Therapy for Relapsed Follicular Lymphoma

Loretta J. Nastoupil, MD:At approximately 6 months after completion of induction, he’s undergoing routine surveillance imaging and is found to have a recurrence of lymphadenopathy. In regards to the size, mesenteric and axillary nodes are increasing—suggestive of disease progression. This is a patient that we consider to be poor risk, given the fact that he had a very short duration of response following completion of induction. And followed for our case vignette, this patient is returning at 6 months for routine follow-up. On surveillance imaging, he’s found to have increasing size of lymph nodes in both the mesenteric region and the axilla. A biopsy is pursued, confirming relapsed follicular lymphoma with no evidence of histologic transformation. These are the very important points.

Oftentimes, in patients who relapse early, there is concern that they have underlying large-cell lymphoma transformation that is driving those short remission durations. I think it’s very valuable to biopsy these patients for 2 reasons. One, to ensure that you know which type of lymphoma you’re dealing with, and secondly, before you commit them to more therapy, or sometimes more intensive therapy, to be certain that this is actually representative of lymphoma. Though rarely, occasionally we will biopsy patients and find underlying granulomatous inflammation or other sources of lymph node enlargement. I don’t biopsy patients at every relapse, but I think the first relapse, particularly if it’s a short duration of response, warrants histologic confirmation that you are dealing with follicular lymphoma. We can also go back and criticize why this patient did not receive maintenance rituximab. That’s something that’s commonly done, particularly following R-CHOP, based off of the PRIMA study. I think this is still a discussion to be had between a physician and the patient. We know maintenance rituximab will lead to an improvement in progression-free survival but no difference in overall survival. And I have found there are patients who would prefer not to be in the physician’s office and would prefer to have their time and forgo the maintenance, understanding that they may have a shorter remission period. I’ve also had patients who are concerned about when that first relapse will happen and are very satisfied with undergoing maintenance rituximab if there’s any chance that that first remission will be delayed or will be prolonged.

We’ve also learned recently from the Casulo paper, which was a retrospective analysis of the National LymphoCare Study, that patients who relapse early (defined as within 24 months of their diagnosis), most of whom received R-CHOP therapy and have an inferior overall survival. So, again, this identifies a high-risk population. And there’s been observations across prospective studies, including the PRIMA study, that about 20% of patients will relapse within 24 months, independent of whether or not they receive maintenance therapy. I still feel it is valuable for some patients to receive maintenance rituximab, or CD20 antibody, particularly if you would like to prolong their first remission period. But is unlikely to reduce a chance of that early relapse from recurring.

The other criticism of the Casulo paper is that there was not routine histologic confirmation that those were actually relapsed follicular lymphoma cases. How many of those patients actually had a transformation that were driving those inferior outcomes? Nonetheless, in an early relapse, we anticipate a high-risk patient—and one that should be thought of differently, given their overall survival or median overall survival—to be at only 5 years. Whereas the counterpart to that, though, is that relapse beyond 24 months. Their median overall survival is expected to be the same as their age and sex match cohort. As described by a colleague, they’re just as likely to make it to their 20-year high school reunion as their classmates.

How will we manage this patient with an early relapse? That’s currently an unknown, meaning there are studies that are being designed to address what the most appropriate management for an early relapse like follicular lymphoma is. There are prospective studies to guide us in, terms of management. The most recent study to be reported is the GADOLIN study, which enrolled patients who were relapsed/refractory to rituximab, meaning they had progressed or failed to respond within 6 months of their last course of rituximab—which this patient would have met those eligibility criteria.

That study was a randomized trial investigating obinutuzumab plus bendamustine versus bendamustine monotherapy, and a primary endpoint was progression-free survival. The patients in the arm that contained obinutuzumab also went on to receive maintenance obinutuzumab. This was a positive study, meaning the study met its primary endpoint of improvement in PFS if patients received obinutuzumab plus bendamustine, suggesting that you can overcome rituximab resistance with a next-generation CD20 antibody.

So, obinutuzumab and bendamustine is a reasonable option for this patient. There are also questions emerging as to whether or not chemotherapy is the preferred approach to a patient who relapses within 6 months of their last chemotherapy-containing regimen. Again, this is currently investigational. There are a number of agents that are emerging, such as immune modulators or targeted agents, and we can talk about some of the recent data surrounding idelalisib, which is reserved for patients who have failed at least 2 lines of therapy, including a chemotherapy and a CD20 antibody. I think transformation is something that should always be considered in a patient who is failing to respond, as we would traditionally expect, meaning they have a progression event that’s occurring within a short period of time. In regards to how you should work up a concern for a transformation, I think it is reasonable to pursue a core needle biopsy, as that’s the most efficient and convenient approach for patients. We are not routinely pursuing excisional biopsies at this time. I think excisional biopsies are still incredibly helpful, and if the morbidity is worthwhile, it should be considered. But we’re relying heavily on core needle biopsies in that setting.

Transcript edited for clarity.

February 2015

• A 44-year-old man presented to his physician with submandibular swelling. He reports losing weight over the past few months.
• Excisional biopsy showed grade 2 follicular lymphoma that was positive for CD20, CD10, Bcl-6 and Bcl-2 co-expression, and t(14;18); KI-67, 15%
• Imaging showed widespread lymphadenopathy and a large mesenteric mass measuring 11.2 cm
• LDH elevated (400 U/L), stage IV follicular lymphoma with bone marrow involvement
• The patient was started on R-CHOP
• PET/CT imaging at end of therapy was consistent with a complete remission.

November 2015

• Follow-up PET/CT at 9 months showed increasing size of the mesenteric mass and progression in the axillary lymph nodes.
• A biopsy was pursued at that time confirming relapsed follicular lymphoma.
• The patient was initiated on obinutuzumab + bendamustine with plan for obinutuzumab maintenance.

October 2016

• Eleven months later, the patient reported having fever and fatigue along with increased swelling in the submandibular node.
• PET/CT showed widespread progression with increased size of the mesenteric mass to 12.5 cm and 3 new lesions (3.2 cm, 2.4 cm, 1.8 cm) in the inguinal region.
• The patient was started on therapy with idelalisib.
• He experienced severe diarrhea from this treatment which was successfully managed with enteric budesonide and systemic corticosteroids.