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A combination of Imbruvica and venetoclax showed significantly prolonged progression-free survival in patients with untreated CLL, an expert explained.
In patients with chronic lymphocytic leukemia (CLL) who did not previously receive treatment, a combination of Imbruvica (ibrutinib) plus venetoclax chemotherapy showed promising outcomes compared with a chlorambucil plus Gazyva (obinutuzumab) combination.
Specifically, researchers from the phase 3 GLOW study evaluated PFS among patients with untreated CLL who received either Imrbruvica plus venetoclax or chlorambucil plus Gazyva.
After a 64-month follow-up in the study, Imbruvica plus venetoclax showed significantly longer progression-free survival (PFS) without significant toxicity or side effects compared with those receiving chlorambucil plus Gazyva (52 months versus 31 months, respectively) in patients with previously untreated CLL.
Progression-free survival (PFS): time during and after treatment that a patient lives without the cancer getting worse.
Overall survival (OS): time that a patient lives after being diagnosed with cancer.
Minimal residual disease (MRD) status: the amount of microscopic traces of cancer that remain in the body after treatment.
Kinetics: the study of how cancer changes over time in the body.
This long-term follow-up provided valuable insights into the combination’s durable efficacy and safety profile, according to the study’s authors. This offers a strong foundation for informed clinical decision-making for patients with previously untreated CLL.
CURE® spoke with study author Dr. Carsten Utoft Niemann, head of the Department of Hematology, at the Rigshospitalet, Copenhagen University Hospital, to discuss his presentation at the 2024 ASH Annual Meeting on first-line treatment with Imbruvica plus venetoclax versus chlorambucil plus Gazyva.
Niemann: We already knew that overall survival was improved, and PFS improved in combination with Imbruvica-venetoclax [versus] chlorambucil plus Gazyva. The question now was, would this improvement be sustainable for a longer period of follow-up? That's what we found in the longer-term follow-up data that we present there, but also to see if the toxicity profile will be slightly longer, more than double the length treatment with Imbruvica-venetoclax as compared to chlorambucil plus Gazyva treatment only being less than six months.
What we see here is that if we define the composed outcome as being progression-free and toxicity-free. Here, toxicity is defined as grade 3 (severe) or above [side effects]. So, what we report here is that the toxicity-free PFS is significantly improved by more than 21 for Imbruvica-venetoclax as compared to chlorambucil plus Gazyva, despite the longer length of treatment combination of Imbruvica-venetoclax.
So, looking at the number of trials testing Imbruvica-venetoclax or other BTK inhibitors … we've seen now for the first time that the patients with the most aggressive type of CLL being unmutated, actually are the ones having the fastest track towards achieving undetectable [minimal residual disease (MRD)] status. We've seen that in the GLOW trial, in the CAPTIVATE trial and in the FLAIR trial, all three of them testing Imbruvica-venetoclax, all three of them showing that patients with aggressive phenotypes have a faster track towards achieving under test of MRD status.
In the GLOW trial, we have the longest follow-up in terms of kinetics of MRD afterward. And there we see that the patients with the idea to be unmutated status also lose the unprotected MRD status faster, whereas it's very stable for patients with idea to be mutated phenotype. This indicates that patients will ideally mutated stages, the less oppressive disease they might actually do well, even not achieving a steep response, whereas the patients will ideally unmuted status, they need to achieve the deep, undetectable MRD status to actually have a longer PFS. And this is also supported by PFS data compared to uMRD data, and this means that it's not enough just to keep at MRD status. We need to combine it with the type of treatment because the treatment kinetics, or kinetics of uMRD are different if we look at the treatment options, and we need to look at the molecular phenotype, meaning that we need to take this into our clients in the coming years, when we have validated these data, with longer follow up in different trials.
So, from the patient perspective, and that's very present in our research group in my clinical work, we actually have patient panels to help us to find the outcomes that are most important patients, and it's been really clear from these interviews with patients that spending time at the hospital is not improving your quality of life. It's acceptable to have [side effects] or toxicity for a shorter duration of time, but not if it actually keeps you in the hospital. The patients want to have their life back. They want to be outside of the hospital. So, looking at the options to see treatment like Imbruvica-venetoclax, it means that it is time defined, just a little bit more than one year of treatment.
It's oral, but you need to spend the first five weeks of the Imbruvica-venetoclax ramp-up with frequent hospital visits, and you have the risk of atrial fibrillation due to Imbruvica and have the risk of infections due to the disease and due to the treatment. Thus, you need to make sure, as a patient, that you discuss with your physician whether this treatment, compared to your comorbidity profile actively would be the one with the least risk of [side effects], or least risk of toxicity, as compared to other treatment options. And then you need to take this discussion with your treating physician, what is actually important for you? Do you live in a place where it's having a lot of problematic logistics to actually come into the hospital at least once or twice a week or five weeks? Or is that something that would work out? Maybe you have a local laboratory close by that could actually make this logistic period a little less hard on you.
Transcript was edited for clarity and conciseness.
“First-line Ibrutinib Plus Venetoclax Vs Chlorambucil Plus Obinutuzumab in Elderly or Comorbid Patients (Pts) with Chronic Lymphocytic Leukemia (CLL): Glow Study 64-Month Follow-up (FU) and Adverse Event (AE)-Free Progression-Free Survival (PFS) Analysis” by Dr. Carsten Utoft Niemann, et al. Blood.
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