Richard R. Furman, MD, Discusses Ibrutinib Versus FCR for Patients With CLL

Richard R. Furman, MD, Morton Coleman, MD, Distinguished Associate Professor of Medicine, Director of CLL Research, Weill Cornell Medical College, New York, NY, discusses ibrutinib compared with the standard chemoimmunotherapeutic regimen of intravenous fludarabine, cyclophosphamide, and rituximab (FCR), for patients with CLL.

Richard R. Furman, MD:  We've heard a lot of data over the past several years regarding FCR and ibrutinib, mostly as Phase 2 data. We really haven't heard much about comparative, head-to-head data.

This past ASH, we finally have the beginnings of two studies. One was a line study looking at FCR versus IR versus ibrutinib as a single agent in patients over the age of 65.

We also heard from an additional group, ECOG, looking at patients who are younger than 70 years of age being treated with either FCR or IR.

Both these studies are actually very important because they really are trying to answer the important question regarding whether or not ibrutinib or fludarabine-based chemotherapy should be our first-line therapy for patients with CLL.

One of the important things about these studies to keep in mind is the follow-up is relatively short. Both of these studies presented data that had a median follow-up of approximately two years.

While we certainly are very comfortable with the acute side effects of both of these agents, the long-term side effects really may play an important role in determining which agent is better for our patients.

One of the features about ibrutinib is the adverse events when they do occur are quickly reversible. With fludarabine-based chemotherapy that may not be true if the patient develops a secondary MDS or AML, or has an overwhelming septic event and actually dies of sepsis. In those regards, it's important that we think about what's going to be most important to our patient's long term.

Looking at the ibrutinib Phase 2 data, we actually show a six-year, progression-free survival on a treatment-naive group of patients at 88 percent. When we look at the FCR300, which is 300 consecutive patients treated with FCR at MD Anderson, we actually see a 30.9 percent progression-free survival at 12.8 years.

On the face of it, we have two very, very different outcomes for groups of patients. One could certainly extrapolate that the ibrutinib group may actually do better long term.

Looking at the FCR data though, it's important to acknowledge that the 30.9 percent plateau that we see at 12.8 years, 74 percent of those patients are immunoglobulin gene-mutated. When we look at the mutated patients specifically, it turns out that 50.3 percent will be free from progression at 12.8 years.

We now have a regimen of mutated patients who get FCR and have a 50 percent chance of being free from progression at 12.8 years, or treating with ibrutinib, which has an 88 percent freedom from progression at 6 years.

While there's no difference in outcome based on mutation status for ibrutinib, the question is, is whether or not given the overwhelmingly beneficial role of being mutated and receiving FCR chemotherapy whether or not that should play a role in choosing therapy and indicating whether or not fixed duration, six months of therapy would really be advantageous for patients with CLL.

My belief specifically is I do worry about the long-term adverse events, and I do worry about patients who receive FCR developing late effects in terms of worsening MDS and AML.

I do use ibrutinib upfront in my patients. One of the important new regimens that I think may actually play a role in the very near future will be the combination of ibrutinib plus venatoclax, which may afford a fixed duration of a year of combined therapy and achieve very, very deep remissions without the toxicities of chemotherapy.

For patients who are interested in fixed duration and avoiding taking a pill a day -- who have concerns over the bleeding and atrial fibrillation associated with ibrutinib, who would normally have chosen FCR -- one of the possibilities is whether or not we may have an option of doing shorter duration of IR and whether or not that would eliminate those adverse events.