Ibrutinib Plus Venetoclax Determined by MRD Improves Survival in Treatment-Naive CLL


Duration of ibrutinib and venetoclax, as determined by the patient’s minimal residual disease, improved survival in patients with treatment-naïve chronic lymphocytic leukemia.

At a duration determined by the patient’s minimal residual disease (MRD), ibrutinib (Imbruvica) and venetoclax (Venclexta) improved patient’s survival vs fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) in patients with treatment-naive chronic lymphocytic leukemia (CLL), according to findings from the phase 3 FLAIR trial (NCT02938520) that were presented at the 2023 ASH Annual Meeting.1

At a median follow-up of 43.7 months, 97.2% (95% CI, 94.1%-98.6%) of patients remained progression free with the investigational regimen vs 76.8% (95% CI, 70.8%-81.7%) with FCR (HR, 0.13; 95% CI, 0.07-0.24; P <.0001). With median follow-up of 43.0 months, 2.0% of patients died with ibrutinib/venetoclax vs 7.0% of patients who received FCR (HR, 0.31; 95% CI, 0.15-0.67; P <.005).

Improved progression-free survival (PFS) was also seen across biological subgroups, including those with unmutated IGHV (3-year PFS rate, 98.3% vs 70.9% with ibrutinib/venetoclax vs FCR, respectively; HR, 0.07; 95% CI, 0.02-0.19; P <.001), ATM (11q) deletion (100% vs 68.3%; P <.001), trisomy 12 (94.5% vs 74.1%; HR, 0.20; 95% CI, 0.06-0.67; P =.002), and 13q deletion (95.3% vs 74.5%; HR, 0.20; 95% CI, 0.08-0.48; P <.001). Patients with mutant IGHV experienced similar outcomes with ibrutinib/venetoclax and FCR, with 3-year PFS rates of 94.3% and 88.8%, respectively (HR, 0.54; 95% CI, 0.21-1.38; P =.199).

“The excellent results seen with ibrutinib plus venetoclax indicate that directing the duration of therapy according to individual MRD response maximizes outcomes,” lead study author Peter Hillmen, MBChB, PhD, consultant hematologist at the Leeds Teaching Hospitals NHS Trust, stated in a presentation of the data.

To be eligible for enrollment, patients had to be 75 years of age or younger with previously untreated CLL requiring therapy by International Working Group CLL criteria. They also had to be fit for treatment with FCR. Patients were excluded from enrollment if they had received prior therapy for CLL, had a history of Richter’s transformation, more than 20% TP53 deletion by FISH, concomitant warfarin or equivalent medication, or symptomatic cardiac failure or angina.

A total of 523 patients with CLL were enrolled at 96 UK centers between July 2017 and March 2021. The primary end point was PFS for ibrutinib/venetoclax vs FCR. Secondary end points included OS, MRD, safety and toxicity.

Two hundred thirty-nine patients were randomly assigned to treatment with 24 mg/m2 of daily fludarabine plus 150 mg/m2 of daily cyclophosphamide for 5 days each with 375 mg/m2 of rituximab for 1 cycle followed by 500 mg/m2 in cycles 2 through 6. Hillmen noted that 6 cycles have been used as the conventional schedule for FCR for the past 20 years in the UK, adding that it can be difficult to complete 6 cycles due to cumulative toxicity.

Two hundred fifty-two patients received 2 months of ibrutinib lead-in at 420 mg daily followed by the addition of 400 mg daily of venetoclax, which could last for 2 to 6 years based on MRD. Venetoclax was escalated weekly starting from 20 mg. Notably, treatment in the investigational arm was administered for twice as long as investigators deemed it would take to become MRD negative.

“We [tested] peripheral blood every 6 months from 1 year after initiation of therapy,” Hillmen said. “If a patient had an MRD-negative result in the blood, it would be repeated 3 months later. If that was negative again, we would repeat blood and marrow 3 months later. If all were negative, the first peripheral blood was [used as] the time when the patient became negative, [and we] doubled that time [on treatment].”

Regarding safety, Hillmen noted substantial differences between arms for blood and lymphatic system disorders (31% vs 5.2% for ibrutinib/venetoclax and FCR, respectively), cardiac disorders (0.4% vs 10.7%), general disorders and administration site conditions (5% vs 1.6%), metabolism and nutrition disorders (0% vs 4%), and eye disorders (0% vs 2.4%).

Other observed adverse effects in the ibrutinib/venetoclax and FCR arms, respectively, included infections and infestations (18.8% vs 22.2%), gastrointestinal disorders (7.9% vs 3.6%), neoplasms (2.1% vs 2.4%), respiratory, thoracic and mediastinal disorders (2.5% vs 1.6%), musculoskeletal and connective tissue disorders (1.3% vs 2.4%), skin and subcutaneous tissue disorders (2.1% vs 1.6%), and nervous system disorders (0.8% vs 2%).

Secondary malignancies were more common with FCR (n = 39) vs ibrutinib/venetoclax (n = 17), with an incidence rate of cancers per 100 person-years of 5.4 (95% CI, 5.11-5.68) vs 2.6 (95% CI, 2.40-2.79), respectively. The most common malignancies included basal cell carcinoma/squamous cell carcinoma (n = 16 vs 13 with FCR and ibrutinib/venetoclax, respectively), myelodysplastic syndrome/acute myeloid leukemia (8 vs 1), lymphoma (5 vs 3), and prostate/other urological tumor (5 vs 1).

“This is the first trial to show that an MRD-guided approach with treatment beyond [MRD] negativity has a significant advantage over chemotherapy, both in terms of PFS and overall survival,” Hillmen concluded.

Findings from the third arm of the trial are expected to be presented next year, Hillmen said.


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. Blood. 2023;142(suppl 1):631. doi:10.1182/blood-2023-178298

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