Triplet Regimen with Acalabrutinib Is Highly Active in Untreated Chronic Lymphocytic Leukemia

A 3-drug regimen of acalabrutinib, venetoclax, and obinutuzumab was highly effective in removing all traces of disease from the bone marrow of patients with chronic lymphocytic leukemia, according to study results presented at the American Society of Hematology annual meeting.
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A 3-drug combination of acalabrutinib, venetoclax, and obinutuzumab, known as AVO, proved to be highly active as frontline therapy for patients with chronic lymphocytic leukemia (CLL) in a new study.

In the single-arm phase 2 study, nearly half (48%) of the patients who were treated with AVO had undetectable disease in their bone marrow after only 8 monthly cycles of therapy. By cycle 16, 75.0% had undetectable disease in their bone marrow, reported Benjamin L. Lampson, MD, PhD, at the 2019 meeting of the American Society of Hematology in Orlando, FL.

The safety profile of the AVO triplet was favorable. Notably, the rate of infusion-related reactions was markedly lower with AVO when compared with historical data for obinutuzumab given alone or with chemotherapy.

In addition, pretreatment with acalabrutinib and obinutuzumab reduced the risk for tumor lysis syndrome (TLS) that is often seen when venetoclax is administered, said Dr. Lampson, medical oncologist at Dana-Farber Cancer Institute, Boston, MA.

Because acalabrutinib, obinutuzumab, and venetoclax work via nonoverlapping mechanisms and have nonoverlapping toxicities, said Dr. Lampson, “it makes sense to ask, can we combine them to achieve even deeper, more durable remissions in CLL?”

A different triplet regimen of ibrutinib, venetoclax, and obinutuzumab is effective in CLL but “the rate of infusion-related reactions was high and the adverse event list is dominated by side effects that we have come to associate with ibrutinib, including bruising, hypotension, and joint pains,” said Dr. Lampson.

Therefore, the AVO regimen studied is an attempt to achieve the benefit of triplet therapy while avoiding some of its side effects, he said.

The study enrolled 37 patients with confirmed, previously untreated CLL. Acalabrutinib, venetoclax, and obinutuzumab were started sequentially, with a 28-day cycle lead-in with acalabrutinib followed by 6 cycles of obinutuzumab. Venetoclax was added at cycle 4. Combination therapy continued for a total of 15 cycles.

Pretreatment with acalabrutinib and obinutuzumab was able to mitigate venetoclax-associated TLS, said Dr. Lampson. At baseline, 98% of patients were considered to be at either medium or high risk for TLS. When TLS risk was assessed by computed tomography and complete blood counts prior to venetoclax, 89% of patients were considered to be at low risk for TLS.

Prior to venetoclax administration, 97% of patients achieved a response, all of which were considered to be partial responses. At cycle 8, after completion of obinutuzumab, the response rate was 100%, 25% of which were complete responses.

At cycle 8, 68% of patients had undetectable disease in their blood, and 17% of patients had a complete response with undetectable disease in their bone marrow. The rates of undetectable disease appear to increase over time, said Dr. Lampson.

Neutropenia was the most frequent hematologic toxicity. The most common nonhematologic toxicities were fatigue (84%), headache (76%), and bruising (46%).

The acalabrutinib dose had to be reduced due to headache in 2 patients. Venetoclax dose reduction was required in 1 patient due to grade 4 neutropenia. One patient with preexisting gastrointestinal symptoms discontinued all study medications.

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Last modified: December 9, 2019

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