Personalized Ibrutinib-Plus-Venetoclax Therapy: New Treatment Standard for Chronic Lymphocytic Leukemia?

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A time-limited approach based on measurable residual disease (MRD) response could signal a potential paradigm shift for front-line treatment of chronic lymphocytic leukemia (CLL), according to data presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition1 and published concurrently in The New England Journal of Medicine.2

Results of the phase III randomized FLAIR trial study showed improved progression-free survival and overall survival with the combination of ibrutinib plus venetoclax compared with conventional FCR (fludarabine, cyclophosphamide, and rituximab) chemotherapy in patients with previously untreated CLL, marking a potential new chemotherapy-free standard of care. This regimen not only may offer a superior alternative to standard chemoimmunotherapy but also introduces a novel treatment duration approach based on MRD response. Guided by MRD response, the time-limited, targeted combination of ibrutinib and venetoclax yielded a 3-year progression-free survival rate of 97.2% vs 76.8% for those assigned to FCR therapy (hazard ratio [HR] = 0.13).

Evolution of CLL Management

“This is the first trial to show that an MRD-guided approach, with treatment beyond negativity, has a significant advantage over chemoimmunotherapy, both in terms of progression-free and overall survival,” said lead study author Peter Hillmen, MB ChB, PhD, Professor of Experimental Hematology at Leeds Institute of Medical Research, St. James’s University Hospital, in the United Kingdom. “Over 90% of patients achieved an antibody-negative remission in the peripheral blood with this combination, which is higher than has been seen in other trials.”

Peter Hillmen, MB ChB, PhD

Peter Hillmen, MB ChB, PhD

As Dr. Hillmen explained, the management of CLL has evolved substantially over recent years, with traditional chemotherapy regimens, such as FCR, losing favor because of associated toxicities and evolving resistance. The emergence of novel agents such as ibrutinib, an irreversible Bruton’s tyrosine kinase (BTK) inhibitor, and venetoclax, a BCL2 inhibitor, has transformed the therapeutic landscape for CLL, providing effective, less toxic alternatives to traditional chemotherapies.

A phase III trial comparing ibrutinib plus venetoclax (for 15 months) with chlorambucil plus obinutuzumab led to the approval of ibrutinib plus venetoclax in Europe.3 However, mathematical disease modeling and phase II studies favor defining the duration of ibrutinib plus venetoclax according to individual patient sensitivity.

Study Design: MRD-Guided Approach

The FLAIR trial is a phase III, multicenter, randomized, controlled, open-label, parallel group trial for patients with previously untreated CLL. Investigators from the UK National Cancer Research Institute (NCRI) randomly assigned 523 participants to receive either six cycles of FCR chemoimmunotherapy or daily venetoclax (400 mg) plus ibrutinib (420 mg), with treatment duration based on MRD response. Participants who had more than 20% of cells with deletions of chromosome 17p were excluded from this study.

Patients initially received ibrutinib alone for 2 months. After this, venetoclax was added to their treatment. Over a period of 4 weeks, the dosage of venetoclax was incrementally increased until it reached 400 mg/d. This combination treatment was then continued for up to 6 years.

The duration of the ibrutinib-plus-venetoclax treatment depended on the MRD response of the individual patient. Flow cytometry was used to assess MRD at the end of the first year and subsequently every 6 months. If an undetectable MRD result was observed, the test was conducted again at the 3-month and 6-month marks in peripheral blood and bone marrow. If all these tests resulted in undetectable MRD, the ibrutinib-plus-venetoclax treatment was continued for double the time period from the start of the combined treatment to the time when an undetectable MRD result was first observed. This duration could range from 2 to 6 years.

Improved Progression-Free and Overall Survival

In addition to the progression-free survival benefit for ibrutinib plus venetoclax, Dr. Hillmen reported a significant improvement in overall survival. At 3 years, 2.0% of patients randomly assigned to the ibrutinib-plus-venetoclax arm had died vs 7.0% of those given FCR (HR = 0.31).


  • Results of the phase III UK NCRI FLAIR study showed that ibrutinib-plus-venetoclax treatment duration can be personalized based on MRD response, with the potential to optimize outcomes.
  • The combination treatment with MRD-guided duration led to superior progression-free survival and overall survival compared to conventional FCR chemotherapy.

“Our findings expose quite emphatically that the ibrutinib-plus-venetoclax therapy outperforms the conventional regimen, especially with respect to progression-free survival rates,” said Dr. Hillmen.

The only subgroup to show no benefit from the combination of ibrutinib plus venetoclax were patients with IGHV-mutated disease. Compared with FCR therapy, no significant difference in progression-free survival or overall survival was observed in these patients, said Dr. Hillmen, although the hazard ratio still favored the combination approach guided by MRD.

In addition to better performance, the combination of ibrutinib and venetoclax also demonstrated fewer toxicities and secondary malignancies compared with the FCR group. The only exception was a greater incidence of cardiac abnormalities observed with the ibrutinib-based combination.

Patients assigned to FCR therapy also experienced twice as many secondary primary malignancies (2.6 per 100 patient-years in the ibrutinib-plus-venetoclax arm vs 5.4 per 100 patient-years with FCR).

“The survival results [of the FLAIR trial] are better than any other phase III trial with targeted treatment,” Dr. Hillmen concluded. “Ibrutinib plus venetoclax guided by MRD should be considered the new gold standard for previously untreated CLL.” 

DISCLOSURE: Dr. Hillmen is an employee of and holds equity in Apellis ­Pharmaceuticals.


1. Hillmen P, Cairns DA, Bloor AJC, et al: Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: Report of the phase III UK NCRI FLAIR study. 2023 ASH Annual Meeting & Exposition. Abstract 631. Presented December 10, 2023.

2. Munir T, Cairns DA, Bloor A, et al: Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. December 10, 2023 (early release online).

3. Niemann CU, Munir T, Moreno C, et al: Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 24:1423-1433, 2023.


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