Venetoclax/Atezolizumab/Obinutuzumab Elicits Durable Responses in Richter Transformation

The combination of venetoclax (Venclexta), atezolizumab (Tecentriq), and obinutuzumab (Gazyva) elicited responses and prolonged time progression, in patients with chronic lymphocytic leukemia with Richter transformation, according to data from the phase 2 MOLTO trial (NCT04082897) presented at the 17th Annual International Conference on Malignant Lymphoma.¹

In the intent-to-treat patient population (n = 28), the overall response rate (ORR) was 67.9% (95% CI, 47.6%-84.1%), meeting the primary end point of the study. Notably, the complete remission (CR) rate was 28.6%, and 39.3% of patients experienced partial remission. Additionally, 21.4% of patients had progressive disease, and 10.7% of patients were not evaluable for cycle 6 response.

“[The] Venetoclax, atezolizumab, and obinutuzumab combination showed to be effective in patients with Richter [transformation], and allowed us to achieve the primary end point of the study of an ORR greater than 67%,” lead study author Anna Maria Frustaci, MD, of the Niguarda Cancer Center in Milan, Italy, said in a presentation of the data. “Responses were independent from biological characteristics, including TP53 mutations, complex karyotypes, [and] PD-1, PD-L1, BCL-6, BCL-2, and c-MYC expression.”

Richter transformation is the development of an aggressive B-cell lymphoma that occurs in approximately 5% to 12% of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.² Acquired genetic lesions can lead to refractoriness to chemotherapy, and since most patients with Richter transformation are older, they are generally unsuitable for intensive treatment or transplant.¹

No standard treatment currently exists for this patient population, and Frustaci said there is a need for novel, tailored combinations.

“On this basis, the combination of a BCL-2 inhibitor with a checkpoint inhibitor and an anti-CD20 monoclonal antibody could be an effective strategy in patients with Richter [transformation],” she said.

The international MOLTO trial enrolled patients with previously untreated Richter transformation who were at least 18 years of age with an ECOG performance status less than 3. Prior treatment for CLL was permitted. However, patients were excluded if they had central nervous system localization, received prior venetoclax, atezolizumab, or obinutuzumab, or had a history of autoimmune disease.

The first patient was enrolled in October 2019, and the last patient was enrolled in October 2022. At a median follow-up of 11.6 months and a data cutoff of February 2023, 28 patients were treated, including the first 9 who were part of the safety run-in portion.

Obinutuzumab was given at 100 mg on day 1 of cycle 1, at 900 mg on day 2 of cycle 1, and at 1000 mg on day 8 and 15 of cycle 1, then day 1 of cycles 2 to 8. Atezolizumab was administered at 1200 mg on day 2 of cycle 1 and day 1 of cycles 2 to 18. Venetoclax was given with ramped-up dosing, starting at 20 mg on days 15 to 21 in cycle 1, then 50 mg on days 1 to 7 in cycle 2, followed by 100 mg on days 8 to 14 of cycle 2, then 200 mg on days 15 to 21 of cycle, and then 400 mg per day in cycles 3 to 35.

The primary end point was an ORR of greater than 67% after 6 cycles. Secondary end points included adverse effects (AEs), serious AEs, and immune-related AEs; CR rate; progression-free survival, overall survival (OS), and duration of response (DOR).

Enrollment of the 28 patients spanned across 7 sites in Italy and 1 site in Switzerland. At data cutoff, 21 patients had completed 6 cycles of therapy, and 7 patients discontinued treatment before cycle 6 due to disease progression (n = 4), AEs (n = 1), or patient/investigator decision (n = 2).

The median age was 70 years (range, 32-81), 53.6% of patients were 70 years of age or older, and 57.1% of patients were female. Moreover, 71.4% of patients were previously treated for CLL with median of 1 (range, 0-3) prior lines of treatment. Previous CLL therapies included a BTK inhibitor only (25%), chemoimmunotherapy only (32.1%), or both a BTK inhibitor and chemoimmunotherapy (14.2%).

The median time from CLL diagnosis to Richter transformation was 48.1 months (range, 0-242.5). In 11 patients, the median time from start of treatment with a BTK inhibitor to Richter transformation was 22.8 months (range, 1.4-64.3). Additionally, 42.9%, 35.7%, and 21.4% of patients had an ECOG performance status of 0, 1, and 2, respectively. Notably, 60.7% of patients had a low Richter prognostic score, 10.7% had an intermediate-low score, 14.3% had an intermediate-high score, and 14.3% had a high score.

Regarding tumor lysis syndrome (TLS) risk, 28.6%, 46.4%, and 25% of patients were low, intermediate, or high risk, respectively. Additionally, 57.1% of patients had bulky disease, 78.6% of patients had Ann Arbor stage III/IV disease, and 28.6% of patients were Binet stage C before the start of treatment.

Furthermore, 42.9% of patients had a 17p deletion and/or TP53 mutation, 47.4% of patients had a complex karyotype, and 85.7% of patients had IGHV-unmutated disease. Moreover, 57.9% and 5.3% of patients expressed PD-1 and PD-L1 on tumor cells, respectively, 63.2% expressed PD-1 on T lymphocytes, and 78.9% had PD-L1 expressed on macrophages. All patients had BCL-2 expression, 26.3% had BCL-6 expression, and 89.5% of patients had c-MYC expression. Notably, 82.6% of patients had a related CLL/Richter transformation clonal relationship.

Additional data showed that among the 19 responders, the 12-month DOR rate was 51% (95% CI, 24.6%-72.4%), and the median DOR was 26.3 months. Of 19 responders, 39.3% of patients had continuous remission, including 6 who had continuous remission for at least 2 years. Seven responders (25%) progressed after a median of 14 cycles. Notably, treatment was overall well tolerated. In the 13 patients who did not respond, 10 started second-line treatment, and 4 were alive at a median follow-up of 24 months.

At a median follow-up of 11.6 months (range, 0.5-37.3), the 12-month time to progression rate was 50.9% (95% CI, 29.6%-68.8%), and the median time to progression was 16.2 months. The 12-month event-free survival (EFS) rate was 43.9% (95% CI, 24.8%-61.5%), and the median EFS was 9.9 months. Additionally, the 12-month OS rate was 66.2% (95% CI, 44.8%-80.9%), and the median OS was 31.6 months.

Patients received a median of 10.5 cycles (range, 1-35) of treatment. Notably, 21.4% of patients experienced serious treatment-emergent AEs (TEAEs), 28.6% of patients experienced TEAE that led to dose disruption of at least 1 drug, 3.6% of patients had TEAE that led to treatment discontinuation, and 7.1% of patients had TEAEs that led to death. No patients required dose reductions due to TEAEs.

Moreover, all patients experienced at least 1 any-grade TEAE and 60.7% of patients experienced grade 3 or higher TEAE. Any-grade TEAEs included neutropenia (42.9%), thrombocytopenia (14.3%), anemia (3.6%), neutropenic fever (17.8%), sepsis (3.6%), COVID-19 infection (17.9%), pneumonia (14.3%), elevated aspartate aminotransferase, alanine transaminase, gamma-glutamyltransferase, or bilirubin (14.3%), infusion-related reaction (10.7%), hypercalcemia (3.6%), and purpura (3.6%).

AEs of special interest occurred in 7 patients (25%) and included amylase and lipase elevation (7.1%), immune-related myositis (3.6%), immune-related pancreatitis (3.6%), immune-related encephalitis (3.6%), immune-related neuropathy (3.6%), and myelodysplasia (3.6%). Notably, no patients experienced TLS.

References

1. Frustaci AM, Montillo M, Rossi D, et al. Efficacy and safety of molto, a multicenter, open label, phase ii clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 027.
2. Douglas M. Richter transformation: clinical manifestations, evaluation, and management. J Adv Pract Oncol. 2022;13(5):525-534. doi:10.6004/jadpro.2022.13.5.6