Ibrutinib/Venetoclax Prompts Superior uMRD Data in Elderly or Unfit Patients With CLL

Carolyn Owen, MD

Elderly or unfit patients with chronic lymphocytic leukemia (CLL) treated with fixed-duration ibrutinib (Imbruvica) and venetoclax (Venclexta) in the frontline had deeper and prolonged undetectable minimal residual disease (uMRD) responses compared with chlorambucil and obinutuzumab (Gazyva), according to findings from the phase 3 GLOW trial (NCT03462719).¹

In the GLOW study, patients aged 65 years or older or 18-64 years with a cumulative illness rating scale score of greater than 6 or creatinine clearance of less than 70 mL/min were enrolled. Patients were then randomized in a 1:1 ratio to receive either 3 cycles of ibrutinib followed by venetoclax for 12 cycles or 6 cycles of chlorambucil and obinutuzumab. The primary end point was progression-free survival and uMRD.

These findings presented translated to fewer relapses within the first year after treatment cessation.

Data also showed that at 34.1 months of follow-up after treatment completion, the rate of uMRD below 10-4 and 10-5 was higher with the combination of ibrutinib and venetoclax (n = 106) vs chlorambucil/obinutuzumab (n = 105) in the bone marrow and peripheral blood.

Moreover, the rate of uMRD was 51.9% (10-4, 11.3%; 10-5, 40.6%) with ibrutinib/venetoclax vs 17.1% (10-4, 9.5%; 10-5, 7.6%) with chlorambucil/obinutuzumab in the bone marrow and in the peripheral blood, rates were 54.7% (10-4, 11.3%; 10-5, 43.4%) and 39.0% (10-4, 21.0%; 10-5, 18.1%).

In an interview with Targeted Oncology^TM, Carolyn Owen, MD, associate professor in the Division of Hematology & Hematological Malignancies, University of Calgary, and hematologist at the Tom Baker Cancer Center, discussed findings from the GLOW study of elderly/unfit patients with CLL, which were previously at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

Can you discuss the current treatment landscape for patients with CLL?

Owen: Historically, the first-line treatment for CLL was very much divided based on fitness. That's becoming less and less an issue given the entry of novel agents into the frontline treatment landscape where fitness of the patient is less important because the novel agents are much more tolerable than traditional chemoimmunotherapy. Until recently, chlorambucil/obinutuzumab was a treatment for the unfit, not sort of sturdy patient, often very elderly patients or those with comorbidities.

FCR was the treatment for the very young and fit and then many therapies in between like bendamustine and rituximab can be considered against chemoimmunotherapy still in that realm. Ibrutinib monotherapy and other BTK inhibitors have moved into the frontline space. They work very well, they're usually tolerable, but unfortunately, they are sort of continuous therapies. This is a new move towards trying to include novel agents in the frontline, but in a fixed duration.

What were the methods and design of the GLOW study?

This is a phase 3 randomized clinical trial which is very important because that's usually what leads to funding and that's the highest quality evidence. The comparator of chlorambucil obinutuzumab may not be the best for a lot of people because it wasn't a terribly popular treatment by the time this study was completed, but it was still an accepted standard of care at the time the study was started. Most people would question how this IV combination compares against venetoclax and obinutuzumab, which is a fixed duration novel agent-based therapy. But at the time, that wasn't routinely available in most places so I think you can argue that the selection of the chlorambucil obinutuzumab was a reasonable comparator. But because chlorambucil obinutuzumab was not a treatment we would give to the very fit, the inclusion criteria was around patients who were not appropriate for intensive chemoimmunotherapy, either by age or by comorbidities. It excluded patients who had a known deletion 17P or TP53 mutation, because those patients are known to do poorly with chemoimmunotherapy.

What were the data from the study presented at SOHO 2022?

The primary end points of the study were independent review committee-assessed progression free survival, and those results were presented about a year ago with a 20 month median follow-up, and it strongly favors the IV over the chlorambucil obinutuzumab. Not many people were surprised by that result. To date, there's still no overall survival advantage. There have been a few extra deaths in the chlorambucil obinutuzumab group, but no extra deaths in the IV groups and maybe with time, we might move to seeing an overall survival difference. The presentation at SOHO directed towards the MRD results, which are a secondary end point of the study, it's very interesting to see that MRD, now, isn't predictive of outcome. That is probably just because there are so few progressions in the IV therapy group. We probably need to watch that group for a lot longer.

What do these results mean for the future of this space?

I think that these results from the GLOW study, not the MRD results particularly, but the study in general and the progression-free survival results are valuable in showing us that I plus V or any novel oral combination is a highly effective therapy, fairly well-tolerated, and it would be a desirable and effective option for many patients with CLL.

What did you discuss regarding MRD at the SOHO meeting?

The presentation at SOHO was focused on MRD. I think that MRD is a very interesting area of research, but I think it continues to be an area of research and not really a routine clinical test that should be applied today. I think these results are very informative in telling us that if we had assessed for MRD at the end of therapy and known the result and altered our management based on it, that it might not have been a wise idea. The patients who have detectable MRD are doing just as well as the patients who have undetectable MRD, which is counterintuitive from our past results. But I do think that there's a bit of a desire to have the newest tests available to us. We need to know what to do with them before we use them.

For this test, I think that there's no use for it right now with I plus V or other venetoclax based therapies that people are really motivated to use MRD. I think we need better studies to show us how that might help direct therapy and improve patient outcomes. There are a lot of clinical trials that use MRD to direct the duration of therapy, but there are very few that compare against a non-MRD directed outcome in which you could say at the end of the day that using MRD improved the outcome of the patient. I think that we would do well to design even bigger clinical trials, like cooperative group studies, and answer this question better because MRD itself is going to have cost implications and especially in places like the United States where there are many community [treatment centers], it might not be as easily available. People should know whether they should be obtaining this, whether it's a difficult test to get, and whether they should get it to help their patient if it's more than just an academic test that isn't going to change anything right now. I think that better directed clinical trials would help us answer that question.

What research in the CLL space has caught your attention?

I'm most excited to see the comparison of this novel, oral combination against another novel, frontline, fixed duration combination, but that's not what this study will give us. I think we need a lot more time to decide exactly where IV fits into the treatment landscape. I think it's a very effective therapy and I think many patients will be very motivated to receive it, but I think it is difficult when new therapy is justified by clinical trial and the comparator isn't the one we would have wished was the comparator of the day. Like many different new therapies, I think we need a bit more time to figure out who is the best patient to receive this therapy and how we will recommend it compared with the other therapies that are available now, which are better than the comparator that was included in the clinical trial.

REFERENCE:

Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the glow study. Blood. 2021;138 (suppl1): doi:10.1182/blood-2021-148666