Idelalisib for Follicular Lymphoma

Loretta J. Nastoupil, MD:This patient was administered idelalisib based on the fact that he had short remission duration following 2 lines of chemotherapy containing a CD20 antibody. This is based on the phase II study, which enrolled a similar patient population looking at 150 mg of idelalisib twice daily until disease progression or intolerance. Based on that study, we know that it’s an appropriate choice for someone, particularly in this situation. In regards to the outcome for this patient, he was on therapy and had a response. Approximately 6 months into therapy, he called with significant diarrhea with more than 5 bowel movements per day. Having trained my staff, this was detected early on, the drug was held, and given the severity of symptoms and alternative etiologies of diarrhea excluded, he was initiated on steroids similar to what we would do for a GVHD patient.

After a few weeks, the diarrhea fully resolved to baseline and this patient was rechallenged with 100 mg twice daily—similar to what is recommended by the package insert—and the patient continued to do well. I do believe idelalisib is an appropriate consideration for patients in their third-line or beyond, with relapsed/refractory follicular lymphoma in which you’ve excluded the possibility of underlying diffuse large B-cell lymphoma. I also think it is a very good option in terms of having a high chance of an objective response, where I may also consider transitioning this patient to an allogeneic stem cell transplant given his age and limited comorbidities.

In my experience with idelalisib, there are toxicities that occur at different timeframes that can be taken more or less seriously. For instance, there’s an early onset of diarrhea that traditionally, in my experience, has not been associated with colitis. It usually occurs within the first few weeks to 1 month and is usually self-limiting with very few or infrequent bowel movements. However, though infrequent, the late-onset diarrhea is oftentimes worrisome for colitis, in my experience. And oftentimes, it’s discerning how many bowel movements a day can be very helpful. I generally do not like for patients to get to the point where they’re having 8 bowel movements a day, so, again, I will educate patients and my staff that any diarrhea while on idelalisib warrants a phone call and attention. And oftentimes, we’re going to hold the drug until we further exam the etiologies of the diarrhea. And keep in mind that these patients are oftentimes exposed to antibiotics and CDF colitis and there are other etiologies that should be considered.

But I think early detection and early management can limit the morbidity in these patients. There are other side effects, too, that are also infrequent but warrant attention. For instance, pneumonitis. I think patients who have underlying asthma or COPD may not be appropriate candidates for idelalisib because they may be at a higher risk for pulmonary complications. Monitoring pulsox (pulse oximetry) in the clinic, particularly with someone who’s coming in and complaining of shortness of breath or cough, may be informative. For instance, if you have a patient with traditional normal saturation and he/she is coming in complaining of mild shortness of breath or cough, and now all of a sudden has a pulsox in the low 90s to upper 80s, that may be the first indication of a developing pneumonitis or super infection and may warrant further attention.

Again, we generally will hold the drug until we understand the underlying etiology of the symptoms. These patients will oftentimes be immune-compromised, either given their prior therapies or their underlying B-cell dysfunction due to B or T cells dysfunction due to their lymphoma. The consideration of opportunistic infections or bacterial pneumonia is also important to consider when you have patients on idelalisib. Generally, we will monitor closely for infection. I watch closely for colitis, though it is infrequent. The other side effect that is not infrequent, but usually less severe, is transaminitis. The other important things to keep in mind, in my experience, is this usually will have an onset from around 5 to 6 weeks to up to 12 weeks, oftentimes when patients are doing well and you may not be as concerned or you aren’t seeing them as frequently and they come in and they have an elevated transaminase and they’re asymptomatic. But based on the original study, oftentimes these patients were treated through this and transaminase is resolved even in the presence of ongoing therapy. However, if you have a liver enzyme that’s 3 times the upper limit of normal or higher, we advise to hold the drug and monitor them weekly until this resolves. Though rare, I’ve had situations where patients have ongoing transaminitis for many weeks and it ultimately resolves. But it is not completely unusual to see that occur, and these patients should be monitored frequently during this time period and the drug should be held.

Oftentimes, in these situations where it may take many weeks for liver enzymes to normalize, consideration of rechallenge is one that is done with serious consideration. This means I will rechallenge a patient where it took 12 weeks for liver enzymes to resolve. And this is quite rare, but generally, it’s something that we talk over with the patient. And I generally will not start them at the full dose. I will dose reduce. For patients who have a very transient elevation of liver enzymes, oftentimes we will rechallenge them, and we know from the prospective studies that about 74% of those patients did just fine. They didn’t have recurrence of the liver enzyme elevation and they were able to receive the full dose.

What are the other agents that are currently exciting in terms of targeting the B-cell receptor signaling pathway in relapsed follicular lymphoma? Ibrutinib is an agent that has gained success, particularly in CLL and in mantle cell lymphoma. In follicular lymphoma, most of the data that have emerged is in the relapsed setting as single-agent. There are 2 phase II studies that have been reported, which are looking at the efficacy as determined by the overall response rate—a single-agent ibrutinib in relapsed refractory follicular lymphoma. One of those studies mirrored the patient population that we saw in the idelalisib phase II study. And what we learned from that study is the overall response rate was just shy of 30%. So, in general, in an overall response rate of less than 30%, follicular lymphoma is not exciting because you would expect a similar response rate with single-agent rituximab. So, as a single agent in the relapsed refractory setting, in the absence of a biomarker, that may help choose which patients are going to respond. I do not think that ibrutinib is an appropriate choice, and this is probably why this drug is not currently FDA-approved for that setting.

However, can you overcome some of these limitations with combination approaches, and that is something that is currently ongoing in terms of exploration on clinical trial. It is currently being combined with chemotherapy in combination with a CD20 antibody and other targeted agents. And in that setting, you may be able to achieve a higher and more durable response. There’s also biomarker exploration that’s ongoing to identify either mutation profiles or other molecular features that may predict for a patient that will do quite well with ibrutinib. Again, this is something that is confined to clinical trials or ongoing research.

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.