reported a 62% overall response rate in patients with RT. Unfortunately, however, outcomes for patients with RT have not been very good, with a retrospective study finding that the overall survival for patients with RT is often less than 1 year. In addition, only approximately 12% to 15% of patients undergo a potentially curative allogeneic stem cell transplant, which is the ultimate goal for individuals with RT once they achieve remission. Therefore, new treatment approaches are being investigated for RT, including CAR T cells and bispecific T-cell engagers.

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Several CAR T-cell therapies are US Food and Drug Administration (FDA) approved for DLBCL, but, unfortunately, they seem to have less efficacy in RT. Bispecific T-cell engagers that are FDA approved for DLBCL are also being investigated in patients with RT. Further, the BTK inhibitor pirtobrutinib, which is FDA approved as a later-line therapy for CLL, appears to have promise in treating RT. Finally, BTK degraders are also under investigation for RT, with early data from the phase 1 CaDAnCe-101 trial suggesting that some patients with RT may respond to BGB-16673.