PI3-Kinase Inhibitors for Follicular Lymphoma

Nathan H. Fowler, MD:Other drugs that are approved for patients who have relapsed disease include radioimmunotherapy. The drug Zevalin (ibritumomab) is also approved for patients who have relapsed follicular lymphoma. And, recently, we saw the approval of obinutuzumab, which is approved in combination with bendamustine in patients who have relapsed follicular lymphoma who are Rituxan-refractory.

When thinking about patients who are treated in the third-line setting, idelalisib, as I mentioned, was FDA approved now a couple of years ago. This drug is given orally, and its approval is based upon a phase II trial in patients who had relapsed and refractory follicular lymphoma and other indolent lymphomas.

The drug had an overall response rate of almost 60% with a remission time of around a year. The drug is associated with a very unique side effect profile, and this is mainly colitis, pneumonitis, and transaminitis. These events can occur at different times. Usually, transaminitis occurs fairly early, in the first 1 to 2 cycles, and colitis can occur early or late. Now, colitis is clearly an issue not only because it’s inconvenient for the patient, but in some cases, the colitis can be very severe, and patients have even been admitted to the hospital with low blood pressure and even ended up in the ICU with significant colitis that occurred late with exposure to the drug.

Now, I’ll contrast that to copanlisib, which, again, was also FDA approved, and that drug is associated also with its own unique side effect profile. As I mentioned, it hits the alpha and beta isoform of PI3-kinase, and that gives it side effects such as hyperglycemia and hypertension. The colitis appears to be significantly less than what we see with idelalisib. This could be due to the mechanism of the drug or possibly the route of administration. As I mentioned, this drug is given intravenously, so it bypasses the gut, and, again, we don’t see as much of the acute or the late colitis. Again, whether that’s due to mechanism of the drug or delivery, I think it’s still under investigation.

So, when we’re thinking about when to use each of these 2 drugs, like a lot of things I’ve said in this program, the decision should be made after a detailed discussion with the patient, as well as a close look at the different side effects, as well as the efficacy of the different drugs. In my mind, both copanlisib and idelalisib are effective in this patient population. I would not be giving a drug like idelalisib to a patient who maybe I was worried about colitis or I would not be able to follow closely. And, on the counter, I would probably be looking to avoid a drug like copanlisib in a patient who was at risk for episodes of high blood sugar and for potentially a patient who has uncontrolled diabetes.

But, again, both these drugs are available. I do think that they’re both very effective in low-grade lymphomas. We’ll have several new drugs that are also coming down the pipeline, which are very active, and, hopefully, we’ll see combinations of some of these new drugs in the future for our patients with relapsed low-grade lymphomas.

Transcript edited for clarity.

June 2015

• A 65-year old female presented to her PCP complaining of night sweats and swelling in the neck
• PMH: osteoporosis, neurogenic bladder
• Physical examination:
  • Enlarged spleen 2 cm. below costal margin, bilateral cervical and axillary lymphadenopathy
• ECOG 0
• Laboratory findings:
  • WBC: 12 x 10⁹/L; 45% lymphocytes
  • Hb: 11.5 g/dL
  • Platelets: 213 x 10⁹/L
  • LDH 212 U/L
• Excisional biopsy of the lymph nodes:
  • IHC: CD10+, BCL2+
  • Follicular lymphoma, grade IIIa
• Bone marrow biopsy, 40% involved
• ¹⁸FDG-PET showed SUVmax of 9 with discrete masses bilaterally in the cervical and axillary region and increased uptake in the liver
• FLIPI 4 points, high risk
• The patient was started on bendamustine + rituximab (6 cycles) and was continued on rituximab maintenance therapy for 12 months
• She achieved a partial response with a 75% reduction in tumor volume

February 2018

• After 32 months, the patient complained of her symptoms returning
• CT showed disease progression in the axillary and hilar lymph nodes
• PET with SUV of 11
• Re-biopsy of lymph node, consistent with follicular lymphoma grade IIIa
• The patient was referred to an academic center for treatment
• She was enrolled in an open-label clinical trial of lenalidomide/rituximab (12 cycles)
• She achieved partial remission after 3 months

February 2019

• Twelve months later, the patient presents with low-grade fever and chills, she is otherwise well-appearing and continues to exercise regularly
• ECOG 0
• PET-CT showed further progression in the axillary lymph nodes
• The patient was treated with IV copanlisib and achieved a partial response after 4 cycles; she continues to do well on therapy