Therapeutic Options for Third-Line for Follicular Lymphoma

Loretta J. Nastoupil, MD:This patient initiated bendamustine and obinutuzumab, with planned obinutuzumab maintenance, based on the GADOLIN study. Unfortunately, within 11 months, the patient had evidence of disease progression based on imaging, which suggested that, in addition to the known sites of lymphoma, the patient also had new pathologic adenopathy, including bulky mass in the mesenteric. How would we approach a patient in regards to third-line treatment options for relapsed/refractory follicular lymphoma? Idelalisib is FDA-approved in this setting, and, again, this patient would have met the eligibility criteria for the prospective study that enrolled—meaning he’s failed 2 lines of chemotherapy and a CD20 antibody. Idelalisib is a targeted agent that targets PI3-kinase delta. The phase II study demonstrated very high overall response rates that appear to be quite durable.

There are side effects associated with Idelalisib that are unique in regards to what is traditionally seen with chemotherapy, including transaminitis, pneumonitis, colitis, and risk of infection. The timing of the onset of these adverse events is somewhat different than what we traditionally see with chemotherapy, meaning we have patients who will be doing well and on treatment for many weeks to months and all of a sudden will have significant side effects that occur. In general, the side effects of idelalisib are quite favorable, meaning few patients will have severe or significant side effects. However, given that the side effect profile is unique from traditional chemotherapy, it’s important to ensure that these side effects are identified in a timely fashion. This means addressing them early before they can progress to the point of severity that will lead to prolonged drug hold or prolonged treatment for the side effects. For instance, if you have a patient calling with diarrhea beyond their sixth month of therapy and they’re having more than 5 bowel movements a day, the first advice is to hold the drug and investigate for evidence of colitis or even other etiologies of diarrhea.

It’s also important to educate the office staff, as they will be fielding those first calls and, oftentimes, patients will call with diarrhea. And for someone who’s been on therapy for 6 months and is generally responding, colitis may not be the first side effect that the triage nurse is considering. So, I think it’s important not only to educate the treating team, but also the team that may be fielding those calls, as well as the patient, in regards to the side effects that you may consider more serious.

In addition, infection is something that we have learned is important to monitor for throughout the course of their therapy. Neutropenia has been associated with idelalisib, again, which is not traditionally thought to be associated with targeted therapy. But as we gain more experience with these agents, we know that cytopenias can also be a problem. So, monitoring for neutropenia, which can also put patients at risk for infection, is important. And it’s currently advised to be done approximately every 2 weeks during the first 6 months of therapy.

Rash can also be seen with idelalisib, although, again, most rash is mild and easily managed. Being mindful of more severe eruptions is also important to educate patients and staff who might be managing these patients. And in general, the side effect profile is very manageable with idelalisib, and it’s offered therapy for patients who have traditionally failed chemotherapy, have gone on to receive this agent and respond quite well. It is an agent that’s currently approved for someone who’s had 2 prior lines of therapy for follicular lymphoma. I think it’s a reasonable option to consider for this patient.

In regards to emerging therapies, there are ongoing prospective studies looking at additional agents, such as immune modulators, or other targeted agents, such as enzymes within the B cell receptor signaling pathway. Those are not as far along as idelalisib, meaning they’re not currently FDA-approved. And we’re eagerly awaiting some of those studies to read out. Your approach to patients who’ve relapsed with follicular lymphoma is just as heterogenous as the disease, meaning you have to consider what their prior therapies were and the sequence of those therapies when you’re deciding on their next therapy. I’ve oftentimes treated patients with a CD28 monoclonal antibody, if that’s appropriate—meaning someone who’s of low tumor burden but in need of therapy. I’ve also alternated chemotherapy based on what their prior chemotherapy is.

I think, specifically, for this patient who’s having a short remission duration following chemotherapy, a third-line chemotherapy-based approach is less exciting. I would strongly consider a clinical trial if you cannot or are not in agreement with idelalisib for this patient population. And given his age and likely limited comorbidities, an allogeneic stem cell transplant should also be considered. My approach to patients who are looking at their third-line approach for relapsed/refractory follicular lymphoma takes into account their underlying factors—the patient characteristics, such as their age and their comorbidities. I also consider their disease characteristics. I do consider the GELF criteria, even in this setting, because, as I mentioned, there are oftentimes patients who have low tumor burden but are in need of therapy where it lessens, since the therapies may be appropriate. I will strongly consider a clinical trial, given the emerging targeted and immune therapy approaches, which appear to be promising in this disease but are often restricted to use on a clinical trial. And as I mentioned, given a young patient with limited comorbidities, consideration of an allogeneic stem cell transplant beyond their second remission is absolutely appropriate to consider because it may be associated with a chance for cure.

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.