Follicular Lymphoma: Third-Line Setting and Beyond

Nathan H. Fowler, MD:Twelve months later, the patient presented with symptoms, again, night sweats, but she had an excellent performance status, and she was still exercising regularly. Her ECOG performance status was 0. She had a PET/CT that showed enlargement of the same nodes that we had seen previously, namely in the axilla, the hilum, and the bilateral cervical region, and she was started on copanlisib. After 4 weekly doses, she was found to be in a partial remission, and she remains on treatment.

In this case, we have a woman who has now multiple relapses. She’s relapsed after induction therapy and has relapsed following lenalidomide and rituximab, and now she’s on her third line of treatment. This is not an uncommon scenario in patients with follicular lymphoma. And, many times, the disease is marked by relapses that occur every 3 to 4 months to sometimes longer. But sometimes, again, patients can relapse at early intervals between 12 and 18 months. And, generally, when I think about this group of patients, I think about novel treatment options, about using something that has a different mechanism and something that could potentially put these patients in remission that is durable.

Over the past few years, we’ve seen, I think, a revolution in different therapies that are available for patients with follicular lymphoma. Many of these new drugs are currently FDA approved, and many of them will soon be FDA approved, we hope, within the next several years.

So, the landscape of treatments that are currently available for patients with relapsed follicular lymphoma, especially patients who are in a third line, would include the 2 PI3-kinase inhibitors. Those 2 PI3-kinase inhibitors include a drug called idelalisib and a drug called copanlisib. Both of these drugs hit the PI3-kinase pathway; these are drugs that target the PI3-kinase pathway. We know that this pathway is essential in the function and development of normal B cells. And it’s evolved as a target for drugs that are very active both in lymphoma and in leukemia.

As I mentioned, the 2 drugs that are currently FDA approved are idelalisib and copanlisib. And they have slightly different mechanisms of action. Idelalisib hits mainly PI3-kinase delta. This is a specific isoform of PI3-kinase. And copanlisib hits the PI3-kinase, mainly the PI3-kinase alpha and delta isoform, although it does hit beta and gamma as well at a lower extent.

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