Chemo-Free Triplet Yields 68% Response Rate in Richter Transformation

A three-drug regimen involving a PD-L1 inhibitor and two targeted agents was active and safe for treating the diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation, the phase II MOLTO study found.

Among 28 previously untreated patients, the overall response rate reached 67.9% (95% CI 47.6-84.1) following six cycles of atezolizumab (Tecentriq) plus venetoclax (Venclexta) and obinutuzumab (Gazyva), including complete responses in 28.6% (95% CI 11.8-45.3), reported researchers led by Alessandra Tedeschi, MD, of the Niguarda Cancer Center in Milan.

One-year rates of progression-free and overall survival landed at 42.9% and 64.3%, respectively.

“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,” the study authors wrote in Lancet Oncology.

Richter transformation involves the evolution of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) into an aggressive lymphoma, Tedeschi and colleagues noted in their introduction.

“Despite substantial improvements in outcomes in patients with chronic lymphocytic leukemia with novel targeted agents” — i.e., Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib (Imbruvica) or the BCL-2 inhibitor venetoclax — “the treatment of patients with Richter transformation remains a crucial unmet need,” they said.

In particular, the DLBCL variant represents the most common and difficult-to-treat form, with response rates under 40% due to refractoriness to chemotherapy and constraints on intensive treatment — such as age, comorbidities, and bone marrow infiltration.

In an accompanying editorial, Othman Al-Sawaf, MD, and Barbara Eichhorst, MD, both of the University of Cologne in Germany, commented that because a considerable number of CLL/SLL patients may develop Richter transformation while on a BTK inhibitor, “the MOLTO regimen is particularly interesting as it 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. In fact, a quarter of patients in the study had detectable BTK or PLCG2 mutations (or both), suggesting that BTK inhibitor-based Richter transformation treatment would not have been an effective option for this group of patients.”

The editorialists added that the precise definition of Richter transformation remains controversial, and the biological basis for its response to immunotherapy is poorly understood.

“In contrast to chronic lymphocytic leukemia cells, Richter transformation cells often have features that suggest immunogenicity, such as PD-1 expression, 9p24.1 amplification, β2 microglobulin loss, or increased neoantigen load,” wrote Al-Sawaf and Eichhorst. “However, in the MOLTO study, it was unclear which group of patients would benefit most from this treatment regimen, because no biomarker, including PD-1 expression, was associated with response or progression-free survival.”

MOLTO was a phase II trial conducted across 15 hospitals in Italy and Switzerland from October 2019 to October 2022, including 28 patients without prior treatment for their DLBCL-variant Richter transformation. Median follow-up was 16.8 months. Patients received 35 cycles of intravenous atezolizumab and obinutuzumab, a CD20-targeting monoclonal antibody, along with continuous oral venetoclax.

Participants had a median age of 70 years, 57% were women, and they had an Eastern Cooperative Oncology Group performance status of 0-2. Most (71%) had been treated for CLL, with 25% having received a BTK inhibitor only, 32% chemoimmunotherapy, and the rest both; 29% had a high or intermediate-high Richter prognostic score.

Overall, 19 patients responded, including eight with complete responses. That 67.9% response rate for the primary endpoint met the investigators’ minimum response rate considered necessary to warrant further studies (67%), and also narrowly surpassed the historical best response rate of 67%, notched a decade ago, in this patient population with chemoimmunotherapy.

Grade ≥3 treatment-emergent adverse events (AEs) occurred in 61% of the study population, including neutropenia in 39%. Serious AEs were reported in 29% of patients, 18% of which were infections. Immune-related AEs occurred in 21.4%, although none of these led to treatment discontinuation. No tumor lysis syndrome occurred. There were two (7%) AE-related deaths, one from sepsis and one from fungal pneumonia.

Tedeschi and colleagues pointed out that while the small sample limits conclusions, three of the four patients with clonally unrelated disease did not respond to treatment.

“Combined with the evidence of more favourable outcomes in clonally unrelated diseases, this observation supports that the clonal relationship between DLBCL and chronic lymphocytic leukemia might serve as a predictive biomarker” for directing patients to chemoimmunotherapy if they have clonally unrelated DLBCL-variant Richter transformation, the study authors suggested.

Researchers acknowledged that including patients naive to venetoclax was a limitation, given that in the near future most CLL/SLL patients will have been exposed to the BCL-2 inhibitor by the time of Richter transformation.

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