In a phase II study reported in The Lancet Oncology, Matthew S. Davids, MD, and colleagues found that first-line triple combination therapy with acalabrutinib, venetoclax, and obinutuzumab produced measurable residual disease (MRD)-negative complete remission in a substantial proportion of patients with chronic lymphocytic leukemia (CLL), and undetectable MRD in bone marrow in the majority.
As stated by the investigators, “Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax/obinutuzumab are effective for previously untreated CLL. We hypothesized that front-line, time-limited, MRD-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.”
Matthew S. Davids, MD
Study Details
Thirty-seven patients were enrolled into the trial between August 2018 and May 2019 at Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. Treatment was given in 28-day cycles. Patients received acalabrutinib at 100 mg twice daily alone for cycle 1 and then combined for six cycles with obinutuzumab at 100 mg on cycle 2 day 1, 900 mg on day 2, 1,000 mg on day 8, and 1,000 mg on day 15 and on day 1 of cycles 3 through 7. From the beginning of cycle 4, venetoclax was given daily with a ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Acalabrutinib at 100 mg twice daily and venetoclax at 400 mg once daily were continued until day 1 of cycle 16 or day 1 of cycle 25; patients with undetectable MRD in the bone marrow could discontinue therapy at the start of cycle 16 if they were in complete remission or at the start of cycle 25 if they were in at least partial remission. The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as < 1 CLL cell per 10,000 leucocytes) at cycle 16 day 1, with a hypothesized rate of 60%.
Complete Remission With Undetectable MRD in Marrow
Median follow-up was 27.6 months (interquartile range [IQR] = 25.1–28.2 months). At cycle 16 day 1, 14 (38%, 95% confidence interval [CI] = 22%–55%) of 37 patients had complete remission with undetectable MRD in the bone marrow. The rate remained at 38% at the start of cycle 25. The rate was 14% (5 of 37 patients) at the start of cycle 8.
Overall, partial remission or better was achieved in all 37 patients (100%), with the best complete remission rates of 43% and 46% observed at cycle 16 and 25. Rates of undetectable MRD were 86% in bone marrow at both cycle 16 and 25 and 86% and 89% in peripheral blood at cycle 16 and 25.
Of 12 patients discontinuing therapy at the start of cycle 16 after obtaining a complete remission with undetectable MRD in the bone marrow, none have needed to resume therapy after a median of 13.6 months (IQR = 10.4–13.9 months) off therapy. Among 19 additional patients discontinuing therapy at the start of cycle 25, none have had disease recurrence after a median of 5.3 months (IQR = 3.8–6.7 months) off therapy.
KEY POINTS
- At the start of cycle 16, 38% of patients had complete remission with undetectable MRD in the bone marrow.
- Rates of undetectable MRD in bone marrow were 86% at both cycle 16 and 25.
Adverse Events
The most common grade 3 or 4 hematologic adverse events were neutropenia (43%) and thrombocytopenia (27%). The most common grade 3 or 4 nonhematologic adverse events were hyperglycemia (8%) and hypophosphatemia (8%). No febrile neutropenia was observed. Infection occurred in 38% of patients (grade ≥ 3 in 1 patient). Serious adverse events occurred in 24%, most commonly neutropenia (8%). No deaths occurred during the study.
The investigators concluded, “Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for CLL. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib/venetoclax and chemoimmunotherapy in an ongoing phase III study (ClinicalTrials.gov identifier: NCT03836261).”
Dr. Davids, of the Department of Medical Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award. For full disclosures of the study authors, visit thelancet.com.
