MAJIC: Determining the Optimal Frontline Regimen for Previously Untreated CLL


The phase 3 MAJIC study is underway to compare 2 frontline regimens for patients with chronic lymphocytic leukemia.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

The combination of acalabrutinib (Calquence) plus venetoclax (Venclexta) is being investigated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) in the phase 3 MAJIC study (NCT05057494).

Multiple effective treatment regimens exist for patients with previously untreated CLL, but research has not demonstrated which doublet is most optimal for these patients and what the appropriate duration of time-limited frontline therapy is.

“The current standard of care for frontline CLL is either continuous treatment with a Bruton’s tyrosine kinase inhibitor, such as acalabrutinib, or time-limited therapy with venetoclax plus Obinutuzumab [Gazyva],” Matthew S. Davids, MD, MMSc, director, Clinical Research, Division of Lymphoma, and physician at Dana-Farber Cancer Institute, and associate professor of Medicine at Harvard Medical School, told Targeted Oncology™.

About the Phase 3 MAJIC Study

Trial Name: A Phase III Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Identifier: NCT05057494

Sponsor: AstraZeneca

Recruitment Contact: AstraZeneca Clinical Study Information Center, 1-877-240-9479,

Completion Date: November 30, 2029

These standard of care regimens have led to similar survival outcomes in phase 3 clinical trials, but have not been compared head-to-head.

In MAJIC, a randomized, prospective, multicenter trial, the combination of acalabrutinib plus venetoclax will be compared with venetoclax plus obinutuzumab. Acalabrutinib will be administered orally at 100 mg, once daily, with oral venetoclax 40 mg, once daily. In the comparator arm, patients will be administered venetoclax 400 mg orally, once daily, with obinutuzumab 1000 mg via intravenous infusion, on a daily basis.2

Venetoclax treatment in each arm will include a 5 week ramp up. All therapy will be stopped in the event of undetectable minimal residual disease (uMRD) that is at least a partial response (PR).

Approximately 600 patients will be enrolled in the study and randomized 1:1 to acalabrutinib plus venetoclax or venetoclax plus obinutuzumab. Treatment will occur in 28-day cycles.

“MAJIC seeks to define the optimal frontline time-limited venetoclax doublet therapy in an all-comer population of patients with CLL by comparing venetoclax plus obinutuzumab with venetoclax plus acalabrutinib. The study will also generate data on whether MRD-guided therapy duration can help to optimize outcomes for individual patients,” said Davids.

The study will investigate the primary end point of progression-free survival in addition to the secondary end points of rates of uMRD at sequential timepoints, overall survival, event-free survival, objective response rate, and quality-of-life.

Patients are eligible to enroll in MAJIC given they have documented treatment-naïve CLL or small lymphocytic lymphoma, adequate bone marrow, renal, and hepatic function, and an ECOG performance status 0-2.

The study excludes patients who have received prior therapy for CLL or SLL, excluding rituximab (Rituxan). Patients receiving daily corticosteroids, or who received prior radiotherapy, toxin conjugated antibody therapy, or allogenic stem cell transplant, are also ineligible for the study. In addition, patients requiring treatment with cytochrome CYP3A4 inhibitors/inducers, anticoagulation with vitamin K antagonist, or proton pump inhibitors are ineligible. The study also excludes patients with certain comorbidities that may interfere with the effectiveness of study treatment.

Eligible patients are actively being recruited at study sites in North America, Europe, and Australia.


1. Ryan C, Davids MS, Hermann R, et al. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022 Oct;18(33):3689-3699. doi:10.2217/fon-2022-0456.

2. A study of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (MAJIC). Updated February 23, 2023. Accessed April 13, 2023.

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