Authored by Dr. Brian Koffman
The Bottom Line:
Atezolizumab, obinutuzumab, and venetoclax combination therapy is active in patients with untreated DLBCL-Richter’s Syndrome (RS). The triplet therapy led to durable remissions, longer than two years in one-third of responders.
Who Performed the Research and Where Was it Presented:
Dr. A. M. Frustaci from Milan, Italy, led the presenters at the International Conference on Malignant Lymphoma (ICML) in June 2023 in Lugano, Switzerland.
RS is the name for when chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) transforms into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). It carries a dismal prognosis and remains a critical unmet need, with largely ineffective chemotherapy used as treatment. The study looks at adding atezolizumab, a checkpoint inhibitor that unleashes the immune system to attack cancer, to two more familiar CLL / SLL drugs, obinutuzumab, and venetoclax, that have been shown to have some activity in RS, too.
Methods and Participants:
Treatment consisted of 35 x q21 cycles with obinutuzumab (1000 mg Cycle 1–8), atezolizumab (1200 mg Cycle 1–18) and venetoclax (400 mg/d Cycle 1–35). The primary endpoint was an overall response rate (ORR) of ≥67% at cycle 6. Minimal residual disease (MRD) was tested by eight-color flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Twenty-eight patients were enrolled from October 2019 to October 2022, but one died of infection, and two dropped out of the trial early before any evaluations.
- ORR was 67.9% (19/28), thus meeting the primary endpoint.
- The complete response (CR) rate was 28.6% (8/28).
- No clinical characteristics influenced ORR at Cycle 6.
- After a median follow-up of 11.6 months, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic hemopoietic stem (bone marrow) transplant, and one discontinued due to myelodysplastic syndromes (MDS).
- Six of those were in remission for ≥24 months.
- Seven of the remaining 8 pts progressed after a median of 14 cycles, and one died from sepsis at Cycle 9 in remission.
- The median duration of response was 11.7 months, the median progression-free survival (PFS) was 16.2 months, and the median overall survival (OS) was 31.6 months.
- Of the 13 pts who progressed, 4 received salvage therapy and are alive at a median follow-up of 24.3 months.
- Bulky disease and poor overall health (high ECOG score) affected more inferior PFS.
- A total of 43 Grade 3–4 (more serious) adverse events (AE) occurred in 17 pts (60.7%), primarily hematological (51.2%). Any grade immune-related AEs were reported in 6 pts (Grade 3–4 in 2), and none led to discontinuation. No tumor lysis was observed. Infections ≥G3 occurred in 6 pts, including two who died. One patient developed MDS.
Sixteen months PFS and 31 months OS may not sound super, but it is better than many other RS treatments and is achieved with a chemo-free protocol. Adding a checkpoint inhibitor in past RS trials has not been convincingly helpful. Still, the results with this combination are promising, and RS needs fresh and more effective therapies.
Links and Resources:
Watch Dr. Brian Koffman’s monologue on the abstract:
You can read the actual ICML abstract here: EFFICACY AND SAFETY OF MOLTO, A MULTICENTER, OPEN LABEL, PHASE II CLINICAL TRIAL EVALUATING VENETOCLAX, ATEZOLIZUMAB AND OBINUTUZUMAB COMBINATION IN RICHTER SYNDROME.
Here is early information on this trial from Dr. Nitin Jain from MDACC in Houston, TX, presented at ASH 2021: Dr. Nitin Jain on Triple Combination Therapy with Venetoclax, Obinutuzumab, and Atezolizumab for Richter’s Transformation.
Stay strong; we are all in this together.
Brian Koffman, MDCM (retired), MSEd
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.