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Ibrutinib plus venetoclax shows promise for chronic lymphocytic leukemia
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ATLANTA — The combination of ibrutinib and venetoclax appeared safe and effective among patients with relapsed or refractory chronic lymphocytic leukemia, according to results of the Bloodwise TAP CLARITY study presented at the ASH Annual Meeting and Exposition.
One-third of patients had no detectable disease after 6 months of treatment with ibrutinib (Imbruvica; Pharmacyclics, Janssen) and venetoclax (Venclexta; AbbVie, Genentech).
“These initial results are particularly impressive in a patient population for whom previous therapies have failed,” Peter Hillmen, MBChB, FRCP, FRCPath, PhD, professor of experimental hematology at University of Leeds in the United Kingdom, and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust, said in a press release. “We have shown that the two drugs can be given in combination without obvious additional toxicity, and the inability to detect disease with the most sensitive tools we have is a very good sign that the combination is proving to be an effective treatment.”
CLL is the most common leukemia in adults, occurring in about six adults per 100,000 individuals, Hillmen said during a press conference.
“Conventional therapy for CLL is chemotherapy; however, a majority of patients will relapse after chemotherapy. Until recently, the treatment options were limited,” he said.
In the study, 50 patients with CLL (median age, 64 years; 69% men) received 420 mg ibrutinib monotherapy daily for 8 weeks, after which they also received 10 mg venetoclax daily with weekly escalations to 20 mg, 50 mg, 100 mg, 200 mg and a final dose of 400 mg. Patients also received prophylactic uric acid-reducing agents at least 72 hours prior to start of venetoclax.
Patients had relapsed within 3 years of chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (Rituxan, Genentech), or bendamustine and rituximab (94%), or they had had 17p deletion (20%) or 11q deletion (27%) and failed at least one line of therapy. Further, 77% of patients had unmutated VH gene segments.
Researchers monitored CLL levels in the peripheral blood weekly during the first 3 months of combined therapy, venetoclax escalation and monthly thereafter.
Minimal residual disease eradication in the marrow — defined as less than one CLL cell in 104 assessed by 8-color flow — after 1 year of combination therapy served as the primary endpoint. Secondary endpoints included minimal residual disease eradication in the marrow after 6 months and 2 years of combination therapy, and critical safety events such as incidence of laboratory and clinical tumor lysis syndrome.
To date, 38 patients reached 8-month marrow and CT-scan assessments, indicating they completed 6 months of treatment with the combination. The ORR was 100%, with a 39% complete response rate and 53% partial response rate.
In addition, 84% had normal trephine on biopsy; 37% showed no disease in peripheral blood and 32% showed no disease in bone marrow.
“Our assumption was that the trial would be a success if 30% of patients achieved the deepest level of remission after 12 months of combination therapy,” Hillmen said in a press release. “But already, at 6 months, 33% of patients have undetectable disease.”
Sixty-three adverse events occurred, but there were no unexpected serious adverse reactions. Twenty-five grade 3 or grade 4 adverse events occurred, of which 22 were episodes of neutropenia. All serious adverse events resolved, and all patients remained on therapy following resolution.
A single case of tumor lysis syndrome occurred at the 200-mg dose level. This patient stopped venetoclax treatment until abnormalities resolved, and then dosing subsequently escalated to 400 mg venetoclax daily with no further tumor lysis syndrome events.
“This was similar to the 3% rate of tumor lysis syndrome events seen with venetoclax alone,” Hillmen said during the press conference.
Patients will continue on combination treatment for the same duration of time as it took them to achieve minimal residual disease negativity, Hillmen said. As a result, all patients will continue therapy until at least the 14-month assessment. – by Melinda Stevens
Reference:
Hillmen P, et al. Abstract 428. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosure: Hillmen reports consultant roles with AbbVie, Alexion Pharmaceuticals Inc., Gilead Sciences, Janssen, GlaxoSmithKline and Roche; honoraria from AbbVie, Alexion Pharmaceuticals, Gilead Sciences, Janssen, GlaxoSmithKline, Pharmacyclics, Novartis and Roche; and research funding from AbbVie, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, Novartis, Pharmacyclics LLC and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
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Matthew S. Davids, MD, MMSc
This is one of several ongoing studies that include this combination. This study so far seems to be the most mature data we've seen and should garner a lot of attention.
In CLL, we've had many different effective therapies over the years, traditionally with chemotherapy-based approaches. In the last few years, the FDA approved novel agents that typically have been used as monotherapy.
The Bloodwise TAP CLARITY study is one of the first studies to report on the combination of two of these novel agents being used in a combination. One of the limitations of each of these drugs as monotherapy is they typically require continuous or indefinite therapy. Combining the two drugs together could lead to time-limited therapy.
The design of the study is smart because patients will take the drug for as long as it takes them to get to minimal residual disease negativity. It allows for individualization of the dosing regimen for patients based on their response, which is a very innovative design.
In terms of the results, its still relatively early only 25 of 50 patients have reached initial response assessment but, nonetheless, there is impressive efficacy with a 60% complete remission rate, and this is in a refractory population. The 28% rate of bone marrow minimal residual disease negativity also is very high for this population.
There was concern that combining these two agents might enhance risk for tumor lysis syndrome, which is a known risk when venetoclax is used as a single agent. However, these data are reassuring so far; researchers reported a couple of patients had biochemical changes, but no clinical consequences from tumor lysis syndrome. Therefore, it does suggest this will be a feasible combination from a safety perspective as well.
The researchers concluded these data suggest potent synergy between this combination, with which I agree. This is an area that is of particular interest to me. In my laboratory, we've done significant work with this combination in preclinical models, so its really exciting to see it in the clinic benefiting patients.
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Laurie Sehn, MD
The treatment of CLL has changed dramatically over the last several years. We now have novel, targeted therapies that are allowing us to get disease under control in CLL. Patients who have failed chemotherapies in the past are now starting to move forward because these are much less toxic and much more targeted than some of the chemotherapies we usually used. It’s exciting that we can take two therapies that target different aspects of cell biology and merge them together so they synergize and become be more effective in a combination than they might be as single agents.
These are early data, but it is remarkably impressive to see the high response rate. The fact is that within a short period of time, researchers could no longer measure the disease in a certain percentage of patients. That gives us hope that some of these patients could potentially be cured; it certainly is the first step moving forward in that direction.
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