First-Line Acalabrutinib-Based Triplet Therapy Leads to Undetectable Minimal Residual Disease in CLL

JHOP - February 2020 Vol 10, No 1 - ASH Highlights, Leukemia

Almost 50% of patients with chronic lymphocytic leukemia (CLL) who received treatment with the triplet of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) as first-line therapy achieved undetectable minimal residual disease (MRD) in the bone marrow after only 8 monthly cycles of therapy, according to data presented at ASH 2019.

In this open-label, single-arm, phase 2 clinical trial, after cycle 8, 16.7% of patients achieved a complete response with undetectable MRD, said Benjamin L. Lampson, MD, PhD, Medical Oncologist, Hematologic Oncology Treatment Center, Dana-Farber Cancer ­Institute, Boston.

Because these 3 agents have different mechanisms of action and nonoverlapping adverse effects, said Dr Lampson, “it makes sense to ask, can we combine them to achieve even deeper, more durable remissions in CLL?”

Study Details

A total of 37 patients with confirmed untreated CLL were enrolled into the investigator-initiated trial. Patients started treatment with acalabrutinib, venetoclax, and obinutuzumab in a sequential manner. A 28-day cycle of acalabrutinib 100 mg twice daily was given as a lead-in treatment, which was followed by 6 cycles of obinutuzumab at standard dosing. A ramp-up of venetoclax began at day 1 of cycle 4. The 3-drug combination therapy then continued for a total of 15 cycles.

Patients with a complete response who had undetectable MRD in the bone marrow after cycle 15 had the option to discontinue therapy and were monitored for disease recurrence by MRD testing in the peripheral blood, with the resumption of acalabrutinib and venet­oclax if recurrence was detected.

All other patients continued treatment with acalabrutinib plus venetoclax until completing cycle 24, at which time they had their disease restaged. If a complete response with undetectable MRD was achieved at cycle 24, the patient again had the option to discontinue therapy; otherwise, the patient continued treatment with acalabrutinib and venetoclax until disease progression or intolerable toxicity.

The median patient age was 63 years. Many patients had unfavorable disease characteristics at baseline: 62.2% of patients had IGHV mutation–negative status and 27% had TP53-aberrant disease. TP53-aberrant disease was defined as the presence of deletion 17p and/or TP53 mutation, and was present in 10 patients.

After a median follow-up of 11 cycles, the objective response rate (ORR) was 97.3% after cycle 4, which improved to 100% after cycle 8 and continued through cycle 16. A total of 48% of patients achieved undetectable MRD in the bone marrow after cycle 8, which improved to 75% after cycle 16. All responses at cycle 4 were partial responses.

“At cycle 8, after the completion of obinutuzumab, we start to see the appearance of patients with complete responses. Of the 100% response rate at cycle 8, 25% of these are complete responses,” noted Dr Lampson.

In the 8 patients who had received treatment for 16 cycles at the data cutoff, the ORR was 100%. At cycle 8, the rate of undetectable MRD was 68%.

Safety Profile

The safety profile of treatment with the combination of acalabrutinib, venetoclax, and obinutuzumab was favorable, with a rate of infusion-related reactions that was lower with the triplet than with historical data for obinutuzumab alone or with chemotherapy.

The serious adverse events included 2 cases of laboratory tumor lysis syndrome (TLS), which occurred after the initiation of obinutuzumab treatment and before receiving venetoclax, and 1 case of an elevation in cardiac troponin level.

Pretreatment with acalabrutinib and obinutuzumab reduced the risk for TLS at the time of venetoclax treatment administration, Dr Lampson noted. “Indeed, TLS risk was reduced by the 3 cycles of lead-in therapy,” he said.

At baseline, 98% of patients were considered to be at medium or high risk for TLS, according to computed tomography and complete blood counts. Before venetoclax administration, 89% of patients were considered to be at low risk for TLS.

Grade ≥3 neutropenia occurred in 32% of patients. No cases of febrile neutropenia were reported. The most common nonhematologic toxicities were fatigue (84%), headache (76%), and bruising (46%). Grade ≥3 fatigue, headache, and bruising had an occurrence of ≤3% each.

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