Ibrutinib and venetoclax combination therapy for first-line treatment of CLL: updated results from a phase II study

Ibrutinib (IBR), an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), and venetoclax (VEN), a B-cell lymphoma 2 (BCL2) protein inhibitor, are both approved for the treatment of chronic lymphocytic leukemia (CLL),^1,2 and have recently been evaluated in a phase II study of combination therapy in high-risk patients with previously-untreated CLL.³ The first results from this investigator-initiated study, which included efficacy and safety data after 12 cycles of combination treatment with a median follow-up of 14.8 months, were recently published in the New England Journal of Medicine.³ An updated analysis from this study, focusing on measurable residual disease (MRD) outcomes after 24 cycles of combination therapy with a median follow-up of 27.0 months, was presented by Nitin Jain, The University of Texas, MD Anderson Cancer Center, Houston, TX, US, at the 61^st American Society of Hematology Meeting & Exposition, Orlando, FL, US, in December 2019.⁴

Study design

• Phase II, open-label, investigator-initiated study (NCT02756897)
• Patient eligibility:
  • ≥18 years of age
  • Patients with treatment-naïve, high-risk CLL (2008 iwCLL treatment criteria)
  • At least one of the following high-risk genetic features:
    • del(17p)
    • mutated TP53
    • del(11q)
    • unmutated IGHV
    • ≥65 years of age
  • Adequate organ function
• Treatment: IBR 420mg once daily for three cycles followed by the addition of VEN (weekly dose escalation to 400mg daily target dose) at start of cycle 4; each cycle was 28 days
• Combination therapy administered for 24 cycles
• MRD response assessments: after cycle 3 of IBR monotherapy then after cycles 3, 6, 9, 12, 18, and 24 of combination therapy as assessed by multicolor flow cytometry with a sensitivity of 10^-4

Patient characteristics

• 80 patients enrolled, median age 65 years (26–83 years)
• 30% of patients were ≥70 years of age
• 92% of patients had unmutated IGHV, TP53 aberration, or del(11q)

Efficacy results

• Following three cycles of IBR monotherapy, none of the 75 patients had achieved bone marrow undetectable MRD (BM U-MRD)
• After the addition of VEN, the number/proportion of patients who achieved BM U-MRD remission increased over time from 12/74 (16%) after three cycles, to 30/72 (42%) after six cycles, 45/69 (65%) after 12 cycles, and 37/49 (75%) after 24 cycles
• In an intention-to-treat analysis of best response, 60 (75%) of patients achieved BM U-MRD at any point during the study

Safety results

• Grade 3/4 neutropenia occurred in 41 (51%) patients; two (2%) patients experienced grade 3 thrombocytopenia
• IBR dose reductions occurred in 42 (52%) patients; VEN dose reductions occurred in 23 (29%) patients, while 14 (17%) patients withdrew from the study
• Richter’s transformation developed in two patients and three patients died

Conclusions

This study confirmed that the combination of IBR and VEN was tolerable and resulted in high rates of BM U-MRD remission in newly-diagnosed patients with high-risk CLL. Moreover, response rates seem to improve with ongoing combination therapy, with a 75% BM U-MRD rate at 24 months of combination therapy. Additional studies are ongoing to further define the role of this regimen in the treatment of CLL.