Time-Limited Acalabrutinib Combination Has “Encouraging” Response Rates in Previously Untreated Chronic Lymphocytic Leukemia

Watch our interview with Benjamin Lampson, MD.


Preliminary results from a trial presented at the 2019 ASH Annual Meeting suggest that time-limited frontline therapy for chronic lymphocytic leukemia (CLL) with the triplet combination of acalabrutinib, venetoclax, and obinutuzumab (AVO) leads to encouraging rates of complete remission (CR) with high rates of undetectable measurable residual disease (MRD), particularly among patients with TP53 mutations. Lead author and presenter Benjamin Lampson, MD, PhD, from Dana-Farber Cancer Institute, noted that the responses were seen without an increase in toxicity compared to doublet therapy with obinutuzumab and venetoclax.

“The rationale for this combination is the hope that, by adding acalabrutinib, we can increase the rate of MRD and increase the durability and depth of response,” Dr. Lampson told ASH Clinical News. “The real benefit is that acalabrutinib has a non-overlapping toxicity profile with venetoclax and obinutuzumab.”

In this ongoing open-label, single-arm, phase II trial, researchers enrolled patients with previously untreated CLL to receive AVO treatment in 28-day treatment cycles, with each agent started sequentially as follows:

  • cycle 1: lead-in with acalabrutinib 100 mg twice daily
  • cycles 2-3: acalabrutinib plus standard-dose obinutuzumab
  • cycle 4: venetoclax ramp-up
  • cycles 5-7: triplet AVO therapy

After 6 months of obinutuzumab, the acalabrutinib plus venetoclax doublet therapy was continued through cycle 15. Per the protocol, the primary endpoint (CR with undetectable MRD) is assessed after 15 monthly cycles; patients who achieve this endpoint can discontinue therapy, while others continue acalabrutinib plus venetoclax until cycle 24, with the option to discontinue therapy if and when the primary endpoint is achieved.

At the time of presentation, 37 patients (median age = 63 years; range = 41-78) had been treated, with a median follow-up of 11 treatment cycles (range = 6-16). At baseline, 23 patients (62%) had IGHV-unmutated disease and 10 (27%) had TP53-aberrant disease, “which was relatively high for a frontline trial,” Dr. Lampson said.

The most frequently reported nonhematologic adverse events (AEs) during follow-up included: fatigue (84%), headache (76%), bruising (46%), and nausea (43%). Few of these were grade ≥3, the authors noted; however, there were 2 cases of grade 3 laboratory tumor lysis syndrome that occurred immediately after starting obinutuzumab and prior to venetoclax. In terms of hematologic AEs, 70% of patients experienced neutropenia (32% grade ≥3), 59% experienced anemia (8% grade ≥3), and 57% experienced thrombocytopenia (11% grade ≥3).

“Only 8 patients overall experienced an infusion-related reaction. This corresponds to a rate of 22%, which compares favorably to the 50-70% rate that we typically see with obinutuzumab when administered alone or in combination with chemotherapy,” Dr. Lampson said. There also were low rates of atrial fibrillation and hypertension, he added.

Dose reductions and treatment discontinuations were rare, the researchers observed, with 2 reductions of acalabrutinib due to headache (1 patient was able to re-escalate) and 1 reduction of venetoclax due to neutropenia. One patient discontinued study treatment due to worsening gastrointestinal symptoms during cycle 5.

Efficacy was evaluable in all 37 patients who had completed at least 4 cycles of treatment; 32 patients had completed 8 cycles and had completed 16 cycles and were evaluable for the primary endpoint. At cycle 4, prior to initiation of venetoclax, the overall response rate (ORR) was 97% (n=36); all responses were considered partial responses. At cycle 8, the ORR grew to 100%, and responses appeared to deepen, with 8 of the 32 patients (25%) experiencing a CR. This trend continued into the small subset of patients who had received 16 treatment cycles, but these data are not yet mature.

Dr. Lampson noted that there did not appear to be a significant difference in response according to IGHV status. Also, among the patients with TP53-aberrant disease, the AVO triplet was “highly active,” with an ORR of 90% at cycle 4 and 100% at cycle 8. Looking at MRD negativity, “the cycle 8 numbers are encouraging, with a significant fraction of patients in this high-risk subgroup clearly achieving undetectable MRD.” Of 9 patients who had reached cycle 15 by the data cutoff, 3 had undetectable MRD in the bone marrow and 7 had undetectable MRD in peripheral blood.

The study’s findings are limited by its small patient population and lack of a comparator arm, although Dr. Lampson noted that researchers are now enrolling patients in a head-to-head comparison of AVO versus chemoimmunotherapy and acalabrutinib plus venetoclax in a phase III trial.

“We have to remember that the primary endpoint of the trial, the rate of CR with undetectable MRD in the bone marrow, is actually read out after 15 cycles of therapy, so we still await [those findings],” he added. The trial also includes “a component of treatment discontinuation, where patients who reach the primary endpoint will discontinue treatment. I think it will be interesting to learn about the mechanism and kinetics of resistance in patients who eventually develop progression while off therapy.”

Study authors report relationships with Genentech and Acerta Pharma, which sponsored the trial.

Reference

Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Abstract #32. Presented at the 2019 ASH Annual Meeting, December 7, 2019; Orlando, FL.