Is Venetoclax + Ibrutinib better Ibrutinib Monotherapy in CLL?

Is Venetoclax + Ibrutinib better Ibrutinib Monotherapy in...

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So, I presented the interim analysis of the second part of the FLARE trial, which is a randomized phase 3 trial in previous stances, CLL patients which the total trial we recruit just under 1500 patient. What we presented here was the first interim analysis of comparison of Ibrutinib (I) and venetoclax (V) compared to Ibrutinib (I) monotherapy where half the patients had reached 2 years.

That was 2,274 patients randomized. So, we analyze over five total that comparison and setting MRD. First of all, we showed that the treatment well tolerated, there were no. Significant tissues with adding the venetoclax (V) to Ibrutinib (I). We saw slightly more neutropenia, slightly more diarrhea but nothing that was dose limiting or treatment limiting and tumor syndrome was only a very small portion and unmanageable.

The primary endpoint of this past the trial was MRD eradication using in blood and marrow, but maybe marrow 10 minus 10,000. And what we showed was that in the Ibrutinib (I) no patients achieved MRD eradication and in the hyper at 2 years, 71 total, 1% just over a patients achieve node to the blood.

And 65% in the marrow, about 43% had stopped treatment in two years and others will stop at later on we, we guide therapy by MRD early patient. In addition, the complete remission rate was higher for the with just under 60% of patients achieving negativity with I compared to only 8% with alone.

We don't have survival that we expect that to be next year, we're seeing continuing increasing depth of remission with subsequent continuous therapy in flare. We can continue the therapy for up to six years to go and respond. And we also showed similar to some of the phase 2 trials that patients.

For features with chemotherapy IGHG only mutated for example, were more likely to have an MRD negative emission than those who were mutated. So almost 80% of patients with unmutated disease were MRD negative by 2 years. And likewise, 11 deletions more patients achieved naivety with 11 to disease.

Without percent negativity in 2 years, so really by encouraging results, indicating that we can use this combination. Safely and that we will stop the majority of patients where under negativity and we anticipate we to prolonged survivals, progression free survivals without all that data won't be out until next year.

So, I think the most common questions asked, include whether the combination of I plus that is safe. Which we demonstrated earlier say, were also asked about the use of MRD to define duration of therapy. And this is one of the trials which uniquely does that. And I think it's clear that if we use MRD to guide therapy, then we're going to get the most out of the accommodations of who won some patients.

If we use a fixation treatment will still be MRD positive who would be negative with further treatment.

The further question that's often asked is about the poorest features. So, the I unmutated and why we would see a higher response rate and allocation rate would the unmutated rather than mutated, which is for chemotherapy, the wrong way around. And the reason I think is because IGHV unmutated disease is very dependent on BSO receptor signaling and, the targets the BSO receptor pathways.

So, I think specifically like, such as ibrutinib (I) is likely to see a better response rate, the combination of has been studied in a number of other trials, one other phase three trial, which will probably lead to the approval of the combination in re in, in certain bodies. And so, I think the combination of will be available and our data from FLAIR, especially when we have the additional data, which we see next year, which will be.

A large dataset will reinforce the use of this combination for the poorest patients. And so, I think, will it impact routine practice, but probably not just yet. So, in our population, I think we need approval of the combination first and I'm not sure where that's planned for.

But probably in the next 12 months, we'll see approvals coming through, and I think this data becomes important.

So, this is the only the second in FLAIR. We have we expect next year to see the definitive comparison with progression survival as employed for I+V compared to FCR which is a key endpoint of the trial. And also, a building on this combination. I, in terms of MRD and progression through survival. So, I think in the next 12 to 18 months, we should see data emerging from this trial, which include survival outcomes.

And if they show an advantage in favor of the combination and then it'll. It will be treatment changing and we'll change the way we treat patients globally.

This is an early readout of a combination of a large phase trial. And we will show further data in future, but it's important. We get long term data cause the outcomes are so good. For CLL, I think we'll lead it. We're moving towards using IGHD mutations data on (inaudible) to define the type of we're using CLL.

As things stand at the moment, the evidence suggests that we should be using and mutated patients. I mutated. Whereas, for the other patients, unmutated probably 17 (inaudible). If we want to stop therapy, a combination of Ibrutinib (I) is more logical. And so I think we're waiting for obviously more mature data.

But I think it's encouraging that we will be using a biological map cause to define a clear choice.

Professor Peter Hillmen, MD, he leads the Experimental Hematology section in LICAP and the Translational Hematology Research group. He is a Professor of Experimental Hematology and Honorary Consultant Hematologist at Leeds Teaching Hospitals NHS Trust at University of Leeds. In this interview, he speaks about the EHA 2022 Abstract - 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.


Ibrutinib (I) and venetoclax (V) both enhance CLL outcomes. I rarely eliminates measurable residual disease (MRD), whereas V (alone or in combination with anti-CD20) can eliminate MRD, allowing for time-limited therapy. Small studies imply that I and V work together, as I+V resulted in MRD negative in many patients (pts).


The major goal was to compare the rates of MRD eradication between I and I+V. Secondary goals included IWCLL overall response rate (ORR), complete response rate (CR), and safety.


FLAIR (ISRCTN01844152), a phase III, randomized, controlled trial for previously untreated CLL that meets IWCLL criteria and requires therapy. Pts over 75 years old or with a 17p del of more than 20% were excluded. FLAIR was updated in July 2017 to include two additional arms, I monotherapy and I+V. I was prescribed 420mg each day. For I+V, V was added after two months of I, with the dose gradually increasing to 400mg/day over five weeks. MRD established the duration of therapy (DOT), with treatment lasting up to 6 years. MRD was measured centrally using flow cytometry, and MRD negativity was defined as 1 CLL cell in 10,000 leucocytes (IWCLL criteria). MRD was measured in peripheral blood (PB) and bone marrow (BM) at 9 months, 12 months, and subsequently 6 months. When PB was MRD negative, this was repeated three months later, and then three months later in both PB and BM. If both PB and BM were negative, the time to MRD negativity was computed (treatment start to first MRD negative PB), and the DOT was double that. The earliest therapy may be discontinued was two years after randomization. When 50% of points in the I and I+V arms had reached 2 years post-randomization, a formal interim analysis was done, and a p-value of 0.005 was statistically significant.


523 points were assigned to I or I+V. We present an interim analysis of the first 274 points (I [n=138] and I+V [n=136]) reached two years after randomization from 83 UK centers between 13/07/17 and 15/03/19. 72.3 % were male, the median age was 63 years (34.3 % were over 65 years old), and 40.9 % were Binet C. IGHV was available for 256 (93.4 %) patients, with 48.2 % IGHV unmutated (98 % homology to germline), 45.3 % IGHV mutated, and 9.1 % Subset 2. Hierarchical FISH testing found 16.1% 11q del, 19% trisomy 12, 21.9 % normal, and 36.9% 13q del, with 6.2 % failing. For all variables, the arms were well-balanced. MRD negative was reached in BM in 89/136 (65.4 %) and PB in 97/136 (71.3 %) within 24 months in the I+V arm compared to no points in the I arm (p0.0001). Within 24 months, MRD negative for I+V in BM was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months, 49/136 (36%) I+V patients were MRD negative in BM and 56/136 (41.2%) negative in PB, compared to 0/138 with I (p0.0001). ORR at 9 months in 120/136 (88.2%) I+V points and 119/138 (86.2%) I points (p=0.6157). At 9 months, CR was found in 81/136 (59.6%) of I+V cases and 11/138 (8%) of I cases (p0.0001). At any time, the I+V CR was 93.4 %. At 24 months, 54/136 (39.7 %) of the patients ceased I+V because they met the MRD stopping criterion.


Ibrutinib with venetoclax is a safe and effective combination that results in a high rate of MRD negative in blood (71.9%) and marrow (65.4%) in the first two years of treatment.