Treating Richter transformation in CLL

Richter transformation (RT), also known as Richter’s syndrome, is a rare complication of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). It is characterized by the development of an aggressive lymphoma from underlying CLL/SLL and carries a particularly poor prognosis, with an estimated median overall survival of 3–11 months. RT occurs in approximately 2–10% of patients with CLL/SLL, with the most common transformation being CD20⁺ diffuse large B-cell lymphoma (DLBCL). There is no standardized treatment strategy for patients with RT; therefore, a significant unmet need exists for safe and effective novel therapies.^1,2

At the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in 2022, two abstracts were presented addressing the treatment of RT as part of a wider session on CLL. Below, the Lymphoma Hub is happy to present a summary of the key findings.

Subcutaneous epcoritamab in patients with Richter’s syndrome: early results from phase Ib/II trial (EPCORE CLL-1)¹

Epcoritamab is a novel CD3 × CD20 bispecific antibody that has previously demonstrated encouraging clinical efficacy in patients with relapsed/refractory LBCL. Early data from the EPCORE CLL-1 (NCT04623541) trial also showed promising results in patients with relapsed/refractory CLL. Kater presented initial safety data from the RS-LBCL cohort of EPCORE CLL-1, which represents the first standalone dataset of a bispecific antibody for RT.

As of the data cutoff, ten patients with RT had received epcoritamab therapy with six patients receiving the drug as first-line therapy. Median treatment duration was 2.5 months and five patients received ongoing treatment. The most commonly reported treatment-emergent adverse events (TEAEs) of any grade were:

• Grade 1 and 2 cytokine release syndrome (CRS; 90%)
• anemia (40%)
• diarrhea (40%)
• hypophosphatemia (30%)
• injection-site reaction (30%)
• thrombocytopenia (30%)

Notable Grade 3/4 TEAEs included:

• neutropenia (40%)
• anemia (20%)
• COVID-19 (20%)

All instances of CRS were resolved with no patients discontinuing treatment due to AEs or CRS. No patients experienced immune effector cell-associated neurotoxicity syndrome and two patients died due to disease progression. Antitumor activity was detected, with an overall response rate of 60% and a complete response rate (CRR) of 50%.

Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: results from the phase I/II BRUIN study²

Pirtobrutinib is a highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor which has previously demonstrated inhibition of both wildtype and C481-mutant BTKs. In addition, pirtobrutinib has shown encouraging efficacy and a favorable safety profile in patients with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTK inhibitors. Shah presented data from the first sizeable cohort of RT patients included in the phase I/II BRUIN study (NCT03740529).

Out of a total of 82  patients with RT, 74 had received at least one prior RT-directed therapy. Among these patients, 75 were evaluable for response; the overall response rate was 52% with 10 complete responses and 29 partial responses. The median progression-free survival, overall survival, and duration of response was 3.7, 13.1, and 5.6 months in all patients with RT.

The safety portion of the trial found the most frequently reported TEAEs to be:

• fatigue (26%)
• diarrhea (22%)
• confusion (19%)

The most frequent Grade ≥3 TEAEs was neutropenia (20%).

Conclusion

Overall, these data demonstrate both epcoritamab and pirtobrutinibs manageable safety profile and promising efficacy in patients with RT. Despite these encouraging findings, further studies are required to fully elucidate the clinical utility of these novel therapies for patients with RT.