Optimizing the Sequencing of Therapy in Follicular Lymphoma

Panelists use an illustrative clinical case to comprehensively discuss the selection and sequencing of therapies for patients with follicular lymphoma.


Bijal D. Shah, MD, MS: I want to kind of jump into a case, and, as I did before, I’m going to pick on Ian to help guide some of the key observations from the case. A 57-year-old female presenting with symptomatic follicular lymphoma, is one of these cases where we see, yes, it’s a grade 1 to grade 2, but a very high proliferative rate, call it 90% to 95% diffuse pattern, one of these more progressive histologic patterns in the lymph node. [The patient] started on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone] because of these features, and again, perhaps because of the concern for perhaps missed transformation. The patient does well, but 18 months later, relapses. They receive bendamustine and obinutuzumab in combination. A year later, progressing again. At that point, they have moved to a combination of rituximab and copanlisib; 6 months later, progressing again, and now, initiated on CAR T [chimeric antigen receptor T] cell therapy with axicabtagene.

Thinking about that paradigm, are there features or high-risk features more specifically that you can point to beyond the histologic patterns that say, “You know what, there’s something here that doesn’t make sense, and are there other things that we should have looked for to help guide what ultimately occurred?” And the last question, what would you have done differently?

Ian W. Flinn, MD, PhD: Yes, a lot to talk about there. The first high-risk feature is that the patient progressed within 24 months of the initial therapy, so the so-called POD24 [progression of disease within 2 years]. We know that that patient population is very different from the rest of patients with follicular lymphoma. For many patients with follicular lymphoma, as we discussed earlier, many people have nearly a normal life expectancy. But for those early progressors, so those POD24 patients, we know that, unfortunately, they are going to have a shortened survival. And I think we’ve also talked about, Caron mentioned this natural history, that every therapy we give someone, the duration of remission gets shorter and gets shorter. And this is what’s recapitulating this patient, right? Hence, a lot of this was predictable.

There are the biological features that you’ve talked about, the high Ki67 and so forth. Sometimes, I biopsy patients and the pathologists come back and tell me this is grade 1 to 2, and I feel like someone forgot to tell the lymphoma because it’s certainly not behaving that way. I think this is a great example where, in retrospect, maybe getting out of the normal paradigm of just giving subsequent therapies, especially in a younger patient and moving CAR T cells much earlier in the natural history of the disease, makes all the sense to me. We know that that’s just going to get worse for this patient, and by changing it up and using CAR T cells, we have a chance to perhaps change that.

Bijal D. Shah, MD, MS: Wonderful. I’m curious, is anyone at the table customarily doing next-generation sequencing in follicular lymphoma? We had, years ago, the m7-FLIPI [m7-FL international prognostic index] that came out to say, “Hey, here’s some high-risk molecular features.” We talked a little about EZH2 mutations and how they may guide the use of tazemetostat. Is anyone customarily doing this for their follicular lymphoma patients? I can tell you again, rather foolishly perhaps, that I’m not doing it, certainly not at diagnosis.

Brian T. Hill, MD, PhD: I don’t think that we can say that it’s actionable in the frontline setting. Some of these molecular signatures were studied in the sort of R-CHOP era and there are more additional studies being done in the bendamustine era. I do think that it’s worth knowing the EZH2 status of any relapsed follicular lymphoma patient, and that’s something that is routinely available or can be sent out. EZH2 is also included on some of the panels that are available from Foundation Medicine and other groups. You may sometimes get other information, TP53 or other things, from those panels that again might sort of sway you in one direction or the other. Thus, I think it’s worth doing in the relapsed setting, but we are not doing it routinely in the frontline.

Bijal D. Shah, MD, MS: Michael, are you guys sequencing everyone?

Michael Wang, MD: For some of the high-risk [patients], we have the study group to study, to approve everything. Thus, we are working on follicular lymphoma. We have already a lot of genes approved for mantle cell lymphoma, so we’re working on Hodgkin lymphoma and others. Sooner or later we’re going to sequence all.

Bijal D. Shah, MD, MS: Wonderful. Caron?

Caron A. Jacobson, MD, MPH: We aren’t. I mean, the m7-FLIPI came out of a collaboration from Dana Farber [Cancer Institute] with a site in Germany and looked very, very good as being prognostic for responses to R-CHOP and then it was subsequently looked at [to determine] if it was prognostic following BR [bendamustine plus rituximab] and it wasn’t. I think some of the hypotheses about this is that it may actually pick up patients that actually have transformed disease, so that led to better outcomes than expected with R-CHOP. Right now, I think we’re really missing a good prognostic tool for patients with follicular lymphoma at diagnosis. I think our best tools are based on their response to frontline chemotherapy, their lack of complete response to frontline immunotherapy, or early relapse. I think those are the patients that it would be great to know if we could identify those patients before they get chemotherapy and even maybe move some of these other therapies up much earlier in the line of treatment.

Bijal D. Shah, MD, MS: Great. Ian, I don’t know if you have anything to add.

Ian W. Flinn, MD, PhD: Not much to add. I think we have a very similar approach. We don’t generally do it in the frontline setting, just because I’m not sure what to do with the data. But I hope that Caron’s wish there comes true that we do finally know how to…

Bijal D. Shah, MD, MS: That we’re able to do it and integrate it and learn from it.

Caron A. Jacobson, MD, MPH: I do have one question though. You asked Ian if there was anything he would have done differently for this woman. We already knew she relapsed within 24 months and then she had a good response to bendamustine-obinutuzumab. What about autotransplant in that setting? Because it is still [responsive], and Carla Casulo, MD [at the University of Rochester Medical Center] has shown that for these patients, if they get an auto transplant in second remission, about 50% of them will have a response that lasts more than 5 years.

Bijal D. Shah, MD, MS: That’s a great question.

Caron A. Jacobson, MD, MPH: Yes.

Ian W. Flinn, MD, PhD: Yes, so I certainly think it’s a reasonable approach. I haven’t been doing as many autotransplants in follicular lymphoma that I used to do, and I guess I’m much more excited about the potential for CAR T cells in this setting; it’s certainly a reasonable approach.

Caron A. Jacobson, MD, MPH: Yes, I agree. I mean, I think it was the approach I had taken before we had good options in the third line, but now that we have better options in the third line, I tend not to do it.

Bijal D. Shah, MD, MS: Great. Michael or Brian, would either of you have recycled the rituximab? We had R-CHOP, maintenance rituximab progressed, BENDA [bendamustine], obinutuzumab, I mean we usually think of this, we call them Rituxan refractory but are they ever?

Brian T. Hill, MD, PhD: Yes, I think that people do lose response to rituximab and there are some data that obinutuzumab can overcome that. That being said, I don’t think it’s wrong to add it, in this case it was with copanlisib or R2. There are reasons to think you might get synergistic activity.

Michael Wang, MD: Sometimes, when we have relapse and we see it at biopsy, we ultimately see CD20 inactive, so those cases I would not use Rituxan.

Bijal D. Shah, MD, MS:Interesting. It’s a good point.

Transcript edited for clarity.

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