PI3K Inhibition for R/R Follicular Lymphoma

Ajay K. Gopal, MD: Not every patient will need third- or fourth-line therapy. It somewhat depends on the underlying disease, but also the age of the patient at diagnosis. If we think about patients with early progression, about 20% of all patients with follicular lymphoma have progressive disease within 2 years. Then we think of the median age of diagnosis being in the early 60s, although this patient is a bit older. Those factors come into play in terms of the likelihood of having to ever get to third-line therapy. In my practice, in an academic referral center, I do see many patients needing third-line therapy or beyond, so this is a common situation, unfortunately, in our clinical practice.

Fortunately, we have a number of agents and approaches for patients needing third-line therapy. It somewhat depends on what they’ve had previously. If they haven’t had lenalidomide, that’s still on the list. I mentioned before ibritumomab tiuxetan as a potential option for the appropriate patient. But we have an entire class of drugs now called the PI3-kinase inhibitors. There are 3 drugs approved. The first was idelalisib, and this was evaluated in the DELTA study.

The PI3-kinase inhibitors probably have 2 mechanisms of action. The initial thought was that this was primarily a drug that blocks the B-cell receptor signaling pathway. PI3 kinase is part of that. However, more recent data suggest that these drugs are probably also immunomodulatory. They tend to suppress regulatory T cells, probably reflected somewhat in their adverse effect profile, and may also suppress myeloid-derived suppressor cells. So the actual function is not completely clear, but there’s probably a combination of direct effect on B-cell receptor signaling and some immunomodulation.

Transcript edited for clarity.

Case:A 69-Year-Old Woman With Follicular Lymphoma

Initial Presentation

• A 69-year-old woman complains of a 5-month history of fatigue, decreased appetite and a 10-bs. weight loss
• PMH: unremarkable
• PE: right axillary and bilateral cervical lymph nodes palpated ~ 3 cm; spleen palpable 4 cm below costal margin
  
  

Clinical Work-up

• Labs: ANC 1.6 x 109/L, WBC 11.8 x 109/L, 40% lymphocytes, Hb 8.9 g/dL, plt 98 x 109/L, LDH 308 U/L, B2M 3.7 µg/mL; HBV negative
• Excisional biopsy of the lymph node on IHC showed CD 20+, CD 10+, BCL2+; follicular lymphoma grade 2
• Bone marrow biopsy showed paratrabecular lymphoid aggregates, 45% involvement
• Molecular genetics: t(14;18) (q32;q21)
• PET/CT showed enlargement of right axillary lymph nodes (3.1 cm, 3.2 cm), diffusely enlarged nodes in the retroperitoneal and lumbar lymph nodes
• Ann Arbor Stage IV; ECOG 1
  
  

Treatment

• She was treated with R-CHOP for 6 cycles with rituximab maintenance; achieved partial response
• 5 months later she complained of increasing fatigue
  • Repeat PET/CT revealed progression of disease
  • She was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance obinutuzumab
  • Repeat lymph node biopsy remained grade 1-2 follicular lymphoma
• 9 months later she complained of chills and low-grade fever
  • She was started on idelalisib 150 mg PO BID