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Making Progress Toward Predicting Early Relapse in Follicular Lymphoma

Danielle Ternyila
Published Online:5:03 PM, Wed March 20, 2019

Carla Casulo, MD

One of the most vulnerable subsets of patients with follicular lymphoma (FL) are patients that have early recurrence, according to Carla Casulo, MD. In a presentation at the 23rd Annual International Congress on Hematologic Malignancies, Casulo addressed some of the challenges physicians face in managing patients with relapsed/refractory FL.

Patients who relapse within 2 years of initial treatment have poor outcomes, and as such, clinical trials and novel therapies should focus on this patient population and on identifying which patients will fall into this group, said Casulo. During her presentation, Casulo, associate professor in the department of medicine at the University of Rochester Medical Center, addressed the unmet need in predicting response to treatment.

In an interview with Targeted Oncology following her presentation, Casulo discussed challenges in the management of patients with relapsed/refractory FL. She also highlights where she sees the field heading based on ongoing research.

TARGETED ONCOLOGY: What are the current approaches to treating patients with relapsed/refractory FL?

There are many different treatment options for patients with relapsed/refractory FL. That includes standard cytotoxic chemotherapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or bendamustine with either obinutuzumab or rituximab (Rituxan), but they also include some novel targeted agents such as lenalidomide (Revlimid) or the PI3K inhibitor class, of which there are drugs currently approved.

TARGETED ONCOLOGY: What are the challenges in treating patients with relapsed/refractory disease?

The challenges in treating patients with relapsed FL surrounds the fact that there is no clear way to distinguish who will do poorly after their treatment, and there’s no way to really know how to have biomarkers to response to treatment. Right now, with all the different treatments that we have, we might treat someone based on when they recurred. If they recurred early, then you might consider treating those patients more aggressively. If the patient is a little older, you might consider treating them more gently. But for patients who have standard relapsed/refractory FL, given the plethora of options, there is no clear way to say this treatment will be more efficacious in that patient because we don’t have predictors of response to those treatments. I think that is a huge unmet need right now.

TARGETED ONCOLOGY: What were the main points of your talk?

The main points in my talk are focusing on the at-risk population that has relapsed FL. I focused on the research that we did looking at patients that have early disease recurrence. That’s really one of the most vulnerable populations in FL because they have poor outcomes. Patients that relapse within 2 years of their treatment have poor outcomes, but when we compare that to patients who did not relapse during that time, they actually have very favorable outcomes, so you really want to try and focus your clinical trial options and novel therapies on the group of patients that have early relapsed disease. That’s one of the key features of my talk, to help the audience and clinicians understand what are the factors that help to predict patients who have early relapse and what are the treatment options in this space.

The other thing that I talked about was the recently completed AUGMENT study that was presented at ASH last year. The doublet of lenalidomide with rituximab is getting an accelerated FDA approval, and that has been tested in patients that were relapsing on one or more treatments but were not rituximab-refractory. That study met its primary endpoint which was benefit in progression-free survival (PFS) compared to rituximab alone, and there was also an improvement in overall survival (OS). Those are some of the main important teaching points from the talk.

TARGETED ONCOLOGY: What are some of the current factors used in deciding treatment for these patients?

There are several different factors that help us predict risk in FL. At the time of diagnosis, you have the Follicular Lymphoma International Prognostic Index (FLIPI) score and FLIPI2, and those are prognostic markers that help you understand who with FL will have better or worse outcomes. We are now refining those prognostic factors a little bit better with the incorporation of molecular data; there are certain mutations and genes that modify gene expression, such as epigenetic markers. When you combine that with clinical factors, you can now have a better ability to refine prognosis in patients at the time of their diagnosis. That is called the M7FLIPI. This is a third way that we can prognosticate patients.

There’s also emerging data looking at PET-adapted, or incorporation of PET, total metabolic tumor volume in the frontline diagnostic space, to again try to refine who with FL will do better or worse. Ultimately, that’s going to help you treat patients based on risk. Currently, we base treatment for patients based on how much disease they have, but not necessarily how at-risk they are. This is something that will continue to evolve hopefully in the next few years.

TARGETED ONCOLOGY: What are some of the ongoing clinical trials in relapsed/refractory FL?

Research going on right now is revolving largely around novel therapies. There are dozens of new treatments that are being studied that target several different molecular markers that target molecular targets that are small targeted molecular inhibitors of various intercellular pathways. The B-cell receptor has several downstream targets, and that is where the PI3K inhibitors come into play. There’s also BTK inhibitors and other anti-CD20 monoclonal antibodies that are being studied, so that’s a huge area of research that is being looked at, novel treatments.

The other area that is being looked at is the combination of various novel treatments. What goes with what in order to minimize toxicity but improve response rates and duration of response? That’s another really important area that’s being studied.

Recently, there was a large randomized study that was looking at frontline therapy for patients with FL, randomizing patients to R2, which is lenalidomide and rituximab, versus chemotherapy. That study was meant to try and establish non-inferiority of this regimen versus standard chemotherapy. We found that they are not dramatically different. There was a slight improvement in outcomes with one versus the other, but in general, that’s not changing the standard practice too much. However, that’s another area that is being actively looked at [to determine] what are new treatments that we can use at the time of diagnosis for these patients.

New treatments at the time of diagnosis, new treatments either alone or in combination at the time of relapse, and then the area that I’m focused on is specifically trying to identify who will benefit most from what treatments in order to really try to home in and offer precision approaches to patients.

How do you see the field evolving going forward?

In the next decade, I think that there will be a more precise approach to patients with FL. That’s based on some of what’s currently going on, which at the moment is research-based. As I was saying earlier, the M7FLIPI and other gene expression profiling that is being done in the research realm, hopefully will move towards the more practical applicable setting for clinicians so that we can learn who needs what treatment based on what we know about their biology and other things, not just tumor burden, disease stage, and other things like that. I think that will help refine things a little bit better.

I see the field going in that direction, and I think we may find that treating patients with less toxic drugs is better than treating them with numerous drugs that have overlapping mechanisms of action, because FL patients can live up to 20 years, which is a pretty remarkable feat given that this is still a cancer. You really have to try to be very nuanced in order to not limit some of their survival, but also offer them the best chance at reaching those 20 years or more.

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