Case 4: iFCR in Untreated CLL

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

William Wierda, MD, PhD:Matt, can you comment on your work at Dana-Farber Cancer Institute, in terms of chemoimmunotherapy with a small molecule inhibitor—particularly on your results with your iFCR regimen?

Matthew S. Davids, MD, MMSc:The iFCR study, at first glance, may sound somewhat similar to what we just heard about with iFCG. But there are some key differences. It’s nice. Both of these studies are running in parallel, and we’re going to answer some different questions. So, with iFCR, we really had a couple of fundamental questions that we wanted to ask. The first was, what does ibrutinib add to FCR? FCR is a regimen that we really have a lot of historical data for, going back 15 years or more. One of our key questions was, would ibrutinib help to overcome some of the negative prognostic markers that we traditionally have associated with FCR—in particular, the unmutated IgHV status? When we started the study, we were also interested in seeing whether this could overcome the poor prognosis of deletion 17p. So, we actually included some patients with deletion 17p, knowing that they may not have a good response to FCR alone. Perhaps, with ibrutinib, we could overcome that?

In this multicenter study, we’ve now enrolled 35 patients. We reported on this study at the recent ASH meeting. These patients were treated with the usual 6 cycles of FCR, and the median number of cycles received was 6. So, most patients were able to get through all 6 cycles. I think it’s important, in both of these studies, to highlight that these are all younger, fit patients. All the patients in our study were age 65 or younger. In our study, we did start with growth factor support as a mandatory thing from the beginning, along with aggressive antimicrobial prophylaxis.

We’ve got just under 2 years of follow-up on our patients, and we have seen very striking efficacy. All the patients did achieve the IWCLL response—with about a 63% rate of complete remission. The primary endpoint of our study was pretty stringent. It looked at the rate of complete remission and bone marrow MRD-negativity—so both factors together. And there we saw about 37%, which compares favorably with the German CLL Study Group. They saw about 20% in their CLL8 study. In our study, one of the things that was striking was that we allowed patients to continue on ibrutinib maintenance for up to 2 years after finishing FCR. We noticed that responses would deepen over time. This rate of CR with bone marrow MRD-negativity is now approaching 60%.

Probably the most striking finding of our study is, when looking purely at the bone marrow, the MRD-negativity rate was 833%. This is a study that included patients with deletion 17p and patients with unmutated IgHV. And as far as we know, this is the highest rate of bone marrow negativity that we’ve seen with a CLL regimen that includes all the different risk populations. Unfortunately, all 4 of the patients with deletion 17p did not achieve MRD-negativity. And so, as we’ve expanded the study going forward, we have decided to exclude those patients. But outside deletion 17p, looking at even the patients with unmutated IgHV, they’ve done very well with the iFCR regimen. About 70% of them have achieved MRD-negativity in the bone marrow. These are all kind of surrogates. We’re going to be most interested in the progression-free and, ultimately, overall survival, which is going to take time. But certainly, we know, historically, with the FCR regimen, MRD rates correlate nicely with progression-free survival and overall survival. So, I do think it’s a good surrogate for that.

William Wierda, MD, PhD:Did you give routine growth factor for patients on this study?

Matthew S. Davids, MD, MMSc:We did. The rates of neutropenia were around 30% or so, so I think that did help mitigate that. We saw relatively few serious infections, so I think that’s been a successful strategy. I think it’s kind of a combination of the mandatory growth factor, the infective prophylaxis, and then, also, the selection of the patient population to a young, fit population.

William Wierda, MD, PhD:May you comment on the infection prophylaxis?

Matthew S. Davids, MD, MMSc:Yes. We do PJP prophylaxis—typically Bactrim, if patients can tolerate it, or atovaquone, if they can’t. We use acyclovir or valacyclovir for HSV VZV prophylaxis. We do not routinely do antifungal prophylaxis. There have been some fungal infections described in patients on ibrutinib. We haven’t seen that in our study, but certainly it is a risk factor that we’re looking for.

William Wierda, MD, PhD:For this favorable-prognosis patient, having a mutated V gene and being young, we’re still interested in chemoimmunotherapy. I think there is still value in exploring it. Our approach has been to minimize the exposure to chemotherapy while still trying to achieve the same results. Nitin, what does the future hold? Where are we going with treatments? Can you comment on the abstract that you presented at ASH, in regard to the small molecule inhibitor combinations? What does that look like, and how may that relate to this type of patient?

Nitin Jain, MD:Sure. We just talked about chemotherapy and chemoimmunotherapy in combination with targeted therapy. But certainly, there are drugs such as ibrutinib, venetoclax, and others, and there are regimens that are combining these. A year and a half ago, our group initiated a combination of ibrutinib plus venetoclax as a strategy for both patients with relapsed/refractory CLL as well as patients with frontline CLL. In the frontline cohort, we recruited only patients who were at high risk. This is different from this patient, particularly, and the patient population that we discussed for the iFCG and iFCR studies.

For the ibrutinib/venetoclax study, 90-plus percent of the patients were relapsed/refractory. Ninety-plus percent had a deletion 17p, a deletion 11q, or an unmutated V gene. So, they were high-risk patients. Among that group of patients, for the first few months that we gave ibrutinib, the tumor volume decreased when we added venetoclax—at month 4, venetoclax was added. After adding venetoclax, we saw a high rate of MRD-negativity as well as a CR rate that improved with time with ongoing therapy. So, the trial stipulates 2 years of venetoclax. For patients who are MRD-negative, ibrutinib is also stopped at 2 years.

In my opinion, the results are very exciting for treatment in the frontline setting for high-risk patients. One could argue whether similar results could be achieved with the use of the combination in patients who are mutated. There are several other trials with a combination regimen, not just with ibrutinib/venetoclax, that are ongoing in the frontline setting. In the next few years, based on those regimens as well as several ongoing randomized studies, we’ll know more about a potential role for that subset of patients.

William Wierda, MD, PhD:Matt, do you have anything to add, in regard to the new small molecule inhibitor combinations?

Matthew S. Davids, MD, MMSc:The data that we saw at the ASH meeting, including your data and several other studies, were very exciting. The iFC-based regimens that we just talked about really only apply to a smaller subset of the youngest, fittest patients with CLL. The promise of the novel agent-only combinations is that those are regimens that many more patients with CLL could be eligible for. They may be more tolerable and could provide patients with great results. With the novel agent-only approaches, the durability of response remains to be seen. The follow-up does remain short, and we sort of assume that these deep responses will be long-lived—as they were with chemotherapy. We won’t know about this, for sure, until we have longer-term data. So, it’s important that we are pursuing both chemotherapy novel agent combinations as well as novel agent-only combinations. Time will tell—as to what the optimal regimens for patients are.

Transcript edited for clarity.