First-Line R-CHOP a Viable Option in Advanced Follicular Lymphoma, Long-Term Findings Show

Two variants of the chemotherapy regimen R-CHOP (R-CHOP-21 and R-CHOP-14) resulted in comparable overall survival (OS) and progression-free survival (PFS) in patients with previously untreated stage III or IV indolent B-cell lymphoma, including grades 1 to 3 follicular lymphoma (FL), according to a long-term follow-up analysis from a combined phase II/III randomized trial.¹

The trial authors, led by Takashi Watanabe, MD,National Cancer Center Hospital, Tokyo, wrote inLancet Hematologythat a standard first-line treatment in patients with advanced-stage FL remains undetermined. “However, because of the reduction in incidence of transformation without an increase in either secondary malignancies or fatal infectious events, the R-CHOP regimen should be a candidate for standard treatment, particularly from the viewpoint of long-term follow-up,” they wrote.

The new analysis found that 10-year PFS did not differ significantly between R-CHOP-21 and R-CHOP-14. The R-CHOP-21 ten-year PFS rate was 33% and the R-CHOP-14 ten-year PFS rate was 39%. The hazard ratio (HR) was 0.89 (95% CI, 0.67-1.17). The median follow-up was 11.2 years.

More than 80% of the patients in each group had grade 1 to 3a FL (R-CHOP-21, 84%; R-CHOP-14, 81%). Among the 248 patients with FL, PFS was 39% (95% CI, 33-45) at 8 years and 36% (95% CI, 30-42) at 10 years.

JCOG 0203 was a phase II/III trial that enrolled 300 treatment-naïve patients with indolent B-cell lymphoma and FL from 44 hospitals in Japan.²Patients were randomized 1:1 to receive 6 cycles of R-CHOP. Dosing consisted of rituximab (Rituxan) 375 mg/m²on day 1, plus cyclophosphamide 750 mg/m²and doxorubicin 50 mg/m². Patients also received vincristine 1.4 mg/m², capped at 2.0 mg, given intravenously on day 3, and oral prednisone 100 mg once daily on days 3—7.

One group repeated the cycle every 3 weeks (R-CHOP-21). The R-CHOP-14 group followed 2-week cycles with granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8. Maintenance rituximab was not allowed for these patients.

Investigators adjusted for factors including patient age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution. Interventions were not masked for patients or investigators. The primary endpoint of the phase III portion was PFS, and the primary endpoint of the phase II part of the study was the proportion of patients who achieved a complete response (CR).

Study accrual lasted 4.5 years, and follow-up was 3 years after registration closed. The investigators collected data 10 years after the final patient enrolled and updated the data on the cutoff date of Feb 28, 2017. They also defined an additional analysis of the incidence of histological transformation 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, assessed at 10 years after the last patient was enrolled. Follow-up remains ongoing.

In addition to OS and PFS, the authors also assessed the incidence of secondary malignancies, as well as the incidence of histological transformation, in their 10-year follow-up analysis of the JCOG0203 trial.

They found that the cumulative incidence of histological transformation was 3.2% (95% CI, 1.5—6.0) at 5 years after enrollment. At 8 years, 8.5% of patients (95% CI, 5.4-12.4) had experienced transformation, while 9.3% of patients (95% CI, 6.1-13.4) had at 10 years after enrollment. The cumulative incidence of secondary malignancies was 8.1% (95% CI, 5.1–12.0) at 10 years and the cumulative incidence of hematological secondary malignancies was 2.9% (95% CI, 1.3–5.5).

The survival analysis included 299 patients. Of these, 16 patients (5%) were lost to follow-up. The authors found that the 2 treatment groups did not differ significantly in PFS or OS. The 10-year OS was 81% in the R-CHOP-21 group versus 85% in the R-CHOP-14 group (HR, 0.87; 95% CI, 0.52—1.45). Additionally, 47 patients (32%) in the R-CHOP-21 group and 46 patients (30%) in the R-CHOP-14 group experienced disease progression within 2 years of initial treatment.

No patients in either group died from protocol-related causes. In the R-CHOP-21 group, a total of 31 patients had died as of data cutoff. The leading cause of death in this group was disease progression, accounting for 20 deaths. Four patients died from secondary cancers. Four patients died from other diseases, including intracranial hemorrhage, pneumonitis and sepsis. Three R-CHOP-21 patients died from salvage therapy-related causes.

Among R-CHOP-14 patients, 28 patients had died as of data cutoff. As with R-CHOP-21 patients, disease progression was the leading cause of death, accounting for 17 deaths. Five patients died from secondary cancers. One patient each died from intracranial hemorrhage and suicide. Four R-CHOP-14 patients died from salvage therapy-related causes.

The authors attributed the favorable OS data to various factors, including the low incidence of secondary malignancies, reduced incidence of histological transformation, lack of deaths related to first-line treatment, and low fatal infection rates during treatment and follow-up.

Watanabe et al. suggested that clinicians should not compromise the future survival of patients with FL because of late toxicities of the first-line treatment. “According to the long-term outcomes of phase 3 trials, in terms of overall survival, careful consideration is needed to choose the intervention that should reduce the probability of histological transformation and have low genotoxicities, which is one of the factors involved in the development of secondary malignancies,” they wrote. “Clinicians should also consider severe complications of infectious diseases in the long-term follow-up and during the treatment, which could lead to death.”

References

1. Watanabe T, Tobinai K, Wakabayashi M, et al. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.Lancet Haematol. 2018;5:e520—31.
2. Watanabe T, Tobinai K, Shibata T, et al. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial.J Clin Oncol.2011;29(30):3990-98. doi: 10.1200/JCO.2011.34.8508.