Follicular Lymphoma: Rationale for Selecting Copanlisib

Peter Martin, MD:In this case, copanlisib is a perfectly reasonable option for treating. There are other options that can be considered. Some people have argued that ibrutinib would be a reasonable consideration. My bias would not be to use ibrutinib in this circumstance. Ibrutinib has some activity in follicular lymphoma, but the activity is probably a little bit less than PI3-kinase inhibitors. So, ibrutinib is an oral BTK inhibitor. And it has activity that’s probably a little bit less than a PI3-kinase inhibitor. There may be a role in combination with other drugs that we see in the future, but right now, I would certainly not use it prior to using a PI3-kinase inhibitor in follicular lymphoma.

Selecting between copanlisib and idelalisib is probably due to that selection will be based on a number of factors, including patient convenience, patient preference, and also potentially side effect profile. As I mentioned, the copanlisib is given intravenously once weekly with a week off. Some people have argued that that pharmacokinetic profile potentially reduces some of the side effect profile that might be seen with idelalisib. So, some of the studies, and there were numerous abstracts presented at ASH in 2017, suggested that copanlisib has a lower rate of inflammatory or autoimmune colitis. There were some reports of pneumonitis, although they seem to be relatively rare. The primary side effects from copanlisib, interestingly, appear to be hyperglycemia, hypertension, as well as some cytopenias.

Interestingly, the hyperglycemia and hypertension are what you would expect from an alpha isoform PI3-kinase inhibitor, and we’ve seen them from other pan-PI3—kinase inhibitors. And the package insert here is helpful in terms of guiding how to manage the side effects. Primarily, the key to managing them is to know that they’re there, to control glucose and blood pressure before administering the medications, and then not to get too excited about them when they happen. It’s probable that we’ve been inducing hyperglycemia with 5 days of prednisone and pulse dose dexamethasone.

For a long time, we just were never checking glucose levels immediately after administering the dexamethasone. I think patients probably have a lot more to lose by overzealous management of hyperglycemia than they do through simple, sort of common, cautious, easy-to-do strategies, right? So, controlling the glucose beforehand and then encouraging patients to drink a lot of fluids so they don’t become dehydrated, the sugar will come down pretty quickly and not be a major issue. The cytopenias just need to be monitored. So, although the side effect toxicity profile is a little bit new to people like me, hematologists, it’s something that’s relatively easy to get used to with a little bit of experience, I think.

The efficacy of copanlisib has been presented in publication and updated recently by Martin Dreyling at ASH 2017. And in that trial, over 140 patients with heavily pretreated follicular lymphoma received copanlisib. And of these patients, somewhere in the range of 50% to 60% responded to treatment. And the median response duration was just a little bit over a year with a PFS in the 10- to 11-months range. So, it clearly has activity in a population of patients who are otherwise relatively resistant to standard therapies like chemotherapy and anti-CD20 antibodies.

In summary, I think copanlisib is a reasonable treatment option for this patient. He had a relatively resistant disease to both chemotherapy and anti-CD20. It’s important to use something that has a novel mechanism of action. And, in this case, copanlisib, a PI3-kinase inhibitor, is a good choice to provide somebody with a relatively well-tolerated treatment option. Obviously, people have to get used to using copanlisib and get used to managing the novel side effect profile, but I think that can be done with a little bit of preparation and a little bit of practice.

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