Elsevier

The Lancet Haematology

Volume 6, Issue 6, June 2019, Pages e328-e337
The Lancet Haematology

Articles
Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial

https://doi.org/10.1016/S2352-3026(19)30051-1Get rights and content

Summary

Background

Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects.

Methods

In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology–Oncology Programs Evaluation System in China. Young patients (16–60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61–80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1–5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435.

Findings

From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6–77·6) and in the R-CEOP70 group was 72·4% ([66·5–77·5]; HR 1·00 [0·73–1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1–93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7–82·3]; 0·44 [0·25–0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4–83·7%]; 0·49 [0·27–0·86]; p=0·017). Grade 3–4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission.

Interpretation

R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity.

Funding

National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

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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