High-Risk Follicular Lymphoma

Loretta J. Nastoupil, MD:We have a 44-year-old male who presents to his primary care physician’s office with submandibular swelling. This is associated with approximately a 20-pound weight loss over the preceding 2 months, which he attributes to lack of appetite. He is referred to me in T-position and undergoes an excisional biopsy revealing a low-grade B cell lymphoma with a phenotype of CD10-postitive, CD20-positive, BCL2 overexpression, and translocation 14:18. The proliferation index is described as approximately 15%. There’s no clear evidence of large-cell lymphoma present on the excisional biopsy. The patient completes the staging assessment and has adenopathy above and below the diaphragm, but notably, he has a bulky mesenteric mass approximately 11 cm in size and bone marrow involvement.

To summarize, this is a young male with stage 4 follicular lymphoma with bone marrow involvement who has a high tumor burden based on the GELF criteria. Therefore, he is in need of therapy. His medical oncologist chooses to treat this patient with R-CHOP chemotherapy. He has an excellent response and his end-of-therapy PET/CT reveals a complete response. In regard to his lab assessment, there is no evidence of cytopenia. The patient’s LDH is elevated at 400, with the 200 being the upper limit of normal.

I’ve studied practice patterns for untreated follicular lymphoma in the United States, and I can tell you there has been a recent change in the trend. Patients that were treated in the early 2000s were most commonly treated with R-CHOP—that was the preferred regimen. And if you look across prospective studies in Europe where they were given a choice, R-CHOP was chosen about three-quarters of the time over others. That’s changed, recently. It’s been rapidly replaced by bendamustine and rituximab, given the recent results of the GADOLIN study. We’ll be interested to see if obinutuzumab and bendamustine becomes the preferred frontline approach to follicular lymphoma. There are a few prospective studies that address this question. The most common being the Rummel data, which was a randomized study comparing R-CHOP to bendamustine and rituximab. It demonstrated that bendamustine and rituximab was associated with a superior progression-free survival though there was no difference in overall survival.

More recent data have emerged. As I mentioned, the GADOLIN study was a randomized trial looking at obinutuzumab plus chemotherapy. It was investigators’ discretion whether they chose CHOP, CVP, or bendamustine versus R-CHOP, R-bendamustine, R-CVP. And that was recently reported at our ASH meeting, demonstrating there was a benefit if you received the obinutuzumab in combination with chemotherapy followed by obinutuzumab maintenance in regards to an improvement in progression-free survival. I would also comment that most commonly, in the United States for untreated patients, they’re receiving chemotherapy/immunotherapy as their preferred frontline approach, I think sometimes independent of the GELF features.

For this patient, he received R-CHOP. And to put this into context, this patient was treated in February of 2015, which is still in the more modern era where bendamustine and rituximab are being outprescribed over R-CHOP. But there may be some features about this particular case that may have led to that choice. For instance, the LDH was elevated. This is a young patient presenting with associated symptoms, which may imply to the treating physician that this is a more aggressively behaving follicular lymphoma. And for those of us who treat follicular lymphoma, we do know that there’s great heterogeneity in terms of presentation. There are patients that will, oftentimes, present as grossly asymptomatic but have incidental findings of adenopathy on imaging versus those who come into a physician’s office because of symptoms that have prompted the workup.

I think R-CHOP is still a reasonable choice for patients as frontline, but usually, there is some criteria or characteristic about the patient or the presentation that will lead to that choice over bendamustine, or a NCD20 antibody, because traditionally, we thought that bendamustine had a more favorable or a different side effect profile that is oftentimes well received by patients (meaning their change in symptom burden is less dramatic). They have less alopecia and less cytopenias. Their prolonged cytopenias, in rare instances, have been reported. What may have led to the decision in this patient to prescribe R-CHOP may have been based on the fact that his LDH was grossly elevated. He was a young patient presenting with aggressive symptoms in terms of weight loss and bulky disease. We are confident that this is a follicular lymphoma, at least based on the tissue that was sampled. It was an excisional biopsy, so we feel there should be little in the way of sampling error. But we always worry that maybe we didn’t sample the most appropriate lymph node. I think this is where PET can be very valuable at presentation to discern whether or not there’s discordance in SUVmax across the various lymph nodes that are abnormal. We do not know the specifics about this case, but we can assume that the SUVs were very comparable across the lymph nodes and the lymph node that was sampled was the safest to sample.

We will assume that if there are no dramatic differences across SUVs, that the safest lymph node to go after will be representative of the additional site, and we also know, in this case, that he also had follicular lymphoma in the bone marrow. So, we have 2 separate samplings that revealed follicular lymphoma. Nonetheless, it is reasonable to consider R-CHOP, if there is a concern for an underlying aggressive histology that was not identified on the initial diagnostic workup. The end-of-therapy PET, being negative, is also prognostic. There are recent data that have emerged comprising an analysis of 3 prospective studies looking at an end-of-therapy PET, and most of those patients were treated with chemotherapy/immunotherapy in the prognostic value. If you achieve a negative PET at the end of induction, not only do you have an improvement in duration of remission, but there is also an improvement in overall survival for these patients. That is valuable information.

It is still valuable to discern the FLIPI score in this patient. It is not as valuable in terms of choosing one chemotherapy/immunotherapy regimen over another, but it may have implications in terms of how closely we watch this patient now that he’s achieved a complete response following the end of induction. So, this is a high-risk FLIPI patient based on the fact that he is advanced-stage. His LDH is elevated, and he has more than 4 nodal sites involved. We have learned that the low to intermediate risk FLIPI patients do quite well, and there’s probably very little difference between those groups. But for the high-risk FLIPI patients, their overall survival is inferior. And currently, there is still an unmet need in follicular lymphoma. What we’re not very good at, at this point, is discerning if something other than chemotherapy/immunotherapy would be the preferred approach or, for instance, if R-CHOP is superior to bendamustine and rituximab, given the fact he has a high-risk FLIPI.

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.