Optimizing Systemic Therapy for Chronic Lymphocytic Leukemia - Episode 2
Transcript: William G. Wierda, MD, PhD: So we talked about ILLUMINATE, which was chemoimmunotherapy with chlorambucil and bivatuzumab; the ALLIANCE study, which was BR [bendamustine and rituximab] compared [with] ibrutinib-based therapy; and then the third abstract that was presented as a late breaker—I wonder, Matt, if you could just summarize the results—was the ECOG [Eastern Cooperative Oncology Group] E1912 trial.
Matthew S. Davids, MD, MMSc: Sure. This was just presented earlier this morning on behalf of the whole ECOG group, and it was looking to compare ibrutinib and rituximab [with] the current standard of care for younger fit CLL [chronic lymphocytic leukemia] patients, which is FCR [fluarabine, cyclophosphamide, and rituximab], developed [by] Michael Keating[, MB, BS,] and Susan O’Brien[, MD,] at The [University of Texas] MD Anderson Cancer Center, a regimen [in which] we have long-term follow-up now at patients out 12 to 15 years. And we see patients particularly with mutated IGHV having still disease-free survival at that type of interval.
So in this ECOG trial, they randomized over 500 patients to either ibrutinib and rituximab with rituximab for the first 6 months or so, and then followed by ibrutinib maintenance essentially as a monotherapy, as a continuous therapy, until time of progression. And this was compared [with] the standard 6-month course of FCR. There was actually a 2:1 randomization in this trial in favor of the ibrutinib-containing arm.
And really I think the most significant benefit was seen in the progression-free survival [PFS], very dramatic improvement in PFS in the ibrutinib-Rituxan arm. When they broke it down by the IGHV mutations status the benefit seemed to be really most profound for the patients with the unmutated IGHV. It actually was not quite statistically significant in the mutated IGHV patients. We can talk about the implications of that. I think what was surprising to most of us was the overall survival benefit, but they also observed for the ibrutinib-Rituxan arm over FCR. And FCR is a regimen that can have some infectious toxicities. And from the presentation today, it actually did not seem like infection that was the cause of death but more CLL disease progression.
To Susan’s point before, we have several effective salvage therapies. So I think this is an interesting finding. The numbers are relatively small. There were only 10 deaths in the arm with FCR and 4 in the arm with ibrutinib and rituximab, although as it was pointed out, there were twice as many patients in the ibrutinib arm, so effectively it’s almost like a 20:4 comparison.
So this is something we’re going need to further see in follow-up. We know again that FCR is going to have this long-term plateau. And so even though there’s an early overall survival difference in favor of ibrutinib and rituximab, it’s hard to know in the long term if that’s going to translate into an overall survival benefit.
Just 1 last point on the study. To me what was pretty striking was the toxicity profile of ibrutinib and rituximab in the younger patients. It actually looked a lot more favorable than what we’re used to seeing in the older population. The risks of infection were lower. Obviously, [there are] risks of atrial fibrillation in this population with fewer comorbidities. And so until now we really haven’t had a robust data set for ibrutinib in the younger fit patients, and I think this really adds to our knowledge of that population.
William G. Wierda, MD, PhD: For me the survival data [are] interesting. That trial excluded patients with 17p deletion, and if you look at the survival curve, the events are happening after a year or 2 years. So they’re having patients who are early progressors and have very aggressive, these 6 patients who progressed and died with CLL-related causes.
Anthony R. Mato, MD: Although keep in mind, they did not screen for TP53 mutations.
William G. Wierda, MD, PhD: They did not screen.
Anthony R. Mato, MD: It could be very well that 6 patients could have gotten through.
William G. Wierda, MD, PhD: So those details will be interesting, and I assume we’ll see that in the manuscripts that should be available relatively soon. The other question in my mind is among those 6 patients, what was the proportion who had a mutated V gene versus an unmutated V gene, because of this lack of difference that was seen in terms of PFS for the mutated cases between the 2 treatment arms. I guess the question that I’d give to you is, what is the role of chemoimmunotherapy these days in the frontline setting? Where is it appropriate? Is there a very select patient population that it’s appropriate for? And who are those patients?
Anthony R. Mato, MD: I think a short answer to the question is [that] the role is diminished further still. For me the conversation regarding older patients has already moved beyond bendamustine-based therapy. So I feel like the ALLIANCE data confirmed what I was already doing and what I was already recommending was to not recommend VR for older patients regardless of their IGVH status. The younger-patient population, I think, will probably move again toward ibrutinib. But there’s that little footnote that we really didn’t have a significant difference in PFS with the IGVH-mutated patients. Although it’s hard for me to really think about that…as a critique, because it wasn’t powered to answer that question. And so it certainly favored ibrutinib, at least at the data cut that we saw so far. So I think the role is diminished. The only patients who we’ll even have the conversation with at this time are the young, fit, non-del17p, non-TP53-mutated patients who happen to be Coombs-[test] negative. That’s 5% of patients for me.
Susan M. O’Brien, MD: It’s a small percentage, but I think it still is relevant because even if—let’s just say at this point the ibrutinib looked a little bit better than the difference we saw here and was statistically significant, for the sake of discussion. I would still be cautious about offering ibrutinib to the patient who’s young, fit, and mutated. Because what I really want to know is their plateau on that curve with ibrutinib.
Matthew S. Davids, MD, MMSc: Totally agree.
Susan M. O’Brien, MD: There might be, but we don’t have the follow-up to know that, and that’s the group who really, with FTR, may be cured. Some of those patients probably are cured, and it’s difficult to give up what might be a cure fraction, or let’s even say they’re not cured but they get 17 years’ remission after 6 months of chemo, it’s hard to dispute that as a fantastic endpoint. So even if the curves were a little bit more separate now, it still wouldn’t, in my mind, address the plateau issue, which we’re going to have to have longer follow-up to know.
Anthony R. Mato, MD: So if a patient comes in and they’re like young, fit, all the characteristics we described, and they say, “Make the decision for me,” would everybody here decide on FCR or would they; if you could make the decision.
Matthew S. Davids, MD, MMSc: For mutated-IGHV patients, I would still use FCR. I think, based on these data for unmutated patients, I’d favor an ibrutinib regimen, probably not with rituximab based on our prior discussion.
Anthony R. Mato, MD: I agree with that.
Alexey V. Danilov, MD, PhD: I agree with that as well, and I would reiterate that for patients for whom I would consider FCR—young, mutated-IGHV patients—I also would perform next-generation sequencing. And if I find TP53 mutation, or NOTCH1 mutation, I would possibly also steer away from FCR in that setting.
William G. Wierda, MD, PhD: And I think it’s important to emphasize the point that Anthony was making, and that is, while it’s more routine for people to get FISH [fluorescence in situ hybridization] and to know 17p status, I think fewer people in the community are getting TP53-mutation status, and that is a very important characteristic to know about patients when selecting frontline [treatment] and treatment for relapsed disease.
Alexey V. Danilov, MD, PhD: Is there still a role for chlorambucil and obinutuzumab or obinutuzumab single agent in up-front therapy of CLL, older patients with CLL? I still occasionally use this regimen.
Matthew S. Davids, MD, MMSc: I do as well, and I think about the oldest, frailest patients who have significant cardiac comorbidities. Where I’m worried about ibrutinib in that particular population, I would still consider using it.
Susan M. O’Brien, MD: And then there’s also the patients who the finances are just problematic. You simply cannot. There are some patients you simply cannot give ibrutinib to because it’s not affordable.
Alexey V. Danilov, MD, PhD: It’s still a regimen associated with 26-month progression-free survival, which often is acceptable.
Matthew S. Davids, MD, MMSc: And about a 4-year time to next treatment as well.
Transcript Edited for Clarity