Podcast Summary: The Fellow on Call: The Heme/Onc Podcast

Episode 138: Follicular Lymphoma Series, Pt 3 – Relapsed/Refractory Management (Non-Cellular Therapy Options)
Date: September 10, 2025
Hosts: Ronak (A), Vivek (B), Dan (C)
Setting: Rouleaux University Medical Center

Episode Overview

In this episode, the hosts continue their Follicular Lymphoma series, focusing on maintenance strategies and the management of relapsed/refractory follicular lymphoma (FL) without cellular therapy. The discussion is case-based, highlighting evidence-driven approaches and the latest developments in monoclonal antibody and oral therapeutic options. They emphasize nuanced, individualized treatment decisions in a disease noted for its heterogeneity.

Key Discussion Points

1. Frontline Management Recap

[01:15 – 04:34]

• Key Steps:
  • Rule out transformation to DLBCL via excisional biopsy and PET-CT (biopsy most avid node).
  • FL terminology updated: classic FL (“grade 1–3A”), follicular large B-cell lymphoma (formerly grade 3B), and overt transformation to LBCL.
  • Management based on symptom burden and stage:
    • Stage 1: Observation or radiation (no OS difference, avoid unnecessary treatment).
    • Asymptomatic stage 2-4: Observation or rituximab monotherapy.
    • Symptomatic: Bendamustine-rituximab (BR) or R^2 (revlimid/rituximab) preferred over R-CHOP for better toxicity profile.

“Roughly 30 to 40% of patients will follow a very indolent course and will never actually need treatment... Why subject these patients to unnecessary treatments and toxicities?” – Ronak [03:47]

2. Rituximab Maintenance After First-Line Therapy

[05:28 – 09:57]

• Prima trial: Rituximab maintenance every 2 months for 2 years post-induction vs observation.
  • Results: PFS benefit (59% vs 47% at 6 years, and median PFS of 10.5 vs 4.1 years at 9 years), no OS benefit.
  • At 10 years, 53% in Rituxan arm vs 41% in observation arm did not require additional lymphoma treatment.
• Clinical Pearls:
  • Decision to use maintenance is highly individual—benefit is a 10% absolute reduction in need for retreatment after 10 years.
  • Maintenance comes at the cost of more infusions and doubled incidence of severe infections.

"The decision to pursue maintenance is really individualized... Some patients say 'I will do anything to delay the time to next treatment.' However, it comes with time in the infusion clinic, and there is double the rate of severe infections." – Vivek [08:10]

3. POD24 – Key Prognostic Marker

[09:57 – 12:38]

• Definition: Progression of disease within 24 months (POD24) of starting chemoimmunotherapy signifies high risk.
• Outcomes:
  • POD24 patients have 5-year OS of 50% vs 90% in non-POD24.
  • Not relevant for those treated with rituximab monotherapy; must have had chemoimmunotherapy.

"The concept of POD24... is by far the most important prognostic factor for our patients." – Dan [10:45]

4. Imaging and Follow-up Strategy

[12:38 – 14:52]

• Surveillance Imaging: Individualized, not indefinite—based on disease stability, anxiety levels, and new symptoms/clinical findings.
• OS not improved by routine long-term imaging in remission.

5. Relapsed/Refractory FL: Management Without Cellular Therapy

a. General Principles

[14:52 – 17:10]

• Not all relapses require immediate therapy if asymptomatic.
• Single-agent anti-CD20 (rituximab or obinutuzumab) preferred for older, frail, or minimally burdened patients.
  • Obinutuzumab is a type 2 antibody with different activity/side effect profile than rituximab.
  • Study (JCO 2015): Obinutuzumab had a higher ORR but similar PFS/OS as rituximab.
• Radiation reasonable for local control or palliation.

"Obinutuzumab is a type 2 antibody with increased antibody dependent cellular cytotoxicity, phagocytosis and direct cellular cytotoxicity... there are high response rates with obinutuzumab, but it does not translate into improved overall disease control." – Ronak [16:00]

b. When to Avoid Repeat Chemotherapy

[17:45 – 21:26]

• Historically, re-treatment with chemoimmunotherapy (BR or R-CHOP) was standard, but concern over toxicity (secondary leukemia, lymphodepletion, infection risk).
• R-CHOP reserved for transformation, not preferred for indolent relapse.

c. Rituximab + Lenalidomide (R^2) – AUGMENT Study

[21:26 – 23:52]

• AUGMENT trial (JCO 2019): R^2 vs rituximab monotherapy:
  • ORR: 78% (R^2) vs 50% (ritux alone)
  • CR rate: 34% vs 18%
  • Median PFS: 39 months vs 14 months
• Toxicities: Rash, cytopenias, fatigue (dose modifications may be necessary). Renal dose adjustment required.

d. Triplet Therapy: Tafasitamab + Lenalidomide + Rituximab (INMIND Study, ASH 2024)

[21:26 – 23:52]

• Tafasitamab: Anti-CD19 mAb (weekly infusions x3 months, then q2 weeks x9 months).
• INMIND trial: Triplet improved median PFS (22 vs 14 months), CR rate higher (50% vs 40%) in high-risk, anti-CD20-refractory FL.
• Clinical context: Regimen is cumbersome and may be superseded by new therapies (bispecific Abs, CAR T); practical adoption uncertain.

"Hard to say... Is this practically something that we're going to be seeing a lot of use for if we're having these other therapies that are so highly active on the horizon as well?" – Dan [23:31]

e. Obinutuzumab + Lenalidomide (GALEN Study)

[24:52 – 25:59]

• GALEN (Phase 2, single-arm):
  • 18 months lenalidomide, 2 years obinutuzumab maintenance.
  • 2-year PFS ~65% (similar to R^2 in AUGMENT) but longer therapy and more infections.
  • May truncate maintenance in practice; longer therapy now less desirable due to bispecific options.

f. Oral Tazemetostat (EZH2 Inhibitor) for Multiply Relapsed/Refactory Disease

[25:59 – 28:30]

• Role: Non-cellular oral option pre-bispecific/CAR T or for those averse to these.
• Data (Phase 2): ORR 70% in EZH2-mutant (20% of FL), 35% in wild-type; median PFS ~12 months for both groups; very well-tolerated.
• Approval: For all-comers regardless of EZH2 status.

"The drug was extremely well tolerated with minimal side effects. It can really be a good palliative option for some of our patients." – Vivek [27:41]

Notable Quotes & Memorable Moments

• On PFS vs OS and patient-centered care:
  "Anytime you see that gap of a difference, unless it's a truly transformative therapy, you should think about maybe it's that arm with a really, really long median PFS. Maybe it was hovering just above the 50% line... The bigger question is to next lymphoma treatment." – Vivek [07:46]

• On individualized imaging:
  "Imaging these patients forever is definitely not necessary. You can use it, have a discussion with the patient... It's very individualized and very much important to discuss that with the patient." – Vivek [13:25]

• On the proliferation of new options:
  "It really seems like it's a double-edged sword to have more options in the relapse setting... Good for our patients, but it makes it challenging to know exactly which one to choose." – Vivek [23:52]

• On treatment heterogeneity:
  "Just because you have an FDA approval for a triplet like tafecitumab, lenalidomide, rituximab, doesn’t mean you have to give that to every patient." – Vivek [29:09]

Important Timestamps

• Frontline Treatment Recap – [01:15 – 04:34]
• Rituximab Maintenance Evidence – [05:28 – 09:57]
• POD24 & Prognosis – [09:57 – 12:38]
• Surveillance and Relapse Evaluation – [12:38 – 14:52]
• Relapsed FL: Management by Disease Burden – [14:52 – 17:10]
• Second-Line Options & R^2 Evidence – [17:45 – 23:52]
• Triplet Therapy & Next-Gen Agents – [21:26 – 23:52]
• Obinutuzumab + Lenalidomide (GALEN) – [24:52 – 25:59]
• Tazemetostat as a Salvage Option – [25:59 – 28:30]
• Closing Pearls – [29:03 – 29:32]

Final Takeaways

• Relapsed/refractory FL is a diverse disease; management requires individualized, patient-centered decisions.
• Rituximab maintenance can delay need for next therapy but adds infections and does not prolong overall survival.
• Multiple non-cellular therapy options (anti-CD20 mAbs, lenalidomide combos, tafasitamab, tazemetostat) exist, but lack clear OS benefit—treatment should align with patient goals and comorbidities.
• Emerging therapies (bispecifics, CAR T) are covered in future episodes and may further shift practice.

For deeper dives, refer to the listed trials: Prima, AUGMENT, INMIND (ASH 2024), GALEN, and the tazemetostat phase 2 study.