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Frontline, Time-Limited Acalabrutinib, Venetoclax, and Obinutuzumab Active in Treatment-Naïve CLL

December 6, 2021

December 2021

A frontline, time-limited triplet therapy comprising acalabrutinib, venetoclax, and obinutuzumab showed favorable activity and tolerability in patients with chronic lymphocytic leukemia (CLL), according to findings from a phase II study published in The Lancet Oncology.

The time-limited treatment regimen was highly active across patients with varying genetic risk markers and medical comorbidities, suggesting that this approach could provide promising clinical implications for a broad population of patients with CLL, lead study author Matthew Davids, MD, of Dana-Farber Cancer Institute in Boston, told ASH Clinical News.

Researchers analyzed 37 treatment-naïve patients with CLL or small lymphocytic lymphoma from two academic hospitals. Patients were predominantly male (73%) and non-Hispanic white (89%). The median age of the patient population was 63 years. At baseline, approximately 46% and 54% had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0 and 1, respectively. The median platelet count was 142×109/L.

The various cytogenetic profiles within this population were as follows:

  • 17p deletion (del17p; 27%)
  • 11q deletion (35%)
  • trisomy 12 (14%)
  • 13q deletion (49%)
  • 6q deletion (5%)
  • complex karyotype (19%)

Most patients (73%) had unmutated immunoglobulin heavy chain variable (IGHV) status. In terms of high-risk features, approximately 27% of patients had both TP53 mutation and del17p, while 19% had NOTCH1 mutation.

During cycle 1, treatment consisted of twice-daily oral acalabrutinib 100 mg as monotherapy. Following the first cycle, acalabrutinib was combined with intravenous obinutuzumab (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; followed by 1,000 mg on day 1 of cycles 3-7) for a total of six cycles. At the start of cycle 4, the investigators added daily oral venetoclax with an accelerated ramp-up from 20 mg (day 1) to 400 mg (day 22); the latter dose was continued thereafter.

Treatment was administered in 28-day cycles. Patients continued to take twice-daily acalabrutinib 100 mg and once-daily venetoclax 400 mg until day 1 of cycle 16 or cycle 25. Those who showed undetectable measurable residual disease (MRD) in the bone marrow were allowed to discontinue treatment at the beginning of cycle 16 if their disease was also in complete remission, or at the beginning of cycle 25 if their disease was in at least partial remission.

Complete remission with undetectable MRD in the bone marrow was the study’s primary endpoint. The investigators defined this endpoint as <1 CLL cell per 10,000 leukocytes, which was measured on day 1 of cycle 16. All patients who received at least one dose of any study drug were also included in the safety and activity analyses.

Median follow-up was 27.6 months (interquartile range = 25.1-28.2 months). On day 1 of cycle 16, 38% of patients (n=14) met criteria for the primary endpoint of complete remission with undetectable MRD in the bone marrow, an increase from 14% recorded at the start of cycle 8. The complete response (CR) rate of 38% remained at the start of cycle 25. A total of five patients with CR with undetectable MRD at the beginning of cycle 8 had IGHV-unmutated disease, while one of these patients also had TP53-aberrant CLL.

Neutropenia was the most common grade 3 or 4 hematological adverse event (AE; 43%), while hyperglycemia (8%) and hypophosphatemia (8%) were the most common grade 3-4 non-hematologic AEs. Up to 24% of patients (n=9) experienced serious AEs, including neutropenia (8%). No deaths have been reported in this cohort.

Dr. Davids indicated that since the analysis focused on a cohort of 37 patients without any restriction by genetic risk markers, the investigators have since opened a new cohort of 35 patients restricted to those with del17p or TP53 mutation to further explore the activity of AVO (acalabrutinib, venetoclax, and obinutuzumab) as therapy in high-risk patients.

Given that the study lacked a comparator arm, Dr. Davids and colleagues were unable to compare AVO with standard frontline treatment in CLL. An ongoing phase III trial, CL-311, is currently investigating AVO versus AV and chemoimmunotherapy in this patient population.

Dr. Davids also noted that he is currently involved in the co-development of the new phase III MAJIC trial, launching in early 2022, which will compare MRD-guided AV to MRD-guided VO. “We hope [this trial] will help to define the optimal time-limited novel agent combination regimen for frontline CLL treatment,” he said.

Study authors report relationships with AstraZeneca, which funded the study.


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.


In this study, acalabrutinib and obinutuzumab are started first (staggered) to “debulk” and minimize the risk of tumor lysis syndrome. Venetoclax is started on cycle 4, with a faster ramp-up schema than commercially approved, without an increase in the toxicity profile. This regimen was found to be safe and effective in the study participants. Although the median age of 63 is younger than usual for a disease that more commonly affects people in their seventh decade of life, many of the patients had high risk disease.

This is an MRD-driven study at two different time-points (at the start of cycles 16 and 25). The overall response rate was 100% with best CR reported at 46%. Thirty-eight percent of patients achieved a CR with undetectable MRD at the start of cycle 16 (primary endpoint), and 86% of all patients achieved undetectable MRD (1:10,000) in the bone marrow as best response, regardless of TP53 and IGHV mutation status. At a median follow-up of more than two years, no patients have experienced clinical progression or died. All patients received antibiotic and antiviral prophylaxis. No episodes of neutropenic fever were reported, and there was only one instance of grade 3 pneumonia that resolved with oral antibiotics.

Although the primary endpoint of this study (rate of CR with undetectable MRD in the bone marrow) did not meet the prespecified goal of 60%, the results are promising. These findings represent proof of concept that the regimen is safe and well-tolerated in a younger patient population, irrespective of the presence of high-risk disease. At this time, it is unclear whether the triplet combination is necessary to achieve these deep remissions, or whether the use of a doublet will suffice. Randomized trials are required to address this question. Longer follow-up is needed to determine the rate of relapse, whether a new signal is observed post therapy, and whether patients will respond to rechallenge with any of the drugs that were already used.

Jacqueline C. Barrientos, MD
Zucker School of Medicine at Hofstra/Northwell


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