BOVen was found to induce MRD and to have a tolerable safety profile.
The combination of zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta; BOVen) as an initial therapy for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) was found to be well tolerated and may produce high rates of undetectable minimal residual disease (MRD), according to results of a phase 2 study in The Lancet Heamatology.
Currently, venetoclax and obinutuzumab is approved for use in both CLL and SLL. The combination is administered for a fixed duration of 1 year. Adding zanubrutinib, a Bruton’s tyrosine kinase, may help to elevate levels of MRD.
The hypothesis was evaluated in a phase 2 study (NCT03824483) of the triplet combination. The primary end point of the study is the established rate of undetectable MRD at 1 year. During the study, all patients received zanubrutinib 160 mg and obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 8. During cycle 1, obinutuzumab was administered as a split dose at 100 mg on day 1 and 900 mg on day 2. Venetoclax was added starting cycle 3.
“Although ΔMRD400 provides prognostic insight for patients receiving BOVen and might overcome the limitation of peripheral blood and bone marrow discordance, thereby obviating the need for bone marrow biopsy, this potential surrogate endpoint requires external validation in prospective trials and should be validated with different MRD modalities, such as flow cytometry- based MRD assays,” wrote study authors.
Between March 2019 and October 2019, 47 patients signed informed consent to be included at the trial. Eight patients were excluded. Thirty-nine went on to receive protocol therapy and 37 were analyzed for activity. All 39 were analyzed for safety.
The median age of patients was 62 (range, 52-70), 77% were male, and 90% were non-Hispanic white. The median lymphocyte count per uL was 43. Thirteen percent of patients had 17p deletion or a Tp53 mutation. A NOTCH1 mutation was seen in 16% of patients and an SF3B1 mutation in 13% in patients.
At 2 months, MRD was detected in 3% of patients. At 4 months, 28% of patients had an undetectable rate of MRD, at 6 months, 56% of patients had undetectable MRD, and at 8 months, 81% had undetectable MRD. Ninety-five percent of patients had undetectable MRD in the peripheral blood, and 89% had undetectable MRD in the bone marrow.
At 2 months, the overall response rate (ORR) was 92%. At 6 months, the ORR was 97%, with a complete response rate of 25%. At the time of treatment discontinuation, the ORR was 100%, with a 55% complete response rate.
In terms of safety, common grade 1/2 adverse events (AEs) included thrombocytopenia (51%), fatigue (51%), neutropenia (33%), and bruising (51%). Common grade 3 events included thrombocytopenia (8%), rash (8%), and lung infection (8%). Only 2 grade 4 AEs were reported: neutropenia (13%) and infusion-related reaction (3%). One case of grade 5 intracranial hemorrhaging was reported.
In order to participate in the study, patients must be 18 years of age or older, have a diagnosis of CLL or SLL, an ECOG performance status of 0 to 2, adequate hematologic parameters, and adequate renal and hepatic function. Patients with another malignancy, any uncontrolled illness, known infection, known bleeding diathesis, a history of HIV, heart failure, or clinically significant history of liver disease are not eligible to participate.
“The results of this phase 2 study in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma show that MRD-directed therapy with BOVen has a favorable safety profile in comparison to combinations of venetoclax and other [Bruton’s tyrosine kinase] inhibitors, with or without a CD20 antibody,” wrote study authors. “The study met its primary endpoint, with 89% of patients reaching undetectable MRD in both peripheral blood and bone marrow, meeting the prespecified undetectable MRD treatment-discontinuation criterion, and discontinuing therapy after a median of 10 months.”