Efficacy and Safety of Ibrutinib-Containing Regimens in CLL

Transcript: Matthew S. Davids, MD, MMSc: So the Alliance study presented at this 2018 ASH [American Society of Hematology] meeting in the plenary session was really an important study, because it took frontline older CLL patients, age 65 or older, and randomized them to initial therapy with either the standard bendamustine and rituximab for 6 cycles versus ibrutinib, given as a continuous oral therapy, or ibrutinib with rituximab given in combination for about 6 months followed by ibrutinib as a monotherapy, given until time of progression.

And this study actually did allow crossover, as well. So those patients who started on bendamustine and rituximab who later progressed can go on to get ibrutinib-based therapy. And as we saw, the primary endpoint of this study was highly significant, with a major improvement in progression-free survival PFS in both the ibrutinib and the ibrutinib-rituximab arms compared with bendamustine and rituximab.

A couple of key points that we’ve noted in this study are that there was no difference in PFS between the ibrutinib monotherapy and the ibrutinib rituximab arm, suggesting that rituximab does not add benefit to ibrutinib and that ibrutinib monotherapy should be considered the standard.

The other thing that’s important to note with this study is that at least at this short time point, there’s no benefit in overall survival to the treatment with ibrutinib, and, therefore, it still can be considered in a discussion with the patient about whether it might make sense to start with bendamustine and rituximab and then later receive ibrutinib in the relapsed setting.

The ILLUMINATE trial looked at an older population of CLL patients and compared the standard regimen of chlorambucil with obinutuzumab to a new regimen of ibrutinib with obinutuzumab. This is a study where there was a 6-month treatment period of ibrutinib and obinutuzumab followed by continuous ibrutinib therapy afterward, and this study included a fair number of patients with high-risk features, including deletion 17p.

What was observed was a very clear benefit in the endpoint of progression-free survival in those patients who received ibrutinib with obinutuzumab. And one of the things that’s challenging about this study, however, is that there was not an ibrutinib-only arm, and, therefore, we don’t know whether the benefit was due to the combination or whether it would have been seen with ibrutinib on its own. So I think that this study suggests that an ibrutinib regimen should be preferred in most patients compared with obinutuzumab with chlorambucil. But I think it’s still hard to know whether that preferred regimen is obinutuzumab with ibrutinib or just ibrutinib alone.

Yes, I think the trial design does inform the significance of the trial, because…although it provides some helpful data for us, it doesn’t help guide us as to what the optimal regimen is for these patients and whether we should be using ibrutinib monotherapy or using the combination. My own sense is that there may be some benefit to using the combination in patients who have high-risk disease like the deletion 17p, but probably for the majority of CLL patients, it makes more sense to start with ibrutinib as a monotherapy.

The -ACRIN E1912 study was a very important study presented at this ASH meeting. It randomized younger CLL patients, age 70 or younger, to either initial therapy with the gold standard FCR [fludarabine, cyclophosphamide, and rituximab] chemoimmunotherapy for 6 cycles or to ibrutinib with rituximab given in combination for 6 cycles, followed by ibrutinib maintenance until time of progression or unacceptable toxicity.

The primary endpoint of this trial was to look at a difference in progression-free survival, which was strongly positive for the patients who were treated overall with the ibrutinib containing regimen. However, looking at a subset analysis of patients by IGHV mutation status, it seems that the greatest benefit was for those patients with unmutated IGHV, whereas the improvement in PFS was more borderline for those patients with mutated IGHV. The thing that was surprising about the results of the -ACRIN study was that there was actually an overall survival benefit demonstrated for the ibrutinib-rituximab arm over FCR. This was mainly due to early progression events in the CLL patients, although we haven’t yet heard the details about who those patients were and how they were treated and what subsequent therapies they received. So, as we await the publication of this trial, these are some of the details we’ll be on the lookout for.

So at this ASH meeting, we also saw an update on the University of Texas MD Anderson Cancer Centerstudy combining ibrutinib with venetoclax for the up-front treatment of CLL. This is a study that starts with 3 months of ibrutinib given as monotherapy, followed by the combination with venetoclax and the possibility of discontinuation strategy in patients who achieve MRD [minimal residual disease] undetectability.

I think what was very striking to me about this study was the very high rates of both complete remission as well as MRD negativity. And this is a study that is continuing to evolve, and it’s possible that these rates may further increase over time. Ultimately, however, we are going to need to see the long-term progression-free and overall survival data for this cohort.

Transcript Edited for Clarity