High-Risk FL: Optimizing Approaches With Idelalisib

Ajay K. Gopal, MD:This patient is clearly in trouble. This is a very high-risk situation. Now they had 2 prior therapies, short remission durations, and quite intensive therapies. Patient is very symptomatic. The marrow is packed with lymphoma, and the patient has stable disease to idelalisib. Idelalisib is a reasonable regimen. It’s approved for 2 prior lines of therapy, and typically in this situation for someone who is relatively young in their early- to mid-60s, idelalisib would be something that I would think about, if they’re otherwise fit, that would bridge us to something else. We would expect from the original trial for those with 57% overall response rate with idelalisib, the median progression-free survival was 11 months.

There was a subsequent analysis looking specifically at the follicular lymphoma subset. There was a 55% overall response rate, and then the progression-free survival, not surprisingly, paralleled the response. So, those who had a CR had about a 30-month progression-free survival, partial remissions about 11 months, and stable disease only about 8 months. So, this is a different strategy than standard chemotherapy. It’s a way we can control the disease, but we do need to think about what are we going to do when the idelalisib stops working. And in this patient who has got stable disease, I would be concerned that within 12 months we’re going to have to have something else ready to go for this patient.

I’ve treated a number of patients with idelalisib in this situation, and fortunately, my patients have had very manageable toxicity for the most part. But I think we have to be very careful with this drug and other similar drugs in appropriate monitoring. It’s very easy to give a prescription for an oral agent and think there’s not adverse events or side effects. We have to monitor patients early for transaminase elevation. We have to counsel patients to report pulmonary symptoms, to report GI symptoms. The diarrhea and colitis is something that we pay quite a bit of attention to. There is an early diarrhea that can happen really within days or weeks after starting, and that’s typically manageable by anti-motility agents. And then there’s a later diarrhea, which is really the inflammatory colitis that we can see. In the pivotal trial, about 11% had grade 3 inflammatory colitis. The drug needs to be held and typically we will give nonabsorbable steroids, and sometimes patients can be rechallenged and restarted. And it sounds like this patient got rechallenged in this case and restarted.

We also need to be careful and prophylax patients for PJP (pneumocystis jiroveci pneumonia) with Bactrim, dapsone, or atovaquone. And data from a large phase III trial showed that we do need do monitor for CMV. So, typically about monthly, we’ll monitor for patients for CMV. I’ve been fortunate that I’ve never had a patient develop CMV on idelalisib, but certainly the data say that there does appear to be a high risk of CMV on these drugs.

Fortunately, there are no major cardiovascular issues with idelalisib. Really, the major issues that we watch for are infection, liver early on, GI issues, and there’s a low but not insignificant—not zero—rate of pneumonitis. So, we do need to have patients report any pulmonary side effects.

Overall, our approach for follicular lymphoma has changed quite a bit. We know that survival is better. We can prognosticate better. We can say to patients confidently, “Eighty percent of you, when you’re newly diagnosed, your survival is probably going to be the same as somebody who didn’t have follicular lymphoma.” So, I think that’s really very positive news for patients. And we can cull out, based on the initial remission duration, who are the patients we really need to focus on, who are the ones who need to get referred for transplant, for novel agents, or for clinical trials and that’s the early relapse. And I can’t overemphasize how important that information is in terms of managing patients.

And for those who don’t have early relapse, we have many options that we’ve had before as well as new options that are very gentle therapies that can deal with any symptom, but mostly restraint is important. And then again for the ones who have early relapse, there are novel agents like idelalisib, copanlisib, let’s not forget ibritumomab tiuxetan, and things that are on the horizon like lenalidomide and CAR T cells. There are many other novel classes of drugs within the B-cell receptor signaling pathway that are being evaluated, which hopefully will alter the course for this 20% who have really the high-risk follicular lymphoma.

Transcript edited for clarity.

January 2016

• A 62-year-old male presented with left axillary lymphadenopathy
• PMH: DVT managed on warfarin, CMV infection
  • Laboratory findings: CBC count and LDH WNL
  • Excisional biopsy, IHC staining CD10+, grade 2 follicular lymphoma
  • PET/CT, multicompartmental adenopathy and splenomegaly consistent with stage IV disease
  • Bone marrow biopsy, 30% involvement
  • FLIPI 2 (intermediate-risk)
• The patient was started on bendamustine + rituximab (6 cycles)
• She achieved an unconfirmed complete response

June 2017

• 18 months later, he developed recurrent cervical adenopathy with weight loss and fatigue
• Imaging revealed adenopathy in 2 cervical lymph nodes (4.6 cm and 2.4 cm), a mediastinal node (2 cm) and left inguinal node (3.1 cm) with splenomegaly.
• The patient was treated with R-CHOP
• After 2 cycles he developed anemia and grade 2 fatigue
• He achieved a partial response

November 2017

• Five months later, the patient reports feeling tired and abdominal fullness
• Physical exam remarkable for palpable splenomegaly
• Laboratory evaluation showed marked anemia, thrombocytopenia
• PET imaging showed enlargement of pelvic and retroperitoneal nodes and development of several new mediastinal lesions
• Repeat biopsy showed grade 3 follicular lymphoma, 90% bone marrow involvement
• The patient was started on idelalisib therapy
• After 2 months on therapy, he developed grade 3 colitis which was managed
• After four months on therapy, the patient has stable disease