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Weill Cornell Preceptorship on B-Cell Malignancies: Follicular Lymphoma

Follicular Lymphoma (FL) - Peter Martín
  1. What are the non-chemo options for front-line FL?
  2. Can we identify high-risk FL, and how should we manage it?
  3. Can we agree on acceptable surrogate outcomes in clinical trials of FL?
  4. Response criteria in FL
  5. Low Vitamin D and worse outcomes in FL.

What are the non-chemo options for front-line FL?
In one trial patients with advanced FL not requiring therapy were randomized into one of three arms: watch and wait (WW), weekly rituximab x4 (R4), weekly rituximab x4 followed by maintenance rituximab (R4-M) (Ardesha RR, Blood, 2010). The main outcome was time to next therapy (TTNTI). The study showed  that both arms with rituximab increased the TTNTI, but with NO difference in Overall Survival (OS). Editorial: rituximab is a very costly psychotherapy.

In the E4402 trial FL patients achieving complete remission (CR) or partial remission (PR) after R4 induction were randomized to either maintenance rituximab or re-induction with R4 on relapse.  The total duration of benefit with rituximab was the same in both arms, but the re-induction arm consumed about 75% less rituximab compared to the maintenance arm. Editorial: R4 followed by R4 re-induction on relapse appears to be feasible, and costs less. About 40% of patients treated with rituximab are NED 10 years after induction (Martinelli, JCO, 2010).

Lenalidomide + Rituximab (R4-M) were studied in the CALGB 50803. Lenalidomide was given 25 mg PO qd, x21 days out of 28, x1 year. Overall response rate (ORR): 96%, 2-yr progression-free survival (PFS) close to 90%. We will have to wait for the results of the RELEVANCE trial addressing lenalidomide-based therapy. But the results are expected in 2024.

The AO51103 trial evaluated the non-chemotherapy triplet of rituximab + lenalidomide + ibrutinib (375 mg/m2, 20 mg qd 21/28, 560 mg). The overall response rate was 95%, but rash was very frequent, more than 80%.

Can we identify high-risk (HR) FL patients?
Approximately 20% of patients with FL progress in less than 24 months, and their median OS is about 5 years. The new m7-Flipi appears to discriminate a little better ( 

Can we agree on a acceptable surrogate in FL for clinical trials?
Dan Sargent proposed the FLASH30 (CR at 30 months) (ASCO 2015). Patients without progression at 1-year (EFS12) have essentially normal life expectancy.

Vitamin D in FL patients
Low vitaminD in FL is associated with decreased PFS. Editorial: it is reasonable to supplement vitamin D to vitamin D-deficient FL patients (but there is no rationale for the link).

If chemotherapy is required, Dr. Martin prefers bendamustine + rituximab over R-CHOP unless there is the issue of transformation.

Considerations for relapsed FL.
FL can not be cured, the goal is to maintain good quality of life, for as long as possible. If the patient relapses, the standard of care is rituximab (R4) with a response rate of 40%. Obinotuzumab was not superior to rituximab in FL. Obinotuzumab + bendamustine improved PFS in patients with relapsed FL compared to rituximab. Editorial: this increase in PFS is probably irrelevant considering that OS was not improved.

Idelalisib achieves a 56% ORR, with diarrhea, colitis and pneumonitis (Salles, ASCO, 2015). Idelalisib appears to work well on early progress ors with a median PFS of 11 months.

The combination of idelalisib + rituximab + lenalidomide was highly toxic inducing a cytokine storm. Do not use it.

The anti-bcl2 venetoclax is active in FL and can induce tumor lysis syndrome (TLS).
Immune-checkpoint inhibitors exhibit about 40% ORR and are under investigation.

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