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Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Background
Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups.
Methods
Patients (aged ?18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1·4 mg/m2 (maximum dose 2 mg), and rituximab 375 mg/m2 on day 1, and oral prednisolone 40 mg/m2 on days 1—5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg, rituximab 375 mg/m2 on day 1, and oral prednisolone 100 mg on days 1—5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m2 on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947.
Findings
1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35—57), 2-year OS was 82·7% (79·5—85·9) in the R-CHOP-14 group and 80·8% (77·5—84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70—1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8—79·1, and R-CHOP-21 74·8%, 71·0—78·4; 0·94, 0·76—1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups.
Interpretation
R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study.
Funding
Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.
0140-6736
1817-1826
Cunningham, D.
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Hawkes, E.A.
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Jack, A.
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Qian, W.
4081a032-ee26-4c53-8a87-e9553ccda8fd
Smith, P.
11f678ab-4aee-426a-aedd-19719d80bbbc
Mouncey, P.
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Pocock, C.
a137d833-44ba-4f19-af4b-e7476b8a8d39
Ardeshna, K.M.
2d3f2d63-9861-46f3-8212-29c19b41cc6a
Radford, J.A.
77dd6342-413d-47e4-8c72-1b7829efba99
McMillan, A.
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Davies, J.
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Turner, D.
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Kruger, A.
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Johnson, P.
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Gambell, J.
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Linch, D.
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Cunningham, D.
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Hawkes, E.A.
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Jack, A.
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Qian, W.
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Smith, P.
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Mouncey, P.
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Pocock, C.
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Ardeshna, K.M.
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Radford, J.A.
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McMillan, A.
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Davies, J.
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Turner, D.
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Kruger, A.
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Johnson, P.
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Gambell, J.
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Linch, D.
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Cunningham, D., Hawkes, E.A., Jack, A., Qian, W., Smith, P., Mouncey, P., Pocock, C., Ardeshna, K.M., Radford, J.A., McMillan, A., Davies, J., Turner, D., Kruger, A., Johnson, P., Gambell, J. and Linch, D. (2013) Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. The Lancet, 381 (9880), 1817-1826. (doi:10.1016/S0140-6736(13)60313-X).

Record type: Article

Abstract

Background
Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups.
Methods
Patients (aged ?18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1·4 mg/m2 (maximum dose 2 mg), and rituximab 375 mg/m2 on day 1, and oral prednisolone 40 mg/m2 on days 1—5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg, rituximab 375 mg/m2 on day 1, and oral prednisolone 100 mg on days 1—5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m2 on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947.
Findings
1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35—57), 2-year OS was 82·7% (79·5—85·9) in the R-CHOP-14 group and 80·8% (77·5—84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70—1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8—79·1, and R-CHOP-21 74·8%, 71·0—78·4; 0·94, 0·76—1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups.
Interpretation
R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study.
Funding
Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.

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Published date: 2013
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 353203
URI: http://eprints.soton.ac.uk/id/eprint/353203
ISSN: 0140-6736
PURE UUID: ad2062e5-5648-44e7-a6cd-1d44b5975809
ORCID for P. Johnson: ORCID iD orcid.org/0000-0003-2306-4974

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Date deposited: 03 Jun 2013 13:10
Last modified: 17 Dec 2019 01:55

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Contributors

Author: D. Cunningham
Author: E.A. Hawkes
Author: A. Jack
Author: W. Qian
Author: P. Smith
Author: P. Mouncey
Author: C. Pocock
Author: K.M. Ardeshna
Author: J.A. Radford
Author: A. McMillan
Author: J. Davies
Author: D. Turner
Author: A. Kruger
Author: P. Johnson ORCID iD
Author: J. Gambell
Author: D. Linch

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