Long-Term FOLL05-Up: R-CHOP Outperforms R-FM and R-CVP for Advanced-Stage Follicular Lymphoma

In 2005, the FOLL05 trial sought to determine the optimal immunochemotherapy (ICT) regimen for firstline treatment of advanced-stage follicular lymphoma (FL): R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), or R-FM (rituximab, fludarabine, mitoxantrone).

After a median follow-up of 84 months (range = 1-119 months), patients with advanced-stage FL experienced an eight-year progression-free survival (PFS) rate of 48 percent (95% CI 43-52), according to results published in the Journal of Clinical Oncology.

While a 2013 report from this trial established that R-CHOP and R-FM were superior to R-CVP, with longer time to treatment failure (TTF) and higher rates of three-year PFS, the 2017 post-hoc analysis  suggests that the more favorable toxicity profile associated with R-CHOP makes it the best immunochemotherapeutic option for this patient population.

“With longer follow-up, we can conclude 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,” noted Stefano Luminari, MD, assistant professor of oncology at the University of Modena and Reggio Emilia in Italy, and co-authors. However, “R-CVP might be seen as a good option for patients for whom the goal of therapy is treatment tolerability.”

The prospective, randomized, open-label, multicenter, phase III trial included previously untreated patients with advanced-stage symptomatic FL. Eligible patients had histologically confirmed grade 1, 2, or 3a FL (according to the 2008 World Health Organization classification); Ann Arbor stage II-IV disease; and an Eastern Cooperative Oncology Group performance status score of 0-2.

Patients with evidence of histologic transformation into aggressive lymphoma at diagnosis, central nervous system involvement, or a history of previous malignancy were excluded.

Between March 2006 and September 2010, 534 patients were enrolled from 58 Italian institutions, then randomized to receive:

  • 8 cycles of R-CVP (n=178)
  • 8 cycles of R-CHOP (n=178)
  • 6 cycles of R-FM (n=178)

A total of 504 patients (median age = 55 years; range = 30-75 years) were analyzed: 168 in the R-CVP arm, 165 in the R-CHOP arm, and 171 in the R-FM arm.

Forty-three patients (8.5%) were lost to follow-up after a median of 64 months (range = 1-101 months).

The rate of eight-year TTF rate (primary endpoint) was 44 percent (95% CI 39-49), and TTF rates were better with R-CHOP (45%; hazard ratio [HR] = 0.73; 95% CI 0.55-0.98; p=0.033) and R-FM (49%; HR=0.70; 95% CI 0.52-0.93; p=0.016), than with R-CVP (38%).

A total of 252 PFS events (defined as disease progression, relapse, or death) were reported, including 68 additional episodes that occurred following the original 2013 report (5 disease progressions, 58 relapses, and 5 deaths not related to lymphoma progression). The eight-year PFS rate was 42 percent with R-CVP (95% CI 35-50), 49 percent with R-CHOP (95% CI 40-57), and 52 percent with R-FM (95% CI 45-60; p values not reported).

In separate analyses, R-CHOP was associated with a lower risk for disease progression, compared with R-CVP (HR=0.73; 95% CI 0.54-0.98; p=0.037), while R-CVP was associated with a lower risk than R-FM (HR=0.67; 95% CI 0.50-0.91; p=0.009).

Eight-year overall survival (OS) rates were similar across the three treatment arms: 83 percent (95% CI 78-86) in the entire population, with specific rates of 85 percent with R-CVP (95% CI 77-91), 83 percent with R-CHOP (95% CI 75-89), and 79 percent with R-FM (95% CI 71-85; p values not reported). The researchers cautioned, though, that the study was not originally powered for OS analysis.

Patients developed a total of 41 secondary malignancies (SMs; 14 hematologic and 27 solid tumors), for an eight-year cumulative incidence of 9.4 percent. The risk of SMs was significantly higher in the R-CHOP group, compared with the R-CVP group (HR=2.59; 95% CI 1.09-6.20; p=0.032), but was not significantly increased for R-FM, compared with R-CVP (HR=2.29; 95% CI 0.94-5.56; p=0.067).

Overall, 208 of 248 patients who had primary-refractory disease or who experienced progressive or relapsed disease required salvage treatment: 90 received conventional ICT, 75 underwent autologous hematopoietic cell transplantation (AHCT), 33 received immunotherapy alone, and 10 received radiation therapy alone. The number of patients able to undergo AHCT was similar among treatment arms: 27 with R-CVP and R-CHOP and 21 with R-FM.

Patients who initially received R-CVP were at higher risk for requiring secondline therapy (n=91; 55%), compared with those receiving R-CHOP (n=63; 38%) or R-FM (n=54; 32%; p<0.001). However, patients treated with R-CVP had a 43 percent higher probability of requiring salvage therapy, compared with the R-CHOP cohort (p value not reported).

Seventy-five deaths occurred during follow-up, most of which were a result of lymphoma progression (n=46; 61%). Risk of death resulting from lymphoma was comparable across the three treatment cohorts (p=0.90), but the risk of death from non-lymphoma related causes was higher with R-FM (11.2% at 8 years) than R-CVP (1.8%; p=0.005). There were no fatal infections recorded during induction therapy or among patients who relapsed.

The study did not allow maintenance therapy, “and we were unable to estimate the effect of prolonged use of rituximab in the comparison among study arms,” the authors wrote of the trial’s limitations. The researchers also noted that since the start of the FOLL05 study, bendamustine plus rituximab (BR) “has been rapidly imposed as first-choice therapy” for this patient population. “We believe [both R-CHOP and BR] represent the best available options to achieve long-lasting remission in patients with previously untreated FL,” they wrote.

Dr. Luminari reports financial support from Roche, Celgene, Gilead, Sandoz, Janssen, and Takeda.


Reference

Luminari S, Ferrari A, Manni M, 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. J Clin Oncol. 2017 November 2. [Epub ahead of print]

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