PI3 Kinase Inhibitors as Third-Line Therapy in FL

Peter Martin, MD:Unfortunately, 16 months after starting bendamustine/rituximab, the patient again presented with symptoms consistent with progressive disease. So, this case is playing out exactly the way we expect and exactly the way we don’t want it to play out. He presented with new fatigue again. Imaging with a PET/CT scan demonstrated diffuse lymphadenopathy. He was again biopsied, and transformation was ruled out. There was still just indolent follicular lymphoma. But the term “indolent” follicular lymphoma, although that’s true in terms of grading, really doesn’t apply. It’s not an indolent disease in this case—it’s a follicular lymphoma that’s a bad actor. In this case, he was started on intravenous copanlisib, and after 3 months of therapy, he had achieved a partial response.

The treatment options for this patient really run the gamut again, theoretically, but in practice, I think the idea is that this patient is chemorefractory. He’s not by definition chemorefractory but pretty close to it. He’s had a short remission duration with R-CHOP and an even shorter remission rate and remission duration with bendamustine. So, the likelihood that he’s going to have some overwhelmingly positive remission duration with CDP or repeat bendamustine is pretty unlikely. I think we need to start, at this point, looking away from chemotherapy, unless we’re considering him as a transplant candidate, in which case we might consider some really intensive chemotherapy regimen. His age is getting a little bit older but, again, worth the consideration. Assuming that he’s not a great transplant candidate, my bias at this point is to steer him away from chemotherapy and look at other options. Again, it’s a high-risk patient, so I think clinical trials are worth considering. And, certainly, it’s reasonable to send him for a consultation for something like that.

Outside of clinical trials and transplant, we’ve got 2 approved options from the FDA. One of them is idelalisib; the other is copanlisib. Both are PI3-kinase inhibitors, and both represent a relatively rational strategy in this case. Somebody who’s refractory to anti-CD20 and chemotherapy, you want a relatively resistant chemotherapy. You want to choose something that works in a completely different way, and PI3-kinase is a good target in hematologic malignancies, in particular follicular lymphoma. Multiple clinical trials now have shown that PI3-kinase inhibitors have significant activity in people with heavily pretreated follicular lymphoma.

We have 2 PI3-kinase inhibitors that are approved right now. There are others that are in development. They all have some subtle differences. Of the 2 that are approved, idelalisib is oral. Copanlisib is an intravenous formulation. It’s administered once weekly for 3 weeks followed by a 1-week break. And it’s specific to the alpha and delta isoforms, PI3-kinase.

And therein, those differences probably account for some of the differences that we see in the side effect profile and arguably could impact efficacy as well, although that’s less clear. Ultimately, phase III clinical trials would be required to compare these agents and really evaluate which is more active. I’m not sure that that’s the most important question we face in follicular lymphoma, and I’m not sure that that’s a worthwhile clinical trial to do. I think it’s great that we have these options. And so, it’s better to be aware of what the options are and become comfortable with using them so that we can present them to our patients and help them to pick the treatment option that they think is most reasonable for them given their circumstances.

Transcript edited for clarity.

October 2014

• A 72-year-old man presents to his physician complaining of fatigue lasting several months, recent weight loss of 15 lbs. and a mass on his right side of neck
• PMH: GI reflux controlled on PPI, obstructive sleep apnea
• PE: Right supraclavicular lymph node (7 cm.), spleen palpable 5 cm. below the costal margin
• Performance status, 1
• Laboratory findings:
  • Hb, 9.9 g/dL ,
  • Leukocytes, 3.21 X 10⁹/L
  • Platelets, 110 X 10⁹/L
  • AST, 162 U/L; ALT 201 U/L
  • LDH, 302 U/L
• Excisional biopsy of the right supraclavicular node:
  • IHC staining, CD10+, Bcl2+, CD5-
  • Follicular lymphoma, grade 2
• Bone marrow; paratrabecullar infiltration by small cleaved lymphocytes
• PET-CT showed enlargement of right supraclavicular lymph node (3 X 7 cm) and 3 mediastinal lymph nodes (3.2 cm, 3.5 cm, 4.4 cm); diffusely enlarged nodes in the retroperitoneal, mesentery, and inguinal regions: SUVmax, 9
• FLIPI, 5 points, high risk
• The patient was treated by the local oncologist with R-CHOP (6 cycles)
• Post-treatment he achieved a partial metabolic response
• He was continued on rituximab maintenance therapy and his disease remained stable

July 2016

• 23 months later, the patient complained of his symptoms returning
• PET revealed enlargement of the affected mediastinal nodes
• SUVmax of all nodes was 12
• Repeat CT revealed progression of disease
• The patient was started on bendamustine + rituximab (6 cycles) and achieved a partial response after completing induction therapy

January 2018

• Sixteen months later, the patient reports feeling tired but could resume most normal activities (ECOG 1)
• PET with diagnostic CT showed diffuse¹⁸F-FDG uptake in multiple lymph nodes and spleen; the largest involved nodes are the right supraclavicular (6.2 cm), left mesenteric (4.8 cm), and splenic hilar (2.7 cm) nodes
• Repeat biopsy showed grade 2 follicular lymphoma
• The patient was started on copanlisib
• After three months, he developed a partial response with>50% reduction in lymphadenopathy in all involved nodes