Follicular Lymphoma: Selecting Therapy at Relapse

Ajay K. Gopal, MD:This patient was treated with bendamustine and rituximab, but, unfortunately, 18 months later, he presented to the clinic with weight loss and fatigue. You evaluate him with imaging, and you find out that he does indeed have progressive adenopathy, suggesting recurrent disease. One thing that’s not pointed out in this case is whether or not he had an additional biopsy, and I’d like to make the point that particularly in patients who have short remission durations and patients who possibly have symptoms, it’s not completely clear here. We typically try to rebiopsy and make sure there hasn’t been transformation to diffuse large B-cell lymphoma. That would have a very different treatment algorithm than a grade 1/2 follicular lymphoma. Nevertheless, this patient was treated with R-CHOP, and it appears that he received 2 cycles but unfortunately had complications of symptomatic anemia.

This patient did achieve a partial remission apparently to 2 cycles of R-CHOP but really didn’t tolerate it very well. So, a couple points regarding that. It’s pretty unusual to not tolerate R-CHOP, so I would probably evaluate this patient’s bone marrow. Does the patient have MDS? Is there something else going on? This history of CMV also is a little strange in this case. Does he have some other immunodeficiency that is further complicating this patient’s therapy? So, quite unusual for a 62-year-old who is otherwise presumably healthy to not tolerate R-CHOP.

At every relapse of follicular lymphoma, we always ask the same question: Does this patient require therapy? Because we can still have prolonged periods of watch-and-wait, even if we know patients have relapsed. And I know we’ve all had, in our clinics, patients who we know they’ve had recurrent disease but they’re asymptomatic and we can watch them for many months or even years. This patient appeared to be symptomatic with fatigue and weight loss and does appear that there’s an indication for treatment.

The other question that comes up, and we know more about this now, is what is this patient’s prognosis? We were able to prognosticate, to some degree, from the FLIPI score at the beginning. We actually have a bit of better predictive data now based on the short remission duration. There were some very nice studies done by Dr. Casulo and colleagues looking at early relapse, and she was able to show that patients who relapse within 24 months of their initial chemoimmunotherapy, with the caveat that not only patients had bendamustine and rituximab in that data set, had a very poor prognosis. Their median survival was only about 5 years. Fortunately, this was only about 20% of the patients and about 80% did well. And those who didn’t relapse within the first 2 years did very well, and other subsequent studies have shown that this population has survival similar to age match controls.

So, we learn a lot from the initial remission duration in terms of what we expect to happen in the future. About 80% of the patients do well. Those are the ones where we really want to have restraint. We want to not overtreat those patients, treat them with probably gentler therapies. And for the 20% who have early relapse, those are the ones where more of the same is not going to solve the problem. This gentleman is now presumably only about 63 or 64 years old and with a 5-year survival, that’s not anywhere close to the expected survival for this patient. So, in these patients, I think most of us in the field say we need to do something different. We offer a clinical trial, novel agents, think of high-dose therapy and autotransplant, maybe even think of things like CAR T cells. These are the kind of discussions that we have with patients with these early relapses. We don’t know what the exact right answer is, but we know that more of the same does not lead to good outcomes.

The choice of R-CHOP in this patient was reasonable, but I probably would not use that as a standalone. I wouldn’t expect to get much remission duration unless there was a suspicion of transformation out of R-CHOP. Having only gotten 18 months out of bendamustine/rituximab in a 63- or 64-year-old patient, are we going to consolidate that R-CHOP now with an autotransplant or is there some other strategy to try to maintain that remission?

Another unusual point of this case is that the patient developed anemia after R-CHOP, which is not a major problem typically with R-CHOP. So, I would investigate that. We don’t have any other comment on the other cell lines in terms of thrombocytopenia or neutropenia; potentially look at his bone marrow, make sure he doesn’t have some early MDS. But other than that, we often would just transfuse patients to support their anemia.

Transcript edited for clarity.

January 2016

• A 62-year-old male presented with left axillary lymphadenopathy
• PMH: DVT managed on warfarin, CMV infection
  • Laboratory findings: CBC count and LDH WNL
  • Excisional biopsy, IHC staining CD10+, grade 2 follicular lymphoma
  • PET/CT, multicompartmental adenopathy and splenomegaly consistent with stage IV disease
  • Bone marrow biopsy, 30% involvement
  • FLIPI 2 (intermediate-risk)
• The patient was started on bendamustine + rituximab (6 cycles)
• She achieved an unconfirmed complete response

June 2017

• 18 months later, he developed recurrent cervical adenopathy with weight loss and fatigue
• Imaging revealed adenopathy in 2 cervical lymph nodes (4.6 cm and 2.4 cm), a mediastinal node (2 cm) and left inguinal node (3.1 cm) with splenomegaly.
• The patient was treated with R-CHOP
• After 2 cycles he developed anemia and grade 2 fatigue
• He achieved a partial response

November 2017

• Five months later, the patient reports feeling tired and abdominal fullness
• Physical exam remarkable for palpable splenomegaly
• Laboratory evaluation showed marked anemia, thrombocytopenia
• PET imaging showed enlargement of pelvic and retroperitoneal nodes and development of several new mediastinal lesions
• Repeat biopsy showed grade 3 follicular lymphoma, 90% bone marrow involvement
• The patient was started on idelalisib therapy
• After 2 months on therapy, he developed grade 3 colitis which was managed
• After four months on therapy, the patient has stable disease