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

Dec 16, 2019

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), 1,2and have recently been evaluated in a phase II study of combination therapy in high-risk patients with previously-untreated CLL. 3The 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. 3An 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 stAmerican 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, TP53aberration, 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.

  1. IMBRUVICA (ibrutinib) Summary of Product Characteristics. Janssen-Cilag International NV. https://www.ema.europa.eu/en/documents/product-information/imbruvica-epar-product-information_en.pdf[Accessed December 8, 2019]
  2. Venclyxto (venetoclax) Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG. https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_en.pdf[Accessed December 8, 2019]
  3. Jain N. et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30;380(22):2095–2103. DOI: 10.1056/NEJMoa1900574
  4. Jain N. et al. Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia (CLL); 2019. Oral Abstract #34: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, FL.