Follicular Lymphoma: Selecting Frontline Therapy

Peter Martin, MD:In a case like this, one of my first biases is to try to get away with the least intensive therapy possible. The main consideration in all these cases has to be, what is the goal of therapy? And the goal in follicular lymphoma, outside rare cellular therapy scenarios, is not to cure somebody but to prolong survival and to minimize symptoms related to lymphoma and to minimize symptoms related to treatment. In this case, she already has some symptoms related to lymphoma. It’s likely that she’ll develop worsening symptoms related to lymphoma on the basis of adenopathy and cytopenias.

So, it’s reasonable to initiate treatment. Is it reasonable to start with single-agent rituximab? I think oftentimes that would be a reasonable consideration in somebody like this. Single-agent rituximab has the advantage of being really well tolerated in somebody like this and in somebody who’s, for example, working. Somebody who’s 57 probably has not retired, may be working. They may be more inclined to choose a less intensive therapy and continue going about life as usual. On the other hand, you could argue that rituximab is going to take a little bit longer to work if the facts are not going to be quite as durable. And this patient may prefer something that’s going to work more quickly and will have a more durable effect and result in a longer treatment-free interval. And that’s also reasonable. Under those circumstances, bendamustine and rituximab would absolutely be a reasonable first-line consideration.

The other therapy that would be most commonly considered would be R-CHOP. I think most of us tend to reserve R-CHOP for people who we suspect may have undergone some sort of transformation, which we don’t consider in this space.

And then most recently, there are data from the GALLIUM study that were presented at ASH 2016 and were more recently published that suggest that obinutuzumab could be substituted for rituximab, both in combination with bendamustine, R-CHOP, or CVP. And that prolongs progression-free survival. That comes at the expense of a little bit of toxicity, primarily infusion reactions, a little bit more neutropenia and infection, which I think bendamustine—rituximab is a reasonable choice for this lady.

Maintenance therapy is an interesting consideration, and you can probably get 20 physicians who all say the same thing in the room and then treat their patients differently. And I think that’s a reflection of the fact that we’re all trying to do the best things for our patients, but all our patients are a little bit different. And how do you put together the lymphoma-related information, the patient-related information, and the data from clinical trials and people’s preferences?

So, the PRIMA study was the first study really to look at maintenance rituximab after rituximab plus chemotherapy. And those data were updated by Joel Sal at ASH 2017. And interestingly, they showed that with 10 years of follow-up, about half of the patients who received rituximab maintenance for 2 years were still in remission. So, that’s a pretty attractive concept to let a patient know that you could potentially not require treatment for several years after your initial immunochemotherapy. On the other hand, there was still no overall survival difference. And so, some people might say, “You know, I’m willing to undergo therapy a little bit more frequently. I really just want to be over with this. I went through 6 months of chemotherapy; I don’t want to come back for a while.” And that’s an entirely reasonable consideration as well. So, maintenance rituximab is reasonable to admit as well.

Another consideration from the GALLIUM study is obinutuzumab maintenance. So, the patients who were randomized to the obinutuzumab chemotherapy arm also received 2 years of maintenance. And if their patient were to receive obinutuzumab chemotherapy, the data from that study really only include obinutuzumab maintenance. So, that’s the way it was done in the clinical trial, and if we want the same results, we would do the same thing. I think you could argue, though, that if you’re using obinutuzumab/bendamustine or obinutuzumab/CHOP, you’re not committed to using obinutuzumab maintenance just because that’s how it was done in the trial.

Transcript edited for clarity.

March 2012

• A 57-year old woman presented with lymphadenopathy
• PE: marked swelling in the right supraclavicular region, non-tender
• Laboratory findings: platelets, 98,450/mL; HB, 10.9 g/dL
• CT imaging showed a 4-cm right supraclavicular mass and a diffuse pattern of right-sided enlarged inguinal nodes
• Incisional biopsy, pathology
  • IHC: CD10+, BCL2+, CD23(-), CD43(-), CD5(-) CD20(+), BCL6 (-)
  • Grade 2 follicular lymphoma, 12 centroblasts/HPF
• FLIPI-intermediate
• The patient was started on bendamustine/rituximab and achieved a partial response after 6 months

February 2016

• Four years later, the patient complains of increasing fatigue
• PET/CT shows intense FDG uptake in the right inguinal region and in the left hilar region; SUVmax of 9
• The patient was started in lenalidomide + rituximab
  • After 3 months, her symptoms have resolved
  • After 6 months, she has achieved a partial response with significant shrinkage in the inguinal lymph node

February 2018

• Two years later, the patient now age 63 years, reports having severe fatigue and weight loss; she requires frequent rest during the days and has trouble keeping up with daily activities
• Performance Status, ECOG 1
• Laboratory findings: platelets, 104,000/L; Hb, 9.9 g/dL; LDH, 342 U/L
• PET/CT shows generalized lymphadenopathy bilaterally in the pleural and pelvic regions; FDG uptake in the liver
• Liver enzymes, WNL
• The patient was started on idelalisib 150 mg b.i.d.
• Follow up imaging at 3 months showed significant regression in the liver and pulmonary nodes and stable disease in the pelvic region
• After 4 months on therapy she began to experience watery diarrhea, 5 to 6 times per day