Frontline Immunochemotherapy Recommended in Advanced-Stage Follicular Lymphoma

Long-term follow-up results of the FOLL05 trial confirm the efficacy of immunochemotherapy regimens for patients with previously untreated advanced-stage follicular lymphoma (FL), according to findings of a post-hoc analysis recently published in theJournal of Clinical Oncologycovering a median 7 years of follow-up.¹In the prospective study, there was an 8-year overall survival (OS) rate of 83% seen across 3 regimens with different chemotherapy backbones.

The investigators suggested a preference for frontline R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin [Adriamycin], vincristine, and prednisone), following the results of the trial, as R-CHOP demonstrated similar survival benefits but an improved safety profile and a reduced risk of needing additional therapy compared with the 2 other regimens studied.

“This long-term update of the FOLL05 trial confirms the high efficacy of immunochemotherapy for the initial treatment of patients with advanced-stage follicular lymphoma in need of therapy. In addition, with the 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 3 regimens,” Stefano Luminari, MD, and his co-authors wrote in the report of the updated findings.

In the randomized, open-label multicenter phase III FOLL05 trial, 534 patients were originally randomized to 1 of 3 immunochemotherapy treatment arms: R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone; arm A), R-CHOP (arm B), or R-FM (rituximab plus fludarabine and mitoxantrone; arm C).

Of the 504 patients eligible for the intent-to-treat analysis, the median age was 55 years (range, 30-75), more than half were male, and the majority had a FLIPI score of 0 to 2. Patients had grade 1 to 3a FL by World Health Organization classification and Ann Arbor stage II to IV disease.

The primary analysis followed patients for a median of 34 months and demonstrated a 3-year time to treatment failure (TTF) of 46% in arm A, 62% in arm B, and 59% in arm C. At 3 years, the progression-free survival (PFS) rates were 52%, 68%, and 63%, respectively.²

While each of the regimens were generally tolerated, there was a higher degree of grade 3/4 adverse events (AEs) seen in arm C. Grade 3/4 neutropenia was seen in 28% of patients treated with R-CVP, 50% with R-CHOP, and in 64% of patients in the R-FM arm. Grade 3/4 thrombocytopenia was experienced by 0%, 3%, and 8% of patients treated with R-CVP, R-CHOP, and R-FM, respectively. Five cardiac events were observed, including 2 of grade 3/4 (1 each from the R-CVP and R-CHOP arms). There were no treatment-related deaths in the study.

In the long-term analysis, the 8-year TTF was 45% with R-CHOP compared with 38% with R-CVP (HR, 0.73; 95% CI, 0.55-0.98;P= .033), and 49% with R-FM (HR compared with R-CVP, 0.70; 95% CI, 0.52-0.93;P= .016). Overall, the 8-year TTF was 44% (95% CI, 39%-49%) across the 3 treatment arms. PFS at 8 years was 42%, 49%, and 52% in arms A, B, and C, respectively, and 48% (95% CI, 43%-52%) overall.

When adjusting for FLIPI2 scores, the hazard ratio for PFS for R-CHOP versus R-CVP was 0.73 (95% CI, 0.54-0.98;P= .037), and the hazard ratio was 0.67 for R-FM versus R-CVP (95% CI, 0.50-0.91;P= .009).

Analysis of the intention-to-treat population demonstrated an OS of 85% (95% CI, 77%-91%) at 8 years for R-CVP, 83% (95% CI, 75%-89%) with R-CHOP, and 79% (95% CI, 71%-85%) with R-FM (P= .243). Stable responses (complete or partial) were experienced by 41% in arm A, 51% in arm B, 51% in arm C, or 47% overall.

“Considering the updated results, we conclude with high confidence that patients treated with R-CHOP had a lower risk of progressive disease than those treated with R-CVP. In addition, our analysis of OS suggests that survival is similar between R-CHOP and R-CVP,” the co-authors wrote.

Within the study, 248 patients had primary refractory disease or had experienced progression or relapse. Of these, 208 (41%) required salvage treatment, of which 90 received conventional immunochemotherapy, 75 had autologous stem cell transplant, 33 received immunotherapy, and 10 had subsequent radiotherapy. Patients who were initially randomized to R-CVP had a higher risk for requiring a second-line therapy (55%) versus 38% with R-CHOP and 32% with R-FM (P<.001).

Secondary malignancies were reported in 41 patients, including 14 hematologic malignancies, 27 solid tumors, and 11 patients had a histologic transformation of their disease. The median time to development of secondary malignancy was 33 months (range, 8-96). A higher incidence of secondary malignancies was seen in arm B (12%) at 8 years compared with 6.2% in arm A and 9.6% in arm C.

Non-lymphoma—related risk of death was higher with R-FM than R-CVP (11.2% vs 1.8% at 8 years;P= .005), no statistically significant difference was demonstrated between the 2 in non-lymphoma—related cause-specific mortality (P= .157).

&ldquo;Our cause-specific mortality data provide a better description of the consequences of late events for patient survival, focusing on life-threatening events and reducing the impact of curable conditions that are also subject to under-reporting. Patients treated with R-FM had high rates of secondary malignancies and a higher risk of dying as a result of causes unrelated to lymphoma progression compared with those receiving R-CVP,&rdquo; Luminari et al wrote.

The authors also noted that these results compared favorably with that of similar studies, supporting the preference for R-CHOP.

References:

1. 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 [published online November 2, 2017].J Clin Oncol.doi: 10.1200/JCO.2017.74.1652.
2. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.J Clin Oncol.2013;31(12):1506-1513. doi: 10.1200/JCO.2012.45.0866.