1. Fuerst, Mark L.

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ATLANTA-Preliminary results from two clinical trials show a combination of ibrutinib plus venetoclax leads to high rates of overall response, complete remission (CR), and minimal residual disease (MRD) eradication in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to presentations at the 2017 American Society of Hematology Annual Meeting.

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In an international study, one-third of patients with previously treated CLL had no detectable disease after 6 months of combination therapy with the targeted agents ibrutinib and venetoclax, with no increase in the occurrence of tumor lysis syndrome (TLS), a serious treatment side effect, reported researchers from the U.K. (Abstract 428).


In the second study (Abstract 429), researchers at MD Anderson Cancer Center, Houston, found that all patients who completed at least 3 months of the combination therapy had a response, and several patients achieved undetectable bone marrow MRD.


U.K. Trial

In the U.K. trial, of 36 patients who completed 6 months of combination treatment, all responded and 33 percent achieved the deepest measurable level of remission, with no detectable disease in the bone marrow, said lead author Peter Hillmen, MBChB, PhD, Professor of Experimental Hematology at Leeds Institute of Cancer and Pathology in the U.K.


"These initial results are particularly impressive in a patient population for whom previous therapies have failed," stated Hillmen. "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."


The mechanisms of action of the two drugs are complementary. Ibrutinib works by blocking signals that stimulate cancerous cells to multiply; venetoclax promotes tumor cell death by blocking a protein that helps the cells survive. Both medications are approved by the FDA as single-agent therapies to treat CLL.


Hillmen and his colleagues evaluated the combination therapy in the phase III CLARITY trial, which enrolled a total of 50 patients, median age 64 years, with relapsed/refractory CLL. After 8 weeks of ibrutinib monotherapy 420 mg/day, venetoclax was added first at a dose of 10 mg/day with weekly escalations to 20 mg, 50 mg, 100 mg, and 200 mg to a final dose of 400 mg/day. No TLS was seen for the first three patients starting at 10 mg/day of venetoclax, so all subsequent patients began venetoclax at 20 mg/day.


To date, only one patient in the CLARITY trial has developed TLS and that patient was safely treated without adverse effects. "We have not seen an increase in the rate of TLS with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy," said Hillmen.


After 6 months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL, he said. "Our assumption was that the trial would be a success if 30 percent of patients achieved the deepest level of remission after 12 months of combination therapy. But already, at 6 months, 33 percent of patients have undetectable disease," said Hillmen.


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, he noted.


A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Hillmen is leading a randomized, controlled, phase III trial, called FLAIR, to compare ibrutinib plus venetoclax with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL.


U.S. Trial

The rationale for combining ibrutinib and venetoclax includes preclinical models showing synergism with combined therapy, non-overlapping toxicity profiles, non-overlapping mechanisms of action, and complementary activity in treating disease compartment, said Nitin Jain, MD, Assistant Professor, Department of Leukemia, Division of Cancer Medicine, at MD Anderson Cancer Center.


He reported the preliminary results of a phase II trial of combined ibrutinib and venetoclax for patients with CLL. The researchers enrolled two cohorts, one with relapsed/refractory CLL and one with untreated patients with at least one high-risk feature, either del(17p), mutated tP53, del(11q), unmutated IGHV, or age 65 or older.


Treatment consisted of ibrutinib monotherapy 420 mg daily for the first 3 months, followed by addition of venetoclax weekly dose escalation to the target dose of 400 mg daily. Ibrutinib may be continued indefinitely and venetoclax for a total of 2 years.


Jain reported on 72 patients who have initiated treatment, 33 patients in Cohort 1 and 39 patients in Cohort 2, with a median follow-up of 7.5 months. Overall, 61 patients have completed ibrutinib monotherapy and have initiated venetoclax dose escalation.


Three months of ibrutnib resulted in 51 percent down-grade of TLS risk category. Two of 61 patients (3%) were high-risk for TLS at the time of initiation of venetoclax.


In Cohort 1, of the 29 patients who received ibrutinib monotherapy and then venetoclax, 14 patients who completed at least 3 months of combination therapy had a response. "There was a significant decrease in bone marrow infiltrate with the addition of venetoclax, including MRD-negativity in several patients with high-risk cytogenetics," Jain said.


In Cohort 2, 32 patients received ibrutinib monotherapy followed by venetoclax. All 16 patients who completed at least 3 months of combination therapy had a response, including nine CRs and CRs with incomplete blood count recovery and seven partial responses. "Several of these patients achieved undetectable bone marrow MRD status with the addition of venetoclax," said Jain.


Overall, dose reductions were required for 24 percent of patients on ibrutinib monotherapy and 18 percent with venetoclax. The most common reason for dose reduction was neutropenia. Eight patients developed atrial fibrillation, likely secondary to ibrutinib, he said. One patient had laboratory TLS, but no patients had clinical TLS. A total of 10 patients have come off study, five patients in each cohort.


"The combination of ibrutinib and venetoclax is safe and active in patients with CLL. These early results of efficacy are highly encouraging. Significant improvement in bone marrow CLL infiltrate is noted with several patients achieving undetectable MRD status as early as 3 months of the combination therapy," Jain explained.


Mark L. Fuerst is a contributing writer.