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ASH 2021: MAJIC – A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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Dr. Matthew S. Davids from Dana-Farber Cancer Institute presented the trial design of the global, multicenter, open-label MAJIC study at the American Society of Hematology Annual Meeting, which was held in December 2021 (ASH 2021)

Background

 The chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment paradigm has been revolutionized by the development of novel oral agents, which have replaced prior standard-of-care chemoimmunotherapy regimens in most patients. Efficacy and safety data from randomized clinical trials are required to inform treatment decisions regarding how best to combine available novel agents in newly diagnosed patients. The role of measurable (minimal) residual disease (MRD) status in guiding therapy duration remains unestablished.

The MAJIC trial is a phase III, prospective, multicenter, randomized trial of acalabrutinib plus venetoclax (AV; Arm A) versus venetoclax plus obinutuzumab (VO; Arm B) in previously untreated CLL/SLL, which will address these unresolved issues. 

Therapeutic agents in MAJIC trial and their mechanism of action  

  • Venetoclax (Veneclexta) is a potent BCL2 inhibitor with a pro-apoptotic effector (promoting cancer cell death) function
  • Acalabrutinib (Calquence) is a selective, second-generation BTK inhibitor that blocks B-cell receptor signaling in cancer cells.
  • Obinutuzumab (Gazyva) is a type 2, glycoengineered anti-CD20 antibody that targets CLL cells for antibody-dependent cellular cytotoxicity and can directly induce cancer cell death.

Takeaways

  • All patients will receive venetoclax either with acalabrutinib (arm A) or  obinutuzumab (Arm B)
  • The trial incorporates next-generation sequencing-based MRD (clonoSEQ®) status (defined as less than one CLL cell per 100,000 leukocytes) to individually guide therapy duration.
  • In both intervention arms, after 12 cycles (~12 months) of venetoclax combination therapy, peripheral blood MRD will be assessed by clonoSEQ® assay.
  • Patients who have achieved at least partial remission by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and peripheral blood undetectable MRD will discontinue treatment.
  • Patients with detectable MRD will continue treatment through cycle 24.
  • All CLL patients ultimately will discontinue treatment after a maximum of 2 years
  • The study will assess, among other things, whether MRD-driven finite acalabrutinib plus venetoclax treatment is non-inferior to MRD-driven finite  venetoclax plus obinutuzumab treatment with respect to free from disease progression

Conclusion

Despite the recent approval of several highly effective novel agent-based regimens in CLL/SLL, key questions remain regarding the optimal doublet combination therapy and duration of “time-limited” frontline therapy for CLL/SLL patients. This study will address key unanswered questions in frontline CLL/SLL therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen by comparing the addition of arguably the best approved monoclonal antibody to adding a very effective and well-tolerated BTK inhibitor,

In summary, the results of MAJIC will help to inform the selection of time-limited doublet therapy approaches for patients with CLL/SLL and help define the duration of venetoclax in combination with either acalabrutinib or obinutuzumab.

If you are interested in enrolling in the MAJIC study, learn more at ClinicalTrials.gov: NCT05057494

Please enjoy this interview between Dr. Anthony Mato and Dr. Matthew Davids.

Reference:

Syed Ali Abutalib, MD.
Co-Director, Hematology, BMT/Cellular Therapy Programs
Director, Clinical NMDP Apheresis Program at CTCA
Cancer Treatment Centers of America, Part of City of Hope, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science
Email: abutalib110@gmail.com
Twitter: @syed_abutalibmd