Advances in treatments for follicular lymphoma: results of the FOLL12 and NCT01865617 studies

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (iNHL). Frontline treatment for FL usually comprises of an anti-CD20 monoclonal antibody, such as rituximab, and chemotherapy (or chemoimmunotherapy).

Maintenance with rituximab after response to frontline therapy is considered safe, improves progression-free survival (PFS), and typically has manageable side effects. However, rituximab (R)-maintenance has not resulted in a significant change to overall survival (OS). 

The FOLL12 study, conducted by Massimo Federico, from the Dipartimento Chirurgico, University of Modena and Reggio Emilia, Modena, IT, investigated patients with intermediate-high risk FL, and found that the omission of R-maintenance resulted in a significantly lower 3-year PFS.

FOLL12 study design

• Multicenter, randomized, phase III, non-inferiority study
• Compared standard vs response adapted maintenance
• Primary endpoint was three-year PFS
• Patients had stage II-IV, previously untreated, intermediate-high risk FL and required therapy
• N=790; n=394 in standard arm, n=396 in experimental arm
  • Patients were well-balanced according to baseline characteristics
• All patients received induction immunochemotherapy (ICT) with 6 cycles of R-CHOP or R-bendamustine, followed by two additional doses of rituximab
  • Patients in standard arm were treated with bimonthly rituximab doses for up to two years
  • Patients in the experimental arm were managed according to their metabolic and molecular response
    • Complete metabolic and molecular response: no therapy
    • Complete metabolic response without molecular response: 4 weekly rituximab doses
    • Lack of metabolic response: radio-immunotherapy with ibritumomab tiuxetan followed by standard rituximab maintenance

FOLL12 results

• After induction therapy, 88% of patients were PET-negative and 91% were MRD negative
• After median follow-up of 37 months (range, 1–71 months):
  • 3-year OS was 96%
  • 3-year PFS was 76%
• A planned interim analysis which was submitted to the data safety monitoring committee (DSMC) showed that the response-oriented experimental arm was significantly inferior to the standard maintenance arm in terms of PFS
  • Estimated 3-year PFS, 68% vs 84%; HR, 2.05 [95% CI 1.50–2.81; P<0.0001]
  • The DSMC considered it unlikely that a longer follow-up would modify the results

FL follows a relapsing, remitting course and as it is still incurable, novel treatment options are being explored. The outcome of transformed FL (tFL) is often poor, and immunotherapy (and the introduction of chemoimmunotherapy) could lead to a reduced incidence of tFL.

A phase I/II clinical trial (NCT01865617), conducted by Alexandre Hirayama and colleagues, from the Fred Hutchinson Cancer Research Center, Seattle, US, investigated CD19 CAR T-cell immunotherapy in patients with clinically aggressive relapsed/refractory (R/R) FL. The study found that CAR T therapy resulted in durable remissions in a high proportion of patients.

NCT01865617 study design

• Phase I/II trial
• N=21 adult patients with R/R CD19+ B-cell malignancies
  • 75% had Stage III or IV disease
  • 62% had extranodal involvement
  • 75% had intermediate or high Follicular Lymphoma International Prognostic Index (FLIPI) score
  • N=8 had FL, n=13 had transformed FL (tFL)
• Patients with FL had received a median of 4 prior therapies (range, 2–7)
  • All patients had failed chemoimmunotherapy with an anti‐CD20 antibody and alkylating agents
  • 75% had progressive disease after the last therapy
  • 50% had failed prior autologous (n = 3) or allogeneic (n = 1) hematopoietic cell transplantation
• All patients received lymphodepletion with cyclophosphamide and fludarabine, followed by 2x10⁶ CD19 CAR T cells/kg
• Best responses reported according to the Lugano criteria

NCT01865617 Results

• N = 7/8 patients with FL achieved CR after CAR T therapy
• Median time to CR was 29 days (range 27–42)
  • All patients who achieved CR remained in remission without therapy (median follow up 24 months)
• In patients with tFL, the best overall response without additional therapy 46% (95% CI, 20 – 74)
  • All responding patients achieved CR
    • Median PFS was 11.2 months (95% CI, 3.3–not reached [NR]), after a median follow-up of 38 months
  • In all tFL patients, the median PFS was 1.4 months (95% CI, 1.2 – NR)
  • More patients with tFL had elevated lactate dehydrogenase (LDH; FL vs tFL, 13% vs 69%, P = 0.02) versus patients with FL and fewer had bone marrow involvement (50% vs 15%, P = 0.15)
• No significant difference observed between patients with FL and those with tFL in peak CAR T-cell counts in blood, or in the incidence or severity of cytokine release syndrome (CRS)/neurotoxicity (NT)
• No Grade ≥3 CRS/NT were observed

Conclusion

The FOLL12 study found that in patients with intermediate-high risk FL, omitting R-maintenance resulted in a significantly lower 3-year PFS, despite the attainment of post-induction complete metabolic response. In the phase I/II trial, CD19 CAR T immunotherapy was found to be highly effective, and even resulted in durable CR in a high proportion of adult patients with clinically aggressive R/R FL.

Results of these studies show the effectiveness of R-maintenance in the treatment of high-risk R/R FL. Due to the nature of the disease course, new treatment options are required, with CAR-T potentially being a promising option for FL. As it is very heterogeneous, FL is difficult to treat, and due to there being very few studies on tFL, treatment is usually individualized. Further studies are needed to verify the positive results observed in the FOLL12 and NCT01865617 studies.