A phase 2 study found that acalabrutinib monotherapy followed by treatment with venetoclax and obinutuzumab in the frontline setting was highly active and tolerable for patients with previously untreated chronic lymphocytic leukemia despite not meeting the primary end point.
Acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) in the frontline setting demonstrated a high level of activity, as well as being a well-tolerated option for patients with chronic lymphocytic leukemia (CLL), according to results from a phase 2 study (NCT03580928) published in Lancet Oncology.
Despite not meeting the study’s primary end point, the regimen yielded undetectable minimal residual disease (MRD) in the bone marrow in a high proportion of patients, warranting further study. A total of 38% (95% CI, 22%-55%) of patients experienced a complete remission (CR) with undetectable MRD in the bone marrow at the start of cycle 16. As this was lower than the alternative hypothesis of 60%, investigators concluded that the study’s primary end point was not met.
“We found that acalabrutinib, venetoclax, and obinutuzumab is an active chemotherapy-free treatment option for previously untreated patients with chronic lymphocytic leukemia, including patients with high-risk disease,” the investigators wrote.
Patients were recruited from the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center in Boston, Massachusetts for the single-arm, open label study. Eligible patients needed to have a diagnosis of previously untreated CLL or small lymphocytic lymphoma (SLL). Additionally, patients also needed to be 18 years of age or older, have an ECOG performance status of 0 to 2, and have measurable disease.
Patients were treated in 28-day cycles, with the first cycle featuring oral acalabrutinib at 100 mg twice daily. On day 1 of cycle 2, patients received obinutuzumab at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 intravenously plus acalabrutinib. Obinutuzumab treatment continued at 1000 mg for cycles 3 through 7. Venetoclax was introduced orally on day 1 of cycle 4 at 20 mg, followed by 50 mg on days 2 to 7, 100 mg on days 8 to 14, 200 mg on days 15 to 21, and 400 mg daily from day 22.
The primary end point of the phase 2 research was CR with undetectable MRD in the bone marrow. Safety and activity end points were also analyzed among patients who received at least 1 dose of treatment.
A total of 37 patients were enrolled in the trial between August 2, 2018, and May 23, 2019. The median age for patients who enrolled on the study was 63 years (interquartile range [IQR], 57-70) and most patients were male (73%). Additionally, 54% of patients had Rai stage III or IV disease at the time of therapy initiation. The median follow-up was 27.6 months (IQR, 25.1-28.2).
The CR with undetectable MRD rate increased from 14% at the beginning of cycle 8 to 38% at the start of cycle 16, which continued through to cycle 25. The best CR rate of 46% was observed at cycle 25.
Furthermore, the best rate of undetectable MRD for all patients was 92% in the peripheral blood and 86% in the bone marrow. The median time to undetectable MRD was 6.7 months (95% CI, 6.5-11.1) and 10.3 months (95% CI, 6.6-13.9) in peripheral blood and in the bone marrow, respectively.
Although grade 3 or 4 adverse effects (AEs) were uncommon, all patients eligible for analysis experienced any grade of AE. Neutropenia (43%) was the most common grade 3/4 hematological AE, and hyperglycemia (8%) and hypophosphatasemia (8%) were the most common grade 3/4 non-hematological AEs. Twenty-four percent of patients experienced infusion-related reactions to obinutuzumab, and 14% of patients required dose delays or reductions of acalabrutinib or venetoclax, or both.
Nine patients reported serious AEs, with neutropenia seen in 8% of those patients. Of this population, 78% of the serious AEs could possibly be attributed to 1 of the study drugs. No patients died while on the study.
“Acalabrutinib, venetoclax, and obinutuzumab is now being studied in a registrational phase 3 trial and has the potential to become a new standard frontline therapy option for patients with chronic lymphocytic leukemia,” the investigators concluded.
Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi:10.1016/S1470-2045(21)00455-1