ASH 2017: CLARITY Trial: Combination Treatment With Two Targeted Agents Shows Promise in Previously Treated CLL
One-third of patients with previously treated chronic lymphocytic leukemia (CLL) had no detectable disease after 6 months of combination therapy with the targeted agents ibrutinib (Imbruvica) and venetoclax (Venclexta), with no increase in the occurrence of tumor-lysis syndrome, a serious treatment side effect, Hillmen et al reported at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 428).
Of 36 patients who completed 6 months of combination treatment, all responded and 33% achieved the deepest measurable level of remission, with no detectable disease in the bone marrow, said lead study author Peter Hillmen, MBChB, PhD, Professor of Experimental Hematology at Leeds Institute of Cancer and Pathology in the United Kingdom.
“These initial results are particularly impressive in a patient population for whom previous therapies have failed,” he said. “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.”
Ibrutinib works by blocking signals that stimulate cancerous cells to multiply, whereas venetoclax promotes tumor cell death by blocking a protein that helps the cells survive. Both medications are approved by the U.S. Food and Drug Administration as single-agent therapies to treat CLL. Because the mechanisms of action of the two drugs are complementary, Dr. Hillmen and his colleagues wanted to evaluate them as combination therapy.
CLARITY Trial
The phase III CLARITY trial enrolled a total of 50 patients with CLL that had relapsed or had not responded to prior treatment. Patients’ median age was 64 years. After 8 weeks of treatment with ibrutinib alone, venetoclax was added at a low dose that increased over several weeks. Before starting venetoclax, patients also began taking a drug to prevent tumor-lysis syndrome. To date, only one patient in the CLARITY trial has developed tumor-lysis syndrome and was safely treated without adverse effects.
“We have not seen an increase in the rate of [tumor-lysis syndrome] with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy,” Dr. Hillmen said.
After 6 months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL, Dr. Hillmen added.
“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,” he said. “But already, at 6 months, 33% of patients have undetectable disease.”
Results for the trial’s secondary endpoints of safety and absence of detectable disease in the bone marrow after 6 and 24 months of combination therapy will be reported at a later time, Dr. Hillmen said.
A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Dr. Hillmen is leading a randomized controlled phase III study—the FLAIR trial—to compare the ibrutinib-plus-venetoclax combination with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL.
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