ArticlesAnthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial
Introduction
Diffuse large B-cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma, with various clinical, immunophenotypic, and genetic features.1 Treatment outcome has been substantially improved with the use of an anti-CD20 monoclonal antibody, rituximab, in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).2, 3, 4, 5 Nevertheless, remission failure or relapse occurs in about 30–40% of all patients and remains a major clinical issue in diffuse large B-cell lymphoma.6, 7 Since R-CHOP was established as the standard of care,3 a revised International Prognostic Index (R-IPI; low-risk, intermediate-risk, or high-risk R-IPI),8 the cell of origin (germinal centre B-cell, or non-germinal centre B-cell),9, 10 and BCL-2 and MYC double expression11, 12 have been revealed as important clinicopathological factors in risk stratification of diffuse large B-cell lymphoma.
Anthracycline is a key cytotoxic drug of R-CHOP. Anthracycline dose intensification has been reported to improve prognosis in acute myeloid leukaemia.13, 14 Since increasing doxorubicin dose is difficult in clinical practice because of cardiotoxicity, epirubicin, a 4′-hydroxyl epi-isomer of doxorubicin, has been proven to be less cardiotoxic than doxorubicin and is a potential candidate for anthracycline dose intensification.15 A randomised trial16 of Chinese patients with diffuse large B-cell lymphoma and follicular lymphoma grade 3B showed that rituximab, cyclophosphamide, epirubicin 70 mg/m2, vincristine, and prednisone (R-CEOP70) had an efficacy similar to that of R-CHOP50 (50mg/m2 doxorubicin). Moreover, incorporation of high-dose epirubicin (90mg/m2 epirubicin, R-CEOP90) resulted in more patients having improved overall survival and progression-free survival than with R-CHOP50 in another phase 2 study.17 Therefore, establishing whether R-CEOP70 is non-inferior to R-CHOP50 with less long-term cardiotoxicity is of great interest, as is whether R-CEOP90 has superior efficacy to R-CHOP50 or R-CEOP70 with clinically acceptable toxic effects.
For the purpose of anthracycline dose optimisation, we compared the efficacy and safety of R-CHOP50, R-CEOP70, and R-CEOP90 in a Chinese cohort of patients with diffuse large B-cell lymphoma.
Section snippets
Study design and participants
We did a multicentre, phase 3, randomised controlled trial (NHL-001), in which patients were enrolled at 20 centres (appendix p 7) in China within cooperative network of the Multicenter Hematology–Oncology Programs Evaluation System (M-HOPES).
Eligible patients were aged 16–80 years; had newly diagnosed, histologically confirmed diffuse large B-cell lymphoma or follicular lymphoma grade 3B;1 an Eastern Cooperative Oncology Group performance status of 2 or less; had no previous history of
Results
Between May 15, 2013, and March 16, 2016, 648 patients were enrolled, with 404 (62%) young patients randomly assigned to receive R-CHOP50 (n=135), R-CEOP70 (n=134), or R-CEOP90 (n=135) and 244 (38%) older patients randomly assigned to receive R-CHOP50 (n=122) or R-CEOP70 (n=122; figure 1). The number of patients screened was not formally collected. Four patients were excluded for withdrawing consent and one for misdiagnosis of Hodgkin lymphoma. The remaining patients received at least one dose
Discussion
This study was a multicentre, phase 3, randomised controlled trial, incorporating different doses of anthracycline into the front-line treatment of diffuse large B-cell lymphoma. Both objectives of this study were met, with the inclusion and exclusion criteria2, 3, 18 and the staging of the patients5 consistent with previous trials. Among all patients, R-CEOP70 showed similar efficacy to R-CHOP50 with mild cardiotoxicity. For young patients, R-CEOP90 significantly prolonged progression-free
Data sharing
There are currently no plans to share data not included in this paper.
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