Two Venetoclax Studies Show Promise in CLL Patients


At the American Society of Clinical Oncology (ASCO) virtual annual meeting, one abstract looked at the triplet combination of zanubrutinib, obinutuzumab, and venetoclax as a treatment for chronic lymphocytic leukemia (CLL), while a second showed the possibility of venetoclax plus dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) as a new treatment approach in patients with CLL who developed Richter’s syndrome.

In this exclusive MedPage Today video, Seema A. Bhat, MD, a hematologist with The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, discusses the two studies.

Following is a transcript of her remarks:

Richter’s transformation, as you know, is a huge unmet need within the realm of chronic lymphocytic leukemia. So this study was a single-arm multicenter phase II study of venetoclax plus dose-adjusted R-EPOCH. This was conducted at three U.S. sites — Dana-Farber Cancer Institute, the Ohio State University, and the University of Texas MD Anderson Cancer Center. This was presented by Dr. Davids.

CLL patients who had a biopsy-proven Richter’s transformation to diffuse large B cell lymphoma were treated with R-EPOCH for one cycle, and then after count recovery underwent accelerated inpatient venetoclax dose ramp-up over 5 days. And subsequently they were treated with venetoclax plus R-EPOCH for up to five more cycles. The venetoclax was given for days 1 to 10 of each cycle, 21-day cycle.

Subsequently, responders went on to allogeneic stem cell transplant if they were candidates for that, or they continued venetoclax daily maintenance, as long as they could.

The study completed accrual with 27 patients. As expected in this population, high-risk features were seen, with complex karyotype and IGHV [immunoglobulin heavy chain variable] unmutated status each seen in about half of the patients.

Toxicities were as expected with an aggressive chemo-immunotherapy. Grade three neutropenia was seen in 58% of the patients with neutropenic fever seen in about 38% of the patients. Anemia and thrombocytopenia was seen in 50% of the patients each. Of note, tumor lysis syndrome was not seen with this regimen.

Of the 20 patients who started the combination therapy, CR [complete response] at end of combination therapy, which was the primary endpoint of the study, was 55%, and in an intention-to-treat analysis, overall response rate was 62% with 50% CRH [complete response with partial hematological recovery], which is very compelling and encouraging given the poor historic responses seen in these patients.

About half of the patients who were candidates for allogeneic transplant went on to receive allogeneic transplant. And the rest of the patients continued with the venetoclax maintenance. Of note also is that the responses were durable both in the allergenic transplant as well as the venetoclax maintenance arm with some patients 2 to 2.5 years out from initial treatment.

So these are highly encouraging results for this patient population, [for whom] otherwise we do not have a standard, treatment. So this study is being further expanded with a plan to explore venetoclax plus R-EPOCH.

So this was the first abstract. So in the frontline setting for CLL initial results of a multicenter investigator-initiated phase II study were presented. This was a triplet combination of zanubrutinib, obinutuzumab, plus venetoclax. Zanubrutinib, as you know, is a highly specific next-generation BTK [Bruton tyrosine kinase] inhibitor with lesser off-target effects. And hence the possibility of lesser side effects, especially when used in combination treatment.

In this study, zanubrutinib was given at 160 milligrams, orally twice a day. Obinutuzumab was also started at cycle one with a thousand milligrams IV on day 1 split between day 1 and 2, and subsequently was given on week 8 and week 15 of cycle one. And subsequent cycles from cycle two to eight it was given on day 1.

Venetoclax ramp-up was started on cycle three day 1 in the standard fashion. Treatment duration was determined by a prespecified undetectable MRD [minimal residual disease] endpoint. MRD was assessed in peripheral blood starting at cycle one, and then every two cycles. Once peripheral blood MRD status was determined and confirmed by bone marrow biopsy treatment continued for two additional cycles.

The study accrued 39 patients; all of the patients were evaluated for toxicity and 37 patients were evaluated for efficacy. The most common treatment-emergent adverse effects were neutropenia, seen in 51% of the patients, thrombocytopenia in about 46% of the patients, and infusion reactions and easy bruising and diarrhea seen in 41% each. Of note, tumor lysis syndrome was not seen, either biochemical or clinical.

So at the beginning of the treatment, 17 patients were at medium to high risk for tumor lysis with two cycles of zanubrutinib plus obinutuzumab; this risk was reduced to a mild to medium in about 15% of the patients.

So the two cycles, as we have seen in other similar studies, pre-treatment before initiation of venetoclax does reduce the risk of tumor lysis that we see with venetoclax.

This regimen worked very quickly at a median follow-up of 11 months. Median time to undetectable MRD in marrow was 6 months; 62% patients have met the undetectable MRD endpoint and have stopped therapy at a median of 8 months.

So these are highly encouraging results; this regimen works very quickly. It will be interesting to see on long-term follow-up how these patients will continue to do.

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    Greg Laub joined MedPage Today in 2005 as Production Manager and led the launch of the video department in 2007. He is currently responsible for the website’s video production. Follow

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