Ibrutinib Plus Venetoclax Produces High MRD Negativity Rate in Previously Untreated CLL

The addition of venetoclax to ibrutinib resulted in a high rate of minimal residual disease negativity in the blood and marrow of patients with previously untreated chronic lymphocytic leukemia.

The addition of venetoclax (Venclexta) to ibrutinib (Imbruvica) resulted in a high rate of minimal residual disease (MRD) negativity in the blood and marrow of patients with previously untreated chronic lymphocytic leukemia (CLL), according to data from an interim analysis of the phase 3 NCRI FLAIR trial (ISRCTN01844152) presented during the 2022 EHA Congress.1

No patients who received ibrutinib monotherapy (n = 138) achieved MRD negativity in the peripheral blood (95% CI, 0%-2.64%) or marrow (95% CI, 0%-2.64%) at 2 years vs 65.4% (95% CI, 56.81%-73.38%) and 71.3% (95% CI, 62.95%-78.75%), respectively, of those who received ibrutinib plus venetoclax (n = 136; P < .0001).

Because no patients achieved an MRD-negative remission on the ibrutinib-monotherapy arm, investigators needed to apply penalized logistic regression models to allow for finite parameter estimation. Doing this revealed a 454-fold chance of achieving MRD negativity with the doublet vs the monotherapy, which was statistically significant (95% CI, 29.0-7122; P < .0001). No significant difference was observed with regard to gender, age, or stage of disease.

“Ibrutinib plus venetoclax in this interim analysis of a large, phase 3 trial showed very high rates of MRD negativity in the blood and the marrow; this was at least numerically higher for patients with IGHV-unmutated disease at 2 years vs those with mutated disease, and for those with 11q deletion vs those with isolated 13q deletion,” Peter Hillmen, MD, PhD, lead study author and consultant hematologist at the Leeds Teaching Hospitals NHS Trust, said in a presentation on the data.

FLAIR is an adaptive design trial that was launched to answer several questions, according to Hillmen. The initial trial opened in 2014, and it compared treatment with ibrutinib plus rituximab (Rituxan) with fludarabine, cyclophosphamide, and rituximab (FCR) in 771 patients with previously untreated CLL. Data showed that the ibrutinib combination resulted in superior progression-free survival (PFS) vs FCR in this patient population.2 At a median follow-up of 52.7 months, the median PFS had not yet been reached with ibrutinib/rituximab vs 66.53 months with FCR (HR, 0.44; 95% CI, 0.32-0.60; P < .001).

“It became clear that additional combinations were of interest…and so, at the end of 2017, we added 2 additional arms to FLAIR: the control arm of ibrutinib monotherapy and ibrutinib plus venetoclax,” Hillmen explained.

First, investigators compared ibrutinib with ibrutinib plus venetoclax, with a primary end point of MRD negativity. At the meeting, Hillmen shared data from the planned interim analysis, where half of these patients had reached 2 years post randomization and had MRD results.

However, Hillmen added that data on the primary end point comparing ibrutinib plus venetoclax with FCR in 523 patients are expected to read out next year. Single-agent ibrutinib is also being compared with FCR in 525 patients, with a key secondary end point of PFS. Additional phase 2 randomization is being done for patients with 17p deletions and/or TP53 mutations and it will compare ibrutinib vs ibrutinib/venetoclax.

“The other difference with FLAIR compared with most trials is that we have a fixed duration of ibrutinib; we do not continue ibrutinib until disease progression,” Hillmen noted. “Also, within the ibrutinib arm, we have stopping rules dependent on MRD. We reasoned that we need to continue treatment beyond the MRD negativity to get to a level where we could potentially cure patients. The design was that we would continue treatment for the same duration it took to get to MRD negativity.”

To be included in this analysis, patients needed to have previously untreated CLL that required therapy per iwCLL criteria, they needed to be 75 years of age or younger, and they needed to be considered eligible to receive FCR.

If patients previously received therapy for CLL, had a history of Richter transformation, had higher than 20% TP53 deletion by FISH, were receiving concomitant warfarin, or had symptomatic cardiac failure or angina, they were excluded.

The primary objectives of the research were to evaluate whether ibrutinib plus venetoclax was superior in PFS to FCR, and to assess whether the combination was superior to ibrutinib monotherapy with regard to MRD negativity.

Secondary objectives included PFS of ibrutinib/venetoclax vs ibrutinib alone, PFS of ibrutinib vs FCR, overall survival, proportion of participants obtaining undetectable MRD, iwCLL response to therapy, safety and toxicity, health-related quality of life, and cost effectiveness.

For the second part of the trial, a total of 786 patients with CLL requiring therapy by iwCLL criteria were randomized 1:1:1 to 3 arms. One arm received oral fludarabine at 24 mg/m2 daily for 5 days and for cycles 1 through 6, oral cyclophosphamide at 150 mg/m2 for 5 days and for cycles 1 to 6, and intravenous rituximab at 375 mg/m2 for cycle 1 and 500 mg/m2 for cycles 2 through 6. The second arm received ibrutinib at a daily dose of 420 mg for a maximum of 6 years. The third arm received venetoclax at a daily dose of 400 mg plus ibrutinib at a daily dose of 420 mg for 2 to 6 years.

Notably, in the ibrutinib monotherapy and combination arms, MRD was tested in the peripheral blood every 6 months. If MRD negative, investigators repeated the testing after 3 months, and then tested the peripheral blood and bone marrow at 6 months. If all tests came back as MRD negative, then the first peripheral blood MRD-negative result counted as the time to MRD negativity.

In the analysis presented during the meeting, which compared ibrutinib/venetoclax with ibrutinib monotherapy, the median age among all 274 patients was 63 years, with 34.3% of patients over 65 years of age. Moreover, 72.3% of patients were male, and 59.1% had Binet stage prog A or B disease. The duration of disease before randomization was a median of 27.2 months. Additionally, 50.7% of patients had B symptoms, and 45.6% had B2-microglobulin of 4 mg/L or higher.

Regarding prognostic markers, 37.7% of patients in the ibrutinib monotherapy arm had mutated IGHV, 43.5% had unmuted IGHV, 12.3% had IGHV subset 2, and 6.5% did not have this information available; these rates were 40.4%, 47.1%, 5.9%, and 6.6%, respectively, in the combination arm.

Moreover, 10.9% of patients on the ibrutinib monotherapy arm had 11q deletion vs 21.3% of those on the ibrutinib/venetoclax arm, 17.4% vs 20.6% had trisomy 12, 23.2% vs 20.6% had normal status, 41.3% vs 32.4% had 13q deletion, and 7.2% vs 5.1% had failed or incomplete FISH results.

“In terms of treatment compliance, we saw that about half of patients had at least 1 modification of a dose in the first year of treatment of both ibrutinib in the [monotherapy] arm and ibrutinib/venetoclax in the [combination] arm,” Hillmen noted. “This was reduced in the second year, and significantly less in the third year. The combination and ibrutinib [monotherapy were] well tolerated.”

Additional data from the assessment of iwCLL response assessment 9 months following randomization showed that ibrutinib monotherapy elicited an objective response rate (ORR) of 86.2% vs 88.2% with ibrutinib plus venetoclax. In the monotherapy arm, 8.0% of patients achieved a complete response (CR), 78.3% had a partial response (PR), and 13.8% had stable disease; these rates were 59.6%, 28.7%, and 11.8%, respectively, in the combination arm.

The median time to MRD negativity with ibrutinib plus venetoclax was 12 months (range, 10.2-17.5) vs 19 months (range, 12.5-26.0) in the bone marrow.

“There’s a continuing depth of remission with continuous therapy beyond the second year, suggesting that a fixed duration of 1 or 2 years of combination [treatment] may leave some patients MRD positive who will eventually become MRD negative,” Hillmen said. “The first time a patient can stop therapy is at 2 years, but to do that, they have to achieve MRD-negative remission at 1 year. In the ibrutinib/venetoclax arm, 42.6% of patients achieved MRD negativity after 1 year, and hence, stopped therapy at 2 years, while the others continued therapy.”

When looking at MRD at 2 years by subset, no significant difference was observed in the ibrutinib/venetoclax arm with regard to age, gender, and stage, according to Hillmen.

In terms of mutational status, more IGHV-unmutated patients who received the combination achieved MRD negativity than those with IGHV-mutated disease; MRD negative remission rates at 2 years in these patients was 79.7% (95% CI, 67.8%-88.7%) and 56.4% (95% CI, 42.3%-69.7%), respectively. “This is consistent with the phase 2 trials we have seen,” Hillmen noted.

In terms of FISH, it was found that a higher proportion of patients with 11q deletion achieved MRD negativity at 2 years vs those with good-risk 13q deletion, at 82.8% (95% CI, 64.2%-94.2%) and 54.5% (95% CI, 38.8%-69.6%), respectively.

The most common all-grade toxicities reported on the ibrutinib/venetoclax and ibrutinib monotherapy arms, respectively, were diarrhea (52.6% vs 29.4%), nausea (40.7% vs 14%), anemia (28.9% vs 16.9%), and white blood cell decrease (36.3% vs 8.8%).

The most frequent grade 3 or higher adverse effects (SAEs) that occurred in 3% or more of participants in the combination and monotherapy arms, respectively, were white blood cell decrease (27.4% vs 5.1%), anemia (7.4% vs 2.9%), platelet count decrease (5.9% vs 1.5%), other (4.4% vs 2.2%), and rash (2.2% vs 4.4%).

With regard to serious AEs, no significant differences were observed between the arms, however there were slightly more infections reported with ibrutinib alone vs the combination, at 19.9% vs 14.8%, respectively. Moreover, cardiac disorders occurred in 11.9% of those who received the doublet vs 8.1% of those who received the monotherapy.

Slightly more patients on the combination arm experienced AEs that resulted in early discontinuation of ibrutinib vs those on the monotherapy arm, at 13.2% and 9.4%, respectively.


  1. Hillmen P, Pitchford A, Bloor A, et al. The combination of ibrutinib plus venetoclax results in a high rate of MRD negativity in previously untreated CLL: the results of the planned interim analysis of the phase III NCRI FLAIR trial. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S145.
  2. Hillmen, P, Pitchford, A, Bloor, A, et al. Ibrutinib plus rituximab is superior to FCR in previously untreated CLL: results of the phase III NCRI FLAIR trial. Blood. 2021;138(suppl 1):642. doi:10.1182/blood-2021-152319