Elsevier

The Lancet Haematology

Volume 4, Issue 1, January 2017, Pages e46-e55
The Lancet Haematology

Articles
Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group

https://doi.org/10.1016/S2352-3026(16)30171-5Get rights and content

Summary

Background

In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49–67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment.

Methods

For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day −7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day −7 to day −4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of oral prednisone on days 1–5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714.

Findings

Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2–3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5–30·1). The 2-year overall survival was 64·7% (95% CI 55·3–72·7) and median overall survival was not reached (95% CI 30·2–not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3–4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3–4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions.

Interpretation

Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years.

Funding

The Lymphoma Study Association, GlaxoSmithKline.

Introduction

About 30% of all diffuse large B-cell lymphomas (DLBCL) occur in patients older than 70 years and the incidence increases exponentially from ages 20 to 79 years.1 In 2011, the Lymphoma Study Association (LYSA) reported the results of a large phase 2 study in patients older than 80 years treated with an attenuated regimen of rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients older than 80 years with untreated CD20-positive DLBCL, Ann Arbor stage I bulky to IV, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were eligible. 150 patients were included with a median follow-up of 20 months. The 2-year overall survival was 58·9% (95% CI 49·3–67·2%). Toxicities were manageable, with most occurring during the first two cycles.2 In 2008, Pfreundschuh and colleagues published the large phase 3 RICOVER study.3 To prevent early toxicity, they suggested that a pre-phase with vincristine and hydrocortisone could be useful for patients aged 60–80 years with poor performance status.

Ofatumumab is a novel, second-generation, fully human monoclonal antibody that recognises a different epitope of the CD20 antigen than the widely used rituximab. As an anti-CD20 drug, ofatumumab has shown a higher cytotoxic potential against lymphoid cells in vitro than rituximab.4, 5

Research in context

Evidence before this study

We searched PubMed, the American Society of Hematology, the European Society of Hematology, the American Society of Clinical Oncology, and the European Society of Medical Oncology databases with for articles published in English between database inception and Sept 1, 2016, using the search terms “lymphoma, diffuse large B-cell”, “elderly”, “geriatric evaluation”, “prephase”, and “ofatumumab”. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy worldwide, with an incidence that steadily increases with age. In the next 50 years, the number of people aged 85 years and older is likely to quadruple. Since 2005, studies in elderly people have focused on this challenging health issue. These studies emphasised that very elderly patients require adequate therapeutic management, as shown in the case of DLBCL, for which lower doses provided a trade-off between efficacy and safety in patients aged 80 years and older. The Groupe d'Etude des Lymphomes Agressifs reported a prospective phase 2 study of attenuated chemotherapy (miniCHOP) with rituximab, a monoclonal antibody against CD20, at a conventional dose. Median overall survival was 29 months with 62% of patients having a complete response or unconfirmed complete response. Unfortunately, the study results also showed unacceptable early toxicity, occurring mainly during the first two cycles. The German High-Grade Non-Hodgkin Lymphoma Study Group strongly suggested that a pre-phase with vincristine and hydrocortisone could be useful to prevent early toxicity.

Added value of this study

We report an open-label, phase 2 study in patients aged 80 years and older with untreated CD20-positive DLBCL. Patients with DLBCL at any Ann Arbor stage and with any performance status were eligible. Patients received a pre-phase of vincristine and prednisone treatment before starting the first cycle of ofatumumab and miniCHOP combination treatment. The primary objective was to assess the efficacy of the treatment with overall survival. Our result confirms that a substantial proportion of patients with DLCBL aged 80 years and older could achieve a complete response with immunochemotherapy with a pre-phase of ofatumumab and miniCHOP. Additionally, a pre-phase seems to reduce both early death risk and toxicity.

Implications of all the available evidence

This finding shows the importance of the management of patients aged 80 years and older with a specifically designed protocol. Our results and those from the German High-Grade Non-Hodgkin Lymphoma Study Group are strongly in favour of a systematic pre-phase before immunochemotherapy for DLBCL in elderly people. The combination of miniCHOP plus a monoclonal antibody against CD20 with a pre-phase treatment could be the platform to design randomised clinical trials for DLBCL treatment in elderly people.

A phase 1/2, open-label, dose-escalating, multicentre clinical trial4, 5 of ofatumumab reported data in 40 patients with CD20-positive relapsed or refractory follicular lymphoma. The authors concluded that ofatumumab shows a similar activity and tolerability to rituximab in relapsed or refractory follicular lymphoma.4, 5 When we designed the protocol for the present study, very few data had been reported about ofatumumab in DLBCL, but in view of the drug's efficacy in follicular lymphoma, we proposed to test it in DLBCL.

Consequently, we designed a prospective phase 2 study (LNH 09-7B) to test a new combination of ofatumumab plus miniCHOP with a short pre-phase treatment of vincristine and prednisone to reduce early toxicity and increase the number of treatable patients.

Section snippets

Study design and patients

We did an open-label, multicentre, single-arm, phase 2 study of a miniCHOP chemotherapy regimen plus ofatumumab in patients with DLBCL. All patients received pre-phase treatment with vincristine and prednisone, starting 7 days before the first cycle of ofatumumab plus miniCHOP. LYSA ran the study in 41 academic and hospitals centres in France and Belgium (appendix p 1). Patients were eligible if they were older than 80 years and had histologically proven CD20-positive DLBCL (WHO classification,

Results

Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients (55 men and 65 women) into the study, 115 of whom received the pre-phase treatment and at least one cycle of ofatumumab plus miniCHOP and were included in the intention-to-treat analyses. Five patients were excluded during the pre-phase because of one case of steroid-induced manic psychosis, one investigator decision, one major protocol violation (bronchial carcinoma), one persistent performance status 3, and one death due to

Discussion

This large phase 2 study of patients older than 80 years with DLBCL included 120 patients. The study suggests that prolonged overall survival is achievable with a combination of anti-CD20 monoclonal antibodies and miniCHOP, even in very old patients. We report a 2-year overall survival of 64·7% (95% CI 55·3–72·7), with very few toxic effects. The median follow-up was 26·8 (IQR 24·5–30·1) months, which seems to be acceptable regarding the trial population. Furthermore, a 24-month follow-up has

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