Results from a phase Ib study demonstrated that the combination of the BCL2 inhibitor venetoclax with the anti-CD20 monoclonal antibody obinutuzumab was safe and induced high rates of minimal residual disease (MRD)–negativity in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL). The study was published in Blood.
“The combination of venetoclax and obinutuzumab produces deep, durable remissions with MRD negativity in both the blood and the marrow,” lead author Ian W. Flinn, MD, of Sarah Cannon Research Institute/Tennessee Oncology told ASH Clinical News. “As a consequence, many patients treated with this regimen in the frontline setting can discontinue therapy after one year. The ability to come off of treatment with time-limited therapy is very important to patients,” Dr. Flinn noted.
With this study, investigators evaluated the toxicity and preli-minary efficacy of venetoclax-obinutuzumab in adults with CLL who had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate hema-tologic and organ function.
The study was conducted in two phases: a dose-finding phase and a safety-expansion phase. Fixed-dose obinutuzumab was administered at the following doses in six 28-day cycles:
- cycle 1: 100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15
- cycle 2-6: 1,000 mg on day 1
The venetoclax dose was initially escalated from 100 mg to 400 mg in a 3+3 design to determine the maximum tolerated dose when combined with standard-dose obinutuzumab.
Treatment was administered according to one of two schedules during the first cycle: In schedule A, patients received a venetoclax ramp up (from 100 to 400 mg), followed by fixed-dose obinutuzumab; in schedule B, patients received a loading dose of obinutuzumab over 21 days, followed by venetoclax. After receiving the obinutuzumab-venetoclax combination for six cycles, participants then received venetoclax as a single agent until disease progression (in relapsed/refractory patients) or venetoclax for 12 months (in previously untreated patients).
A total of 78 patients were enrolled: 50 with relapsed/refractory disease and 32 with previously untreated disease. Three patients discontinued treatment: one who did not meet study inclusion criteria and two who experienced adverse events (AEs) prior to completing two cycles of the combination treatment.
Overall, the safety and efficacy populations comprised 45 and 43 patients with relapsed/refractory CLL, respectively; all 32 patients with previously untreated CLL were evaluable.
Most patients in each cohort received venetoclax at the recommended phase II dose of 400 mg/day and completed six cycles of combination treatment.
No dose-limiting toxicities were observed during the dose-finding phase, and there were no differences in safety between dosing schedules. Incidence of tumor lysis syndrome (TLS) were similar, with two grade 3 TLS events in each of the schedules. For the expansion study, patients received venetoclax at a fixed dose of 400 mg on schedule B.
All 77 safety-evaluable patients experienced at least one AE, most of which (87%) were grade 1 or 2. The most commonly reported any-grade AEs were infection, diarrhea, infusion-related reactions, nausea, and neutropenia.
The most common grade 3-4 AEs in the safety-expansion phase included:
- neutropenia: 58% in the relapsed/refractory cohort and 53% in the firstline cohort
- infections: 29% and 13%
- thrombocytopenia: 22% and 22%
All infusion-related reactions were grades 1-2, except for two grade 3 AEs in the relapsed/refractory cohort. No deaths were reported in the firstline cohort, while three patients in the relapsed/refractory cohort had a fatal AE (including two instances of pneumonia and one of acute respiratory failure).
Seven of 45 relapsed/refractory patients (16%) and one of 32 previously untreated patients (3%) discontinued venetoclax due to AEs – most of which occurred after one year of treatment – while obinutuzumab was discontinued due to AEs in 2 patients (4%) and no patients, respectively.
After a median follow-up of 29.3 months (range = 3-55 months) in the relapsed/refractory cohort and 26.7 months (range = 16-39 months) in the firstline cohort, the overall response rates were 95 percent and 100 percent, respectively. This included complete response (CR) or CR with incomplete marrow recovery rates of 37 percent and 78 percent, respectively (TABLE). Responses were similar among patients in the different cytogenetic subgroups, the authors reported.
Three months following the last dose of obinutuzumab, the rates of undetectable MRD (sensitivity of <10-4) were 64 percent and 91 percent in the relapsed/refractory and firstline cohorts, respectively. The researchers noted high concordance between MRD-negative levels in peripheral blood and bone marrow samples.
Several other therapeutic combinations are being tested, all of which include venetoclax plus a Bruton tyrosine kinase inhibitor (e.g., ibrutinib or acalabrutinib with or without obinutuzumab). “Of the agents currently being evaluated, the best two- or three-drug combination remains unknown,” commented Dr. Flinn. “We know that the combination of venetoclax and an anti-CD20 antibody such as obinutuzumab appears synergistic, but the addition of obinutuzumab to ibrutinib does not produce the same depth of remission that is seen with obinutuzumab plus venetoclax.”
Ultimately, he added, these findings need to be confirmed in larger, randomized clinical trials. Limitations of this early-phase study include the small number of enrolled patients, the lack of a randomized design, and the single-arm design.
“While the number of patients is small, this combination appeared to work well in both high- and low-risk groups, and MRD-negativity rates were equal in patients who achieved CR compared with those who achieved partial response (PR),” said Dr. Flinn. “This finding is probably due to response criteria classifying patients with small residual lymph nodes seen on CT scans as PR, when, in reality, [these measurable lymph nodes] may be of no consequence.”
The authors report relationships with Genentech and AbbVie, which provided support for this study.
- Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019 March 12. [Epub ahead of print]
The use of novel single-agent therapy, such as ibrutinib, has changed the face of therapy for both upfront and relapsed/refractory CLL, inducing high overall response rates and dramatic increases in progression-free survival. However, lower CR rates and the need to reach MRD-negative status have led to the testing of ‘novel-novel’ drug combinations in CLL.
The BCL2 inhibitor venetoclax used in tandem with the anti-CD20 monoclonal antibody obinutuzumab takes advantage of two drugs with nonoverlapping mechanisms of action, and this phase I study in both relapsed/refractory and upfront CLL adds to our understanding of the safety and efficacy of so-called ‘doublet’ therapy. While each agent is known in its own right to induce reductions in leukemic burden, their combination use has also raised questions about safety and toxicity.
In this study, the venetoclax-obinutuzumab combination resulted in undetectable MRD and concordance between MRD data for blood and marrow – which can be predictive of superior clinical outcomes. In total, the results for both safety and clinical responses are reassuring for future use and testing of this combination in both upfront and relapsed/refractory cohorts of CLL.
Neil E. Kay, MD