Second-Line Monotherapies in Follicular Lymphoma

John Pagel, MD:One of the more interesting emerging things that we’re seeing in the treatment of follicular lymphoma are not only targeted treatments, like the PI3 kinase inhibitor that this patient received, but now we’re starting to see the emergence of immuno-oncology, or immunotherapeutics, that are novel and very distinct. They are things like what we would call bispecific antibodies that are very exciting that might target an antigen on the surface of the B [lymphocyte], or the malignant B lymphocyte, and the patient’s own T cells. This is to get the T cells into proximity and to allow those T cells to kill the malignant lymphoma cell. Or, we can use things like CAR T-cell therapies, chimeric antigen receptor T-cell therapies, that are in development. Immunotherapies are dramatically exploding in the treatment of lymphomas, and not just in antibody-based treatments but in these novel therapies that I’ve just mentioned.

The monotherapies that you might think about [in the] second line are really restricted to single-agent antibody treatments that might be single-agent rituximab. Or as I’ve mentioned, it could be a radial immunoconjugate such as Zevalin. Otherwise, the single agents that are commonly used are really for third-line [treatment] or later. Idelalisib in this case is approved for patients who have failed at least 2 prior lines of treatment.

Idelalisib is an important drug that we shouldn’t forget about in relapsed follicular lymphoma. The reason I think it’s an important drug to remember is because it has a novel mechanism of action for cell killing that’s very different than chemoimmunotherapy approaches.

People will become resistant to more chemotherapy, or they’ll become refractory to rituximab, and the idea of treating them in a different way is very important and rational. That’s why a PI3 kinase inhibitor makes sense in this space and idelalisib is what was used here.

NCCN Guidelines [National Comprehensive Cancer Network Guidelines]] suggest that PI3 kinase inhibitors are important to remember as a treatment choice for patients that have failed at least 2 prior lines of treatment. There are now at least 3 PI3 kinase inhibitors that we can consider for relapsed follicular lymphoma. This patient got idelalisib, but the newer drugs are copanlisib, as well as duvelisib.

We’ve been talking about PI3 kinase inhibitors, but I haven’t mentioned BTK inhibitors, or Bruton’s tyrosine kinase inhibitors, and in particular, ibrutinib. I think it’s important to remember ibrutinib is not approved in the relapsed follicular lymphoma space, and it’s not approved essentially because the data [have] been largely underwhelming. The overall response rate of single-agent ibrutinib in relapsed follicular lymphoma is around maybe 20%, to at best 30%. The durations of remission are quite short. Thinking of idelalisib before ibrutinib certainly makes sense given the fact that idelalisib has a response rate of somewhere around almost 60% for these patients, and a progression free survival or a duration of remission of about 10 or 11 months.

Transcript edited for clarity.

Case:A 70-Year-Old Man With Follicular Lymphoma

H & P:

• A 70-year-old man presents with night sweats and general fatigue
• PMH: hypertension, no history of MACE
• PE: Groin is tender to touch, no tenderness in abdomen
• Initially diagnosed with bilateral axillary contiguous stage II FL 5.5 years ago
  • Grade 2 FL, 4 masses (each >3 cm)
  • FLIPI status: high risk

Current biopsy and labs:

• Biopsy: grade 2 FL without transformation
• ECOG performance status: 1
• Hematologic results
  • ANL: 1200 /µL
  • Platelets: 105,000 /µL
  • Hemoglobin: 11.9 g/dL
• LDH: 335 U/L
• eGFR: 75 mL/min/1.73²
• Imaging: PET/CT reveals inguinal lymphadenopathy, with largest mass 8.5 cm

Treatment and disease history

• Front-line BR
  • Completed 6 cycles, achieved PR by 3 months
  • Maintained PR for 20 months before developing fever and mediastinal lymphadenopahty
• Second-line R-CHOP
  • Competed 6 cycles, achieved PR at 3 months
  • PR maintained for 5 months
  • Time since completion of last treatment: 5 months

Current treatment

• Started on single-agent idelalisib 150 mg twice a day