Optimizing Second-Line Therapy in Follicular Lymphoma

Peter Martin, MD:Four years later, this lady returned to the office—now at the age of 61—with worsening fatigue. Based on those symptoms, repeat imaging was done, which showed, again, growing right inguinal lymphadenopathy up to about 4 to 5 cm in size. And, again, lab testing revealed some cytopenias. So, she is in a similar position to where we were before—symptoms, cytopenias, and diffused lymphadenopathy. As is usual in people with relapsed follicular lymphoma, I think it’s always important to rule out transformation, and so PET/CT was done in addition to CT imaging. And the SUVmax of the lymph nodes was in the 9 to 10 range. So, we didn’t feel that it was necessary to rebiopsy anything to prove that it was still follicular lymphoma, not transformed to diffused large B-cell lymphoma. She was started on a combination of lenalidomide and rituximab, and after 3 months, her symptoms had improved significantly. Her hemoglobin had gone up a little bit, her platelets had gone up a little bit. And by 6 months, her imaging had normalized.

In somebody with relapsed follicular lymphoma, we have a lot of similar considerations that we had in the frontline setting, including, in particular, observation. Just because somebody has lymphoma that has come back, it doesn’t mean that they necessarily need treatment right away. In fact, I would guess that most people who were asymptomatic at the time of relapse don’t require treatment just because the lymphoma’s come back, particularly if it’s picked up on some sort of imaging test. Some of us are occasionally doing imaging for routine surveillance, and an asymptomatic lymph node that’s gone from 1 to 2 cm is certainly nothing to be disturbed about. In this case, however, she was having some symptoms and was, again, developing cytopenias. And so, I think it was reasonable to consider second-line therapy.

Again, the discussion goes back to, what is the goal of treatment in this case? Her preference was to choose some treatment that was likely to result in some sort of durable remission without real intensive therapy. In general, we have a lot of the same treatment options as somebody with a new diagnosis, so single-agent rituximab is there. Probably a reasonable consideration in somebody like this, although, again, it may take a little bit longer to work and it may not work for as long. Rituximab plus chemotherapy is a reasonable option. The same chemotherapy regimens would be used in the frontline setting, although we probably wouldn’t use the exact same chemotherapy regimen over again. So, there are some data that suggest that some people can receive bendamustine more than once, but my bias has been to avoid that in general. Bendamustine as a single agent is approved by the FDA for treatment of people with rituximab-refractory follicular lymphoma, and the combination of bendamustine plus obinutuzumab is also approved for people with rituximab-refractory follicular lymphoma. So, those are the standard approved options.

The NCCN guidelines, however, also list lenalidomide plus rituximab as a reasonable option in the second-line setting. And we’re likely to see, in the near future, a presentation of data from phase III clinical trials that indeed show that it’s a reasonable option. We already have similar data from phase II clinical trials showing the activity of lenalidomide plus rituximab both in the frontline and relapsed settings. But based on phase III clinical trials, I wouldn’t be surprised if we have that regimen approved by the FDA in the near future.

One of the interesting factors we have to consider when we start lenalidomide/rituximab is, how long are we going to continue therapy in this case? In the frontline trials as well as in a published relapsed trial, lenalidomide and rituximab was generally continued for about 1 year. In ongoing phase III trials, there are elements of the regimen that are continued for a longer period of time. So, there’s some heterogeneity in the literature about how long to use these treatments and at what doses, for example. In general, in somebody like this, we would start with 20 mg of lenalidomide plus rituximab for 4 doses and then once every 8 weeks for the next year.

My bias in somebody with indolent follicular lymphoma is not to continue indefinite therapy. And once we’ve achieved our original goal—which was to really get into a complete response, or close to it—chemotherapy and continuing indefinitely and going beyond 1 year in somebody who achieved a good response after 6 months, I’m not sure that there’s a huge role for that. In other words, the toxicities of the treatment at some point start to outweigh the ongoing benefit. As in this case, a complete response was achieved relatively early on in the chemotherapy and continuing indefinitely.

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