A novel, chemotherapy-free triplet regimen consisting of atezolizumab, venetoclax, and obinutuzumab has demonstrated promising activity and safety in patients with the diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation. The phase II MOLTO study, conducted across 15 hospitals in Italy and Switzerland, revealed an overall response rate of 67.9% in previously untreated patients, marking a potential advancement in the treatment of this challenging condition.
Study Details and Findings
The MOLTO trial enrolled 28 patients with DLBCL-variant Richter transformation who had not received prior treatment for this condition. Participants received six cycles of atezolizumab (Tecentriq), a PD-L1 inhibitor, combined with venetoclax (Venclexta), a BCL-2 inhibitor, and obinutuzumab (Gazyva), a CD20-targeting monoclonal antibody. The primary endpoint was the overall response rate. After a median follow-up of 16.8 months, the study achieved its primary endpoint, with 67.9% of patients responding to the treatment. Complete responses were observed in 28.6% of patients. One-year progression-free survival was 42.9%, and one-year overall survival was 64.3%.
Clinical Significance
Richter transformation, the evolution of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) into an aggressive lymphoma, presents a significant therapeutic challenge. The DLBCL variant is particularly difficult to treat, often showing resistance to chemotherapy. According to Alessandra Tedeschi, MD, of the Niguarda Cancer Center in Milan, and lead author of the study, "The clinical activity of this chemotherapy-free regimen translated into durable remissions and a prolonged survival benefit, making the venetoclax, atezolizumab, and obinutuzumab triplet a potential first-line standard treatment for patients with Richter transformation."
Safety Profile
The treatment regimen was generally well-tolerated, although grade ≥3 treatment-emergent adverse events (AEs) occurred in 61% of patients, including neutropenia in 39%. Serious AEs were reported in 29% of patients, with infections accounting for 18% of these. Immune-related AEs occurred in 21.4% of patients, but none led to treatment discontinuation. Two patients (7%) experienced AE-related deaths, one from sepsis and one from fungal pneumonia. Notably, no cases of tumor lysis syndrome were observed.
Implications for BTK Inhibitor-Resistant Cases
An accompanying editorial in The Lancet Oncology highlighted the relevance of this regimen for patients who develop Richter transformation while on Bruton tyrosine kinase (BTK) inhibitors. Othman Al-Sawaf, MD, and Barbara Eichhorst, MD, both of the University of Cologne in Germany, noted that the MOLTO regimen does not rely on BTK inhibitors and could be an option for patients previously exposed to fixed-duration BCL-2 inhibitor treatment for chronic lymphocytic leukemia. A quarter of patients in the study had detectable BTK or PLCG2 mutations, suggesting that BTK inhibitor-based Richter transformation treatment would not have been an effective option for this group of patients.
Unanswered Questions and Future Directions
Despite the promising results, the editorialists emphasized that the precise definition of Richter transformation remains controversial, and the biological basis for its response to immunotherapy is poorly understood. While Richter transformation cells often have features suggesting immunogenicity, such as PD-1 expression, the MOLTO study did not identify any biomarker, including PD-1 expression, associated with response or progression-free survival. Further research is needed to identify which patients will benefit most from this treatment regimen and to elucidate the underlying mechanisms of action.
The study authors also acknowledged that the inclusion of patients naive to venetoclax was a limitation, given that many CLL/SLL patients will likely have been exposed to the BCL-2 inhibitor by the time of Richter transformation. Additionally, the small sample size limits definitive conclusions, although the observation that patients with clonally unrelated disease did not respond to treatment suggests that clonal relationship between DLBCL and chronic lymphocytic leukemia might serve as a predictive biomarker.
