FL

Results from the phase III FOLL05 clinical trial in advanced stage symptomatic follicular lymphoma: long-term data confirm R-CHOP is best choice to achieve most durable disease control

On November 2, 2017, Stefano Luminari of the University of Modena and Reggio Emilia, Hematology Unit of Arcispedale Santa Maria Nuova in Modena, Italy and colleagues published online in The Journal of Clinical Oncology long-term results from the FOLL05 phase III clinical trial of patients with advanced follicular lymphoma (FL).

In this prospective, randomized, open-label, multi-center study, previously untreated advanced-stage symptomatic FL patients were randomly assigned to receive eight doses of rituximab combined with eight courses of cyclophosphamide, vincristine, and prednisone (R-CVP); six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); or six cycles of fludarabine and mitoxantrone (R-FM). The purpose of this clinical trial was to identify the best immunochemotherapy (ICT) regimen for first-line treatment of advanced-stage FL among the three aforementioned, as measured by the primary endpoint, time to treatment failure (TTF). Results from this study had been previously reported at a median follow-up of 34 months, whereby R-CHOP and R-FM demonstrated TTF superiority over R-CVP. The results reported herein will focus on the mature study data set, as defined by the median follow-up of 7 years.

Key Highlights:
  • The 8-year TTF was 44%, while R-CHOP and R-FM had better TTF rates than R-CVP: 45% and 49% versus 38%, respectively.
  • After 8 years post-initial diagnosis, a significant proportion of patients (48%) were still free from lymphoma.
  • FOLL05 trial confirms the high efficacy of ICT for the initial treatment of patients with advanced-stage FL.
Treatment:
  • A total of 534 patients were enrolled by 58 Italian institutions; of these patients, 504 were eligible for ITT analysis
    • Eligible patients had histologically confirmed diagnosis of grade 1, 2, or 3a FL per 2008 WHO classification, Ann Arbor stage II to IV disease, age 18 to 75 years with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and active disease according to Italian Society of Hematology guidelines
  • Patients were randomly assigned to receive either R-CVP, R-CHOP, or R-FM
    • Because it was not reimbursed in 2005, maintenance was not admitted and thus considered a primary endpoint failure if administered
  • Response was assessed with clinical examination, contrast-enhanced computed tomography, and bone marrow biopsy if required
  • In addition to TTF, this long-term analysis was conducted to evaluate secondary endpoints such as progression-free survival (PFS), overall survival (OS), cause-specific mortality (CSM), cumulative incidence of second malignancies (SMs), and frequency of late adverse events
    • Molecular response was also included as a secondary endpoint and results published in a separate report
  • Adverse events were registered in accordance with the standard Common Toxicity Criteria for Adverse Events, version 3 (CTCAE, v.3)
Results:
  • The 8-year TTF was 44% (95% CI, 39–49%)
    • R-CHOP and R-FM had better TTF rates than R-CVP: 45% (HR, 0.73; 95% CI, 0.55–0.98; P = 0.033) and 49% (HR, 0.70; 95% CI, 0.52–0.93; P = 0.016) versus 38%, respectively
  • The 8-year PFS rate was 48% (95% CI, 43–52%)
    • R-CVP patients: 42% (95% CI, 35–50%)
    • R-CHOP patients: 49% (95% CI, 40–57%)
    • R-FM patients: 52% (95% CI, 45–60%)
  • The 8-year OS rate was 83% (95% CI, 78–86%); according to intent-to-treat (ITT) analysis:
    • R-CVP patients: 85% (95% CI, 77–91%)
    • R-CHOP patients: 83% (95% CI, 75–89%)
    • R-FM patients: 79% (95% CI, 71–85%), (P = 0.243)
  • The cumulative incidence of SMs at 8 years was 9.4% (95% CI, 6.8–13.0%), and the median time to SM development was 33 months (range, 8–96 months). Cumulative incidence of actual treatment at 8 years was:
    • R-CVP patients: 2% (95% CI, 2.5% to 14.8%)
    • R-CHOP patients: 12% (95% CI, 7.7% to 18.7%)
    • R-FM patients: 9.6% (95% CI, 6.0% to 15.2%), (P = 0.077)
  • Forty-six deaths (61%) resulted from lymphoma progression, and 29 (39%) resulted from other causes
    • Risk of death resulting from lymphoma was comparable among study arms (P = 0.900)
    • Risk of death resulting from non-lymphoma related (NLR) causes was higher with R-FM (11.2% at 8 years) than with R-CVP (1.8%; P = 0.005)
    • The NLR CSM difference between R-CVP and R-CHOP (6.4% for R-CHOP) was not statistically significant (P = 0.157)

 The 8-year OS rate of 84 percent demonstrated in this phase III study in advanced-stage symptomatic FL shows a considerable improvement in the natural history of these patients when compared to historical data. After 8 years post-initial diagnosis, a significant proportion of patients (48%) were still free from lymphoma. What’s more, this study’s particular use of CSM data has provided a complete depiction of the consequences of late events on patient survival, by focusing on life-threatening events and the impact of curable conditions that may be subject to under-reporting. For example, while the data suggested that patients initially treated with R-CVP maintained high chances of achieving second remission, they also had a 43% higher risk of requiring second-line treatment compared with those receiving R-CHOP. The inference and subsequent conclusion was, that if the aim of initial therapy is to maximize treatment activity and increase the chance of durable disease control, R-CHOP should be the preferred option among the three regimens. However, it is reasonable to consider R-CVP a good option in patients for whom the goal of therapy is treatment tolerability, with the caveat that these patients are more likely to require second-line treatment. In the final analysis, the FOLL05 trial confirms the high efficacy of ICT for the initial treatment of patients

Abstract

Purpose: The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years.

Patients and Methods: Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months).

Results:The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP.

Conclusion:With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.

 

 

References
  1. Luminari S et al. Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients with Advanced-Stage Symptomatic Follicular Lymphoma. Journal of Clinical Oncology. 2017 Nov 2. DOI: https://doi.org/10.1200/JCO.2017.74.1652. [Epub ahead of print].