Evaluating Venetoclax, Obinutuzumab, and Atezolizumab in Patients With Richter’s Transformation

For patients with previously untreated Richter’s transformation (RT), treatment with venetoclax, obinutuzumab, and atezolizumab led to high rates of remission, according to results presented at the 2021 American Society of Hematology Annual Meeting.

In previous studies, BCL2 inhibitor venetoclax and CD20 monoclonal antibody obinutuzumab have shown clinical activity in patients with diffuse large B-cell lymphoma (DLBCL) and RT. PD-L1 checkpoint inhibitor atezolizumab has been approved by the FDA for the treatment of melanoma, lung cancer, and other solid tumors.

From March 2020 to June 2021, researchers led by Nitin Jain, MD, of MD Anderson Cancer Center, enrolled eight patients with DLBCL RT in a phase II trial. Eligible patients with either previously untreated (n = 7) or relapsed/refractory (n = 1) RT were at least 18 years of age, had adequate organ function, and had not undergone prior treatment with venetoclax.

The median age of patients in the study was 70 years (range = 52-80). Patients had previously been treated for CLL with ibrutinib (n = 4), chlorambucil plus obinutuzumab followed by acalabrutinib (n = 1), bendamustine-rituximab (n = 1). All six patients for whom CLL IGHV mutation status was available were IGHV-mutated. Three patients had complex karyotype, three had a TPS53 mutation, and two had a NOTCH1 mutation. CLL FISH panel found the following:

  • del17p (n = 4)
  • del11q (n = 1)
  • trisomy 12 (n = 1)
  • normal (n = 1)

Treatment consisted of the following:

  • intravenous (IV) obinutuzumab: 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, 1,000 mg on cycle 1 days 8 and 15, 1,000 mg on day 1 of cycles 2-9
  • IV atezolizumab: 1,680 mg (split over 2 days) on cycle 1 days 3-4 and days 1-2 of cycles 2-9
  • venetoclax 20 mg daily at the start of cycle 2 with weekly dose escalation to a target dose of 800 mg daily until the end of cycle 26

Responses were evaluated using PET imaging and bone marrow aspirate/biopsy with measurable residual disease (MRD) assessment at the end of cycles 1, 4, 9, and 26. All seven patients achieved a response, including five complete metabolic responses and two partial metabolic responses. All but one of the responses occurred after the introduction of venetoclax in cycle 2. The remaining patient achieved complete metabolic response and bone marrow undetectable MRD after cycle 1.

Three patients underwent allogeneic stem cell transplant (alloSCT) in complete metabolic remission after 4.1, 4.2, and 6.6 months. Bone marrow undetectable MRD remission was also achieved in these three patients. One of the three has since relapsed and is currently receiving salvage therapy, the authors noted.

One patient who achieved partial metabolic remission relapsed prior to a planned alloSCT in cycle 8, but after treatment with a non-covalent BTK inhibitor, is now in remission, they added. Three patients continue to receive treatment on the trial in cycle 2, cycle 5, and cycle 12.

The patient with relapsed/refractory RT was a 58-year-old male with previously untreated CLL (unmutated IGHV, del17p, TPS53 mutation, and NOTCH1 mutation). Prior to enrollment in the trial, this patient received R-CHOP for three cycles but had no response.

No deaths were observed during follow-up. One patient developed pancreatitis associated with checkpoint inhibitor treatment and diabetes mellitus. Another patient required the venetoclax dose to be reduced to 400 mg daily.

Although this study is limited by its small sample size, “these results are encouraging in relation to combined ibrutinib plus nivolumab in previously untreated RT,” Dr. Jain wrote.