Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma

a 10-year follow-up analysis of the JCOG0203 trial

JCOG0203 Collaborators

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods: In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], 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]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Original languageEnglish
Pages (from-to)e520-e531
JournalThe Lancet Haematology
Volume5
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

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Follicular Lymphoma
Incidence
Disease-Free Survival
Neoplasms
Japan
Research Personnel
Therapeutics
Intention to Treat Analysis
Survival
Medical Oncology
Vincristine
B-Cell Lymphoma
Granulocyte Colony-Stimulating Factor
Hematologic Neoplasms
Random Allocation
Prednisone
Doxorubicin
Cyclophosphamide
Communicable Diseases
Maintenance

ASJC Scopus subject areas

  • Hematology

Cite this

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma : a 10-year follow-up analysis of the JCOG0203 trial. / JCOG0203 Collaborators.

In: The Lancet Haematology, Vol. 5, No. 11, 01.11.2018, p. e520-e531.

Research output: Contribution to journalArticle

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title = "Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial",
abstract = "Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods: In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], 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]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50{\%}) were assigned to the R-CHOP-21 group and 151 (50{\%}) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33{\%}, 95{\%} CI 25–41; R-CHOP-14 39{\%}, 31–47; hazard ratio 0·89, 95{\%} CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39{\%} (33–45) at 8 years and 36{\%} (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2{\%} (95{\%} CI 1·5–6·0) at 5 years, 8·5{\%} (5·4–12·4) at 8 years, and 9·3{\%} (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1{\%} (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9{\%} (1·3–5·5). Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.",
author = "{JCOG0203 Collaborators} and Takashi Watanabe and Kensei Tobinai and Masashi Wakabayashi and Yasuo Morishima and Hirofumi Kobayashi and Tomohiro Kinoshita and Takayo Suzuki and Motoko Yamaguchi and Kiyoshi Ando and Michinori Ogura and Masafumi Taniwaki and Naokuni Uike and Tadashi Yoshino and Sigeru Nawano and Takashi Terauchi and Tomomitsu Hotta and Hirokazu Nagai and Kunihiro Tsukasaki and Mitsutoshi Kurosawa and Kayo Yamagishi and Naoki Kobayashi and Koichiro Minauchi and Hideo Harigae and Noriko Fukuhara and Naoto Takahashi and Yoshihiro Kameoka and Shin Matsuda and Yurie Saitoh and Norifumi Tsukamoto and Akihiko Yokohama and Nobuko Kubota and Yosuke Minami and Nobuhiko Yamauchi and Kyoya Kumagai and Hideki Tsujimura and Koji Izutsu and Dai Maruyama and Nobuyuki Takayama and Kazuma Ohyashiki and Daigo Akahane and Tatsu Shimoyama and Takaki Shimada and Yutaro Kamiyama and Nobuaki Dobashi and Izumi Wasada and Fumiaki Sano and Madoka Takimoto and Takaaki Chou and Takuro Ishiguro and Yasufumi Masaki",
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TY - JOUR

T1 - Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma

T2 - a 10-year follow-up analysis of the JCOG0203 trial

AU - JCOG0203 Collaborators

AU - Watanabe, Takashi

AU - Tobinai, Kensei

AU - Wakabayashi, Masashi

AU - Morishima, Yasuo

AU - Kobayashi, Hirofumi

AU - Kinoshita, Tomohiro

AU - Suzuki, Takayo

AU - Yamaguchi, Motoko

AU - Ando, Kiyoshi

AU - Ogura, Michinori

AU - Taniwaki, Masafumi

AU - Uike, Naokuni

AU - Yoshino, Tadashi

AU - Nawano, Sigeru

AU - Terauchi, Takashi

AU - Hotta, Tomomitsu

AU - Nagai, Hirokazu

AU - Tsukasaki, Kunihiro

AU - Kurosawa, Mitsutoshi

AU - Yamagishi, Kayo

AU - Kobayashi, Naoki

AU - Minauchi, Koichiro

AU - Harigae, Hideo

AU - Fukuhara, Noriko

AU - Takahashi, Naoto

AU - Kameoka, Yoshihiro

AU - Matsuda, Shin

AU - Saitoh, Yurie

AU - Tsukamoto, Norifumi

AU - Yokohama, Akihiko

AU - Kubota, Nobuko

AU - Minami, Yosuke

AU - Yamauchi, Nobuhiko

AU - Kumagai, Kyoya

AU - Tsujimura, Hideki

AU - Izutsu, Koji

AU - Maruyama, Dai

AU - Takayama, Nobuyuki

AU - Ohyashiki, Kazuma

AU - Akahane, Daigo

AU - Shimoyama, Tatsu

AU - Shimada, Takaki

AU - Kamiyama, Yutaro

AU - Dobashi, Nobuaki

AU - Wasada, Izumi

AU - Sano, Fumiaki

AU - Takimoto, Madoka

AU - Chou, Takaaki

AU - Ishiguro, Takuro

AU - Masaki, Yasufumi

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods: In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], 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]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

AB - Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial. Methods: In the phase 2–3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1–3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m2], given on day 1, plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], 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]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121. Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25–41; R-CHOP-14 39%, 31–47; hazard ratio 0·89, 95% CI 0·67–1·17). In 248 patients with grade 1–3a follicular lymphoma, progression-free survival was 39% (33–45) at 8 years and 36% (30–42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5–6·0) at 5 years, 8·5% (5·4–12·4) at 8 years, and 9·3% (6·1–13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1–12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3–5·5). Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up—both of which could lead to death. Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

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