PI3K Inhibitors for Relapsed/Refractory FL

Christopher Flowers, MD: The patient in this particular situation was someone who had a high FLIPI [Follicular Lymphoma International Prognostic Index] score and a relatively poor expected overall survival from his diagnosis, based on his advanced age and how advanced his disease was. For many patients with follicular lymphoma who fall into the lower FLIPI risk category or have a very good response to their initial line of therapy, their expected overall survival is not that much different from age-matched controls.

While follicular lymphoma is expected to be a disease that is not curable with standard therapy, many patients will have subsequent relapses and be treated and then retreated and retreated again. It is relatively common to now see patients who were treated in the third-line or fourth-line or even later lines of therapy.

When we think about the options available, there are now 3 PI3-kinase inhibitors that are approved in that setting. Idelalisib is one of those. Duvelisib is a second one of those that is approved in that setting. Copanlisib is an IV [intravenous] formulation of a PI3-kinase inhibitor that is also available.

When we think about relapsed and refractory follicular lymphoma, the efficacy of those drugs appears to be more similar than different. The response rates, overall, are in the 40% to 50% range for the majority of those agents, and patients have meaningful progression-free survival. It can be a year or more for the majority of those agents. The distinguishing features stand in terms of the ways the drugs are given. Copanlisib, as mentioned, is an agent that is given via an IV formulation.

Some physicians and patients may consider the IV formulation an advantage in that patients are getting therapy. You know they’re getting therapy when they come in to get their IV medication. For other patients and physicians, they may consider that a disadvantage when they could, instead, be taking a therapy that is administered as an oral agent at home and not need to come back to the physician’s office to get care.

The other thing that we see as a difference between those PI3-kinase inhibitors is the forms, or isoforms of PI3-kinase. Idelalisib is an inhibitor of the PI3-kinase delta. Copanlisib is a pan inhibitor of PI3-kinase, so it affects both the alpha and beta PI3-kinase. Those are ones that have other adverse effects associated with them, so patients need to be monitored closely for hypertension while the drug is being infused and need to be monitored for hyperglycemia, which can cause additional difficulties if the patient has predisposition to diabetes or hyperglycemia for other reasons. The other form of PI3-kinase inhibitor, duvelisib, is more similar in nature to the PI3-kinase delta inhibitor, idelalisib.

Transcript edited for clarity.

Case:A 77-Year-Old Man With Follicular Lymphoma

Initial Presentation

• A 77-year-old man complains of a 4-month history of occasional fevers, decreased appetite, and an unintentional 7-lbs. weight loss
• PMH: unremarkable
• PE: palpable left axillary lymph nodes ~ 4 cm; spleen palpable 4.5 cm below costal margin
  
  

Clinical Work-up

• Labs: ANC 1.5 x 109/L, WBC 10.6 x 109/L, 42% lymphocytes, Hb 10.1 g/dL, plt 100 x 109/L, LDH 325 U/L, B2M 3.3 µg/mL; HBV negative
• Follicular lymphoma grade 2
• Bone marrow biopsy showed lymphoid aggregates, 35% involvement
• Molecular genetics: t(14;18) (q32;q21)
• PET/CT showed enlargement of left axillary, mediastinal and bilateral para-aortic lymphadenopathy (4.2 cm, 5.3 cm, 3.6 cm and 3.5 cm respectively)
• Ann Arbor Stage IV; ECOG 0
  
  

Treatment

• He was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m3; achieved partial response
• 6 months later he complained of increasing frequency of fevers
  • Repeat PET/CT revealed progression of disease
  • He was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance obinutuzumab
  • Repeat lymph node biopsy grade 2 follicular lymphoma
• 8 months later he complained of increased weight loss
  • He was started on idelalisib 150 mg PO BID