By Gene Emery
NEW YORK (Reuters Health) - 29/5/2019
Combining ibrutinib and venetoclax appears to produce complete remission or complete remission with incomplete normal-blood-count recovery in 88% of patients with chronic lymphocytic leukemia at one year, according to a new phase 2 study.
The rate of remission with undetectable minimal residual disease (MRD) in the bone marrow was 61% among the 80 treated patients, all enrolled at the University of Texas M.D. Anderson Cancer Center in Houston.
AbbVie, which makes both drugs, helped pay for the study.
"We hypothesized that the combination might be synergistic and may lead to a higher rate of complete remissions and higher rate of MRD-negative remissions," chief author Dr. Nitin Jain told Reuters Health in a telephone interview.
"What we found was the combination led to a much higher complete remission rate and a much higher undetectable MRD rate in the bone marrow compared to what's been noted in other studies with the single-agent use of these drugs," he said.
Complete remission is typically seen in up to 25% with venetoclax alone and about 10% with ibrutinib alone, he said.
"Looking at the other published data, these data look much superior," said Dr. Jain, an associate professor of leukemia at M.D. Anderson.
The trial, published in the May 30 New England Journal of Medicine, was for frontline patients who had not had prior therapy for their chronic lymphocytic leukemia (CLL). Patients with four types of high-risk genetic features were included, along with patients 65 years or older without any genetic features "because these patients do not do well with chemotherapy," he said. That means most CLL patients would have been eligible for the trial.
The doctors gave 420 mg of ibrutinib once daily for three 28-day cycles, which successfully lowered the risk of tumor lysis syndrome in preparation for the patients receiving venetoclax. Venetoclax was added on the fourth cycle as an escalating dose targeted to reach 400 mg per day. There were 24 cycles. Median follow-up was 14.8 months.
The rates of complete remission gradually increased over time. "No patient has had CLL progression," the researchers report.
"With the addition of venetoclax, we noted a rapid conversion of partial responses into complete responses (with or without normal count recovery) and a steady increase in the proportion of patients with undetectable minimal residual disease in bone marrow," they write.
Five patients withdrew during ibrutinib monotherapy; six others withdrew during combination therapy.
One man died from complications of disseminated cryptococcal infection, but symptoms began before taking ibrutinib and the patient only received one dose.
Nearly half the volunteers had grade 3 or 4 neutropenia. The dose of ibrutinib ended up being reduced in 44% of patients. The dose of venetoclax was reduced in 24%.
No new side effects were reported as a result of the drug combination.
Each drug costs roughly $135,000 per year, according to Dr. Jain.
Although ibrutinib is given for life, "here we gave the two drugs together for two years only so the cost would double for the initial two years, but after that, the majority of the patients are able to stop both of the drugs. So I think in the long run, the cost would be less compared to indefinite long-term therapy," he said.
N Engl J Med 2019.