Benjamin L. Lampson, MD, PhD
The triplet of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva; AVO) is highly active as frontline therapy for patients with chronic lymphocytic leukemia (CLL), according to results from a phase II study presented at the 2019 ASH Annual Meeting.
In the open-label, single-arm, phase II study, 48% of patients treated with AVO achieved undetectable minimal residual disease (MRD) in the bone marrow after only 8 monthly cycles of therapy, which improved to 75.0% after cycle 16, reported lead author Benjamin L. Lampson, MD, PhD.
After cycle 8, 16.7% of patients achieved a complete response (CR) with undetectable MRD in the bone marrow. This rate was relatively unchanged (12.5%) after cycle 16, said Lampson, medical oncologist at Dana-Farber Cancer Institute.
After a median follow-up of 11 cycles, the objective response rate (ORR) was 97.3% after cycle 4, and 100% after both cycle 8 and cycle 16.
The safety profile of AVO was favorable. Notably, the rate of infusion-related reactions was markedly lower with AVO when compared with historical data for obinutuzumab alone or with chemotherapy. In addition, pretreatment with acalabrutinib and obinutuzumab reduced the risk of tumor lysis syndrome (TLS) at the time of venetoclax administration.
Since these 3 agents work via non-overlapping mechanisms and have non-overlapping toxicities, said Lampson, “it makes sense to ask, can we combine them to achieve even deeper, more durable remissions in CLL?” Preclinical data support that the combination of BTK inhibition and Bcl-2 inhibition can synergistically kill CLL cells.
“Efforts are already under way to examine an IVO [ibrutinib, venetoclax, obinutuzumab] triplet in CLL; the IVO combination is highly active with a high number of patients achieving undetectable MRD, particularly given that this was in the relapsed setting,” Lampson said. 2
“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.”
The AVO regimen studied is an attempt to achieve the benefit of triplet therapy while avoiding some of the aforementioned side effects, he said.
The investigator-initiated trial enrolled 37 patients with confirmed previously untreated CLL without restriction by prognostic marker status. Adequate hepatic and renal function was required.
Acalabrutinib, venetoclax, and obinutuzumab were started sequentially, with a 28-day cycle lead-in with acalabrutinib at 100 mg twice daily, followed by 6 cycles of obinutuzumab at standard dosing. Ramp-up of venetoclax began at cycle 4, day 1. Combination therapy continued for a total of 15 cycles, at which time the primary endpoint of iwCLL CR with undetectable MRD in the bone marrow is assessed.
Patients with bone marrow-undetectable MRD-negative CR after cycle 15 had the option to discontinue therapy, and were monitored for disease recurrence by MRD testing in the peripheral blood, and they could resume acalabrutinib and venetoclax if recurrence was detected. All other patients continued acalabrutinib and venetoclax until completing cycle 24, at which point a full disease restaging was repeated and another decision point was reached. If at cycle 24 the patient was in CR with undetectable MRD in the bone marrow, the patient again had the option to discontinue therapy; otherwise, the patient continued acalabrutinib and venetoclax until progression or intolerable toxicity.
Median age of patients was 63 years. Eligibility criteria included an absolute neutrophil count ≥500/mm3
and platelets ≥30,000/mm3
. Many patients had unfavorable disease characteristics at baseline: 62.2% had unmutated IGHV and 27.0% had TP53
-aberrant disease. TP53
aberrant disease, present in 10 patients, was defined as either del(17p) and/or TP53
Neutropenia was the most frequent hematologic toxicity, with grade ≥3 neutropenia occurring in 32%. There were no cases of febrile neutropenia. The most common nonhematologic toxicities were fatigue (84%; 3% grade ≥3), headache (76%; 3% grade ≥3), and bruising (46%; 0% grade ≥3).
Serious adverse events included 2 cases of laboratory tumor lysis syndrome, both occurring after obinutuzumab initiation and prior to venetoclax, and 1 case of an elevation in cardiac troponin level, “possibly due to demand ischemia in the setting of severe obinutuzumab-related infusion reaction,” he said. “Only 8 patients overall experienced an infusion-related reaction. This corresponds to a rate of 22%, which compared favorably to the 50% to 70% rate that we typically see with obinutuzumab when administered alone or in combination with chemotherapy.” Two patients experienced hypertension and 1 had grade-3 atrial fibrillation.