Ibrutinib–Venetoclax Outperforms Ibrutinib Alone and FCR in Long-Term CLL

Undetectable measurable residual disease (MRD) and extended progression-free survival (PFS) were more common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib (Imbruvica; Janssen Biotech) in combination with venetoclax (Venclexta; AbbVie and Genentech) compared with ibrutinib monotherapy or fludarabine–cyclophosphamide–rituximab (Rituxan, Genentech and Biogen; FCR). The study (ISRCTN01844152) data were published in The New England Journal of Medicine.^1,2

Ibrutinib, Imbruvica tablets | Image Credit: © CLShebley - stock.adobe.com

Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for various cancers beyond CLL, including B-cell malignancies, mantle cell lymphoma, and Waldenström’s Macroglobulinemia. The agent was originally approved for CLL in 2014 as a monotherapy, followed by subsequent approvals over the past decade in combination with other agents. Ibrutinib in combination with venetoclax is not approved for CLL in the United States but is in Europe.^3-6

Despite its lack of approval, ibrutinib plus venetoclax demonstrates clinically meaningful benefits across clinical trials. For example, fixed-duration, first-line ibrutinib plus venetoclax led to comparable survival outcomes in patients with CLL—even those with high-risk cytogenetic features—according to the phase 2 CAPTIVATE study (NCT02910583). In this UK study, the benefit of this combination is further elucidated.⁷

The phase 3, multicenter, open-label trial consisted of patients with CLL who were randomly assigned to receive either ibrutinib and venetoclax, ibrutinib alone, or FCR. The doses and durations are as follows^1,2:

FCR (fludarabine, cyclophosphamide, rituximab; n = 263):

• Fludarabine and cyclophosphamide are taken by mouth on days 1 through 5.
• Rituximab is given by IV: 375 mg/m² on day 1 of the first cycle, then 500 mg/m² on day 1 of cycles 2 to 6.
• Each cycle repeats every 28 days, for a total of 6 cycles.

I (ibrutinib monotherapy; n = 263):

• Ibrutinib 420 mg daily is taken orally for 6 years.

I+V (ibrutinib plus venetoclax; n = 260):

• Ibrutinib 420 mg daily is taken orally for 6 years.
• Venetoclax starts in week 9, with weekly dose increases (20 → 50 → 100 → 200 → 400 mg), then stays at 400 mg daily for 6 years.

The primary end points of the study were MRD in bone marrow within 2 years in the ibrutinib plus venetoclax group as compared with the ibrutinib monotherapy group and PFS in the ibrutinib plus venetoclax group as compared with the FCR group. Secondary end points included PFS in the ibrutinib plus venetoclax group as compared with the ibrutinib alone group and overall survival (OS).²

In the ibrutinib plus venetoclax group, 66.2% of patients (172 of 260) exhibited undetectable MRD in the bone marrow within 2 years. Patients in the ibrutinib monotherapy and FCR groups demonstrated inferior responses. Ibrutinib alone was least favorable with no patients achieving undetectable MRD compared with FCR, which demonstrated superior outcomes to the former (48.3% undetectable MRD).²

With a median follow-up of just over 62 months, disease progression or death occurred in 6.9% of patients receiving ibrutinib plus venetoclax, compared with 22.4% with ibrutinib alone (HR 0.29; 95% CI, 0.17-0.49; P < .001) and 42.6% with FCR (HR 0.13; 95% CI, 0.08-0.21; P < .001). At 5 years, progression-free survival was 93.9% with ibrutinib plus venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR.²

Deaths occurred in 4.2% of patients on ibrutinib plus venetoclax, compared with 9.9% on ibrutinib alone (HR 0.41; 95% CI, 0.20-0.83) and 14.8% with FCR (HR 0.26; 95% CI, 0.13-0.50). Sudden death was reported in 3 patients in the ibrutinib and venetoclax group, 8 in the ibrutinib-alone group, and 4 in the FCR group.²

“With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended [PFS] were more common with ibrutinib–venetoclax than with ibrutinib alone or FCR,” the authors concluded. “The results for [OS] were also consistent with a benefit of ibrutinib–venetoclax.”²

REFERENCES

1. Front-line therapy in CLL: Assessment of ibrutinib-containing regimes. Updated June 17, 2025. Accessed August 20, 2025. https://www.isrctn.com/ISRCTN01844152

2. Munir T, Girvan S, Cairns D, et al. Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia. N Engl J Med. June 15, 2025. DOI: 10.1056/NEJMoa2504341

3. Gerlach A. Real-world study shows comparable survival outcomes with first-line ibrutinib in high-risk and non-high-risk CLL/SLL. Pharmacy Times. Updated May 15, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/real-world-study-shows-comparable-survival-outcomes-with-first-line-ibrutinib-in-high-risk-and-non-high-risk-cll-sll

4. Gerlach A. Fixed-duration ibrutinib plus venetoclax shows long-term efficacy in first-line CLL/SLL treatment. Pharmacy Times. June 4, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/fixed-duration-ibrutinib-plus-venetoclax-shows-long-term-efficacy-in-first-line-cll-sll-treatment

5. Stewart J. Imbruvica FDA approval history. Drugs.com. Updated July 15, 2024. Accessed August 20, 2025. https://www.drugs.com/history/imbruvica.html

6. Ryan C. Fixed-duration ibrutinib plus venetoclax wins EU approval in previously untreated CLL. OncLive. August 25, 2022. Accessed August 20, 2025. https://www.onclive.com/view/fixed-duration-ibrutinib-plus-venetoclax-wins-eu-approval-in-previously-untreated-cll

7. Ibrutinib plus venetoclax in subjects with treatment-naive chronic lymphocytic leukemia /​small lymphocytic lymphoma (CLL/​SLL) (Captivate). Updated December 20, 2024. Accessed August 20, 2025. https://clinicaltrials.gov/study/NCT02910583