Third-Line Therapeutic Options for Follicular Lymphoma

Peter Martin, MD:Two years later, again the patient presented with worsening fatigue. She now had some weight loss as well. She found it difficult keeping up with her activities of daily living, so her performance status had worsened to an ECOG score of 1. She had cytopenias again. Now her LDH was elevated. So, things were clearly progressing symptomatically. Imaging, again, demonstrated diffused lymphadenopathy as well as some diffused uptake in the liver. The SUVmax was in the 7 to 9 range, so, again, no real concern for diffused large B-cell lymphoma, although the symptoms are clearly more significant than they had been in the past. She was started on idelalisib 150 mg twice daily based on the information.

After 3 months of idelalisib, her imaging had improved significantly, as well as her symptoms. She felt much better within the first month or two. Unfortunately, after about 6 months of taking idelalisib, she started to develop some watery diarrhea with a little bit of cramping, and that was worsening over time to about 5 or 6 bowel movements a day throughout the day, which was starting to affect her quality of life in a rather significant way.

On that basis, we felt that it was reasonable to hold the idelalisib for a period of time and wait for her symptoms to improve. Some people have considered use of oral steroids, oral budesonide under these circumstances. In this case, she improved relatively quickly within about a month without any significant intervention. And then guidelines are to consider whether or not to restart idelalisib at a lower dose.

Third-line therapy in follicular lymphoma is, again, similar to first- and second-line, and that would go through all the same considerations as their transformation. In this case, we think no. Does the patient need therapy? Observation is still absolutely a reasonable option in people with relapsed follicular lymphoma regardless of the lines—second, third, fifth relapse. If they’re asymptomatic, observation remains reasonable. However, in this case, the patient was clearly having some symptoms. Her cytopenias were worse. She had an elevated LDH, so treatment was clearly indicated.

Under those circumstances, you have to ask yourself, are we going to continue to do something similar, or should we do something different? So, we have all the same options as before, like single-agent rituximab. Probably not a great choice in this case given her symptoms. Rituximab or obinutuzumab plus chemotherapy are reasonable options. She had a pretty good response to bendamustine/rituximab. If we don’t think she’s transforming, maybe we’re not thinking R-CHOP quite at this point. We might be waiting for the future in case she does have some sort of transformation. Again, my bias is not to repeat bendamustine plus rituximab, although there’s some literature that says that it can be done in some circumstances. She has already had lenalidomide, so that’s probably not the best choice. There are 2 drugs that are approved by the FDA for people who have received 2 prior therapies. Both of them are PI3-kinase inhibitors, specifically idelalisib and copanlisib.

PI3-kinase inhibitors are rational in that they do what you would want a lymphoma drug to do. They interfere with interactions between lymphoma cells and the microenvironment. And importantly, they have a mechanism of action that’s completely different from prior lines of therapy. In other words, if we think that she’s resistant to the other mechanisms of action that she has received before, using a drug that works differently makes sense. And importantly, PI3-kinase inhibitors have demonstrated activity in phase II clinical trials in this setting.

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