Ten-year follow-up of the JCOG0203 trial on R-CHOP in FL patients

On 1 November 2018, Takashi Watanabe from the National Cancer Center Hospital, Tokyo, Japan, and colleagues, published in The Lancet Haematology a 10-year follow-up outcome analysis of the  Japan Clinical Oncology Group (JCOG) 0203 phase II/III trial (NCT00147121).

During the JCOG0203 trial, previously-untreated patients with indolent B-cell lymphoma, including follicular lymphoma (FL) from 44 centers around Japan, were randomly assigned to either rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O), and prednisone (P) (R-CHOP) every three weeks (R-CHOP-21) or every two weeks (R-CHOP-14), without R maintenance. The aim of this follow-up analysis was to assess progression-free survival (PFS), overall survival (OS), incidence of secondary malignancies, and incidence of histological transformation more than 10 years after the JCOG0203 trial.

Study design

• N = 300 (2002–2007) previously-untreated advanced-stage indolent B-cell lymphoma patients were randomly assigned (1:1) to six cycles of R-CHOP-14 (every two weeks; n = 151) or R-CHOP-21 (every three weeks; n =149)
  • Same R-CHOP dosing between the two groups:
  • R: 375 mg/m² on Day 1, C: 750 mg/m², H: 50 mg/m², and O: 1.4 mg/m² (capped at 2.0 mg) administered intravenously on Day 3. Oral P was administered once a day at 100 mg from Days 3–7 (for 5 days)
• In the R-CHOP-14 and R-CHOP-21 groups, 81% (n = 123) and 84% (n = 125), respectively were patients with Grade 1–3a FL
• Data updated in February 2017, 10 years after the last enrolment
• Survival status and disease status was updated for all living participants except for 16 (5%) of them. One patient was not eligible for the survival analysis (n = 299)

Results

• Median follow-up (range) across groups = 11.2 (1–12.7) years
• R-CHOP-14
  • 10-year PFS = 39% (95% CI, 31–47)
  • 10-year OS = 85% (95% CI, 78–90)
  • Disease progression (PD) within two years of initial chemotherapy = 30% (n = 46/151)
• R-CHOP-21
  • 10-year PFS = 33% (95% CI, 25–41)
  • 10-year OS = 81% (95% CI, 74–86)
  • Disease progression (PD) within two years of initial chemotherapy = 32% (n = 47/149)
• The two groups did not significantly differ in their PFS or OS (HR = 0.89, [95% CI, 0.67–1.17] and HR = 0.87, [95% CI, 0.52–1.45], respectively)
• Multivariable analysis revealed the following unfavorable parameters for PFS:
  • Male gender (HR =1.57, [95% CI,1.16–2.12])
• Multivariable analysis revealed the following unfavorable predictor of OS:
  • Age ≥ 61 years (HR = 2.03, [95% CI,1.19–3.45])
  • Increased lactate dehydrogenase (LDH) (HR = 2.38, [95% CI,1.27–4.43])
• In Grade 1–3a FL patients (n = 248):
  • 5-year PFS = 45% (95% CI, 39–51)
  • 8-year PFS = 39% (95% CI, 33–45)
  • 10-year PFS = 36% (95% CI, 30–42)
  • 5-year OS = 94% (95% CI, 91–97)
  • 8-year OS = 87% (95% CI, 82–91)
  • 10-year OS = 85% (95% CI, 79–89)

Safety & histological transformation

• During the follow-up, histological transformation was:
  • diagnosed in 11% (n = 27/248) of patients with Grade 1–3a at enrolment
  • had a 3-year cumulative incidence of 2.4% (95% CI, 1.0–4.9)
  • had a 5-year cumulative incidence of 3.2% (95% CI, 1.5–6.0)
  • had an 8-year cumulative incidence of 8.5% (95% CI, 5.4–12.4)
  • had a 10-year cumulative incidence of 9.3% (95% CI, 6.1–13.4)
• Three deaths (all in the R-CHOP-21 group) were reported due to late infections (pneumonia, interstitial pneumonitis, sepsis)
• After 10 years, secondary malignancies were reported in 9% of the patients in either the R-CHOP-14 or R-CHOP-21 group, and lead to death, five patients in the R-CHOP-14 and four in the R-CHOP-21 group
• Hematological malignancies developed in n = 3 patients in the R-CHOP-14 (1 acute lymphoblastic leukemia, 1 acute myeloid leukemia, and 1 myelodysplastic syndrome) and n = 7 in the R-CHOP-21 group (1 acute myeloid leukemia, 1 chronic myeloid leukemia, and 5 myelodysplastic syndromes)

This long-term follow-up of the JCOG0203 study provided an outcome analysis after more than ten years of the original trial. The investigators showed that approximately 30% of patients with advanced-stage FL receiving R-CHOP, did not progress after ten years without R maintenance. Both histological transformation and the incidence of secondary malignancies remained low after ten years for these patients (11% and 8.1%, respectively). These results indicate that R-CHOP continues to be a treatment option for newly-diagnosed indolent B-cell lymphoma patients but clinicians should be aware of the potential occurrence of late secondary malignancies.