Treatment Challenges Beyond Second-Line in Relapsed/Refractory Follicular Lymphoma


The challenges faced in treating patients beyond second-line treatment are addressed. Kami Maddocks, MD, reviews the frequency of patients who require third- and fourth-line treatment, in addition to the factors that affect treatment decisions in later lines of therapy.

Kami Maddocks, MD: The challenges beyond treating patients in the first- and second-line include that patients for every treatment regimen you give them, they typically have less response. So, their remission isn’t as deep, and the treatment doesn’t last as long. Some of the other challenges are what shape the patient’s in, what therapy they’ve had previously, what toxicities of that therapy, and what other comorbidities do they have. I would say that it’s not uncommon to have to give therapies beyond the second-line, so when you see younger patients, even if they get really greater prolonged remissions to their first-line therapy, it’s not uncommon for them to have several relapses. We know that the median overall survival [OS] of a patient with follicular lymphoma [FL] is greater than 20 years, but over that time there are many patients that will require a new treatment off and on. One of the other challenges with treating patients beyond the second-line of therapy is the toxicity. What toxicities have they had with prior therapies and are any of these toxicities lasting? it becomes difficult to retreat with agents that have similar toxicities as prior.

When I’m deciding on a therapy beyond the second-line, I think of the patient’s performance status. How good of shape they are in? What treatments have they had previously? What toxicities have they had to those therapies? What is my goal of treatment? There are several options for therapy beyond the second-line. We know that the options we’ve already discussed such as the different chemoimmunotherapies and lenalidomide can be used if they’ve not been used in the prior 2 lines. PI3K kinase inhibitors are available for third-line and later treatment, or for patients who’ve relapsed after 2 therapies. We have 4 PI3 kinase available, 3 in this setting and then 1 after 3 or more prior therapies. Idelalisib is an oral PI3K kinase inhibitor, duvelisib is another oral PI3K kinase inhibitor, and copanlisib is a BPI3P - PI3 kinase inhibitor all available. Tazemetostat is an EZH2 inhibitor available for relapsed [R/R] FL in this setting, and most recently, we’ve seen the approval of chimeric antigen receptor T-cell or CAR T-cell therapy in this setting. Although, the use of that I think must be thought out regarding which of your patient… because of the toxicities, if a patient is a candidate for that therapy and where that therapy should be used.

When deciding therapy in both second-line and in third-line, I think it’s also important to look at what the patients have had for their other therapies and their responses to those therapies. We know in a patient like this, who had 2 regimens of chemoimmunotherapy and did not have long remission durations to those therapies, that we often think about using a different type of therapy. Therefore, even in this second-line in this patient, this is a patient I might have considered using something different than chemoimmunotherapy, something with a different mechanism of action, so this is when we think about using the immunomodulator, lenalidomide in the second-line, or when we think about using the PI3K inhibitors in the third-line setting because we know that this patient seems like he’ll respond to chemotherapy, but not get prolonged remissions from chemotherapy.

Therefore, using something that targets the disease in a different way is attractive in a patient like this in the second- and third-line setting. When you look at the different PI3K inhibitors, they have similar overall response rates and progression-free survival [PFS]. To me, there’s no right or wrong 1 to choose in any clinical setting. Their toxicities are a little bit different, and again 2 are oral and 1 is IV [intravenous] that are approved in this setting. You must look at a patient and their comorbidities and what your goals are with the patient in deciding which PI3K kinase inhibitor might fit that patient appropriately. There is some data with both the idelalisib and copanlisib, where they evaluated patients who had progressed within that 2-year time frame, which I’ve said is a higher risk FL patient, which we know has a worse overall outcome. Both of those have been evaluated in that patient population and are shown to have similar responses in PFS in those patients who are considered high-risk by short time to relapse, as in those patients who achieve prolonged remissions with their IV therapy.

Transcript edited for clarity.

Case: A 74-Year-Old Man With Relapsed/Refractory Follicular Lymphoma

Initial presentation

  • A 74-year-old man complains of a 6-month history of fatigue, occasional fevers, decreased appetite, fatigue, and an 8-lb weight loss
  • PMH: unremarkable
  • PE: palpable right axillary and cervical lymph nodes, palpable ~ 3 cm in both locations; spleen palpable 4.5 cm below left costal margin

Clinical Workup

  • Labs: ANC 1.6 x 109/L, WBC 11.2 x 109/L, 44% lymphocytes, Hb 9.6 g/dL, plt 98 x 109/L, LDH 315 U/L, B2M 3.5 µg/mL; HBV negative
  • Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2
  • Bone marrow biopsy showed paratrabecular lymphoid aggregates, 4% involvement
  • Molecular genetics: t(14;18) (q32;q21)
  • PET/CT showed enlargement of right axillary, cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)
  • Ann Arbor Stage IV; ECOG 0


  • He was treated with R-CHOP for 6 cycles, achieved complete response and continued rituximab maintenance
  • 24 months later he complained of increasing weight loss, fever and drenching sweats as well as more enduring fatigue and new onset itching; he was currently taking antibiotics for his 3rd bacterial infection in the past year
    • Repeat PET/CT revealed progression of disease
    • He was started on bendamustine + rituximab for 6 cycles and continued on rituximab maintenance
    • Repeat lymph node biopsy grade 2 follicular lymphoma
  • 12 months later he complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued
    • He was started on idelalisib 150 mg PO BID
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