Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial

Summary

Background

Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma.

Methods

We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m² rituximab, 400 mg/m² cyclophosphamide, 25 mg/m² doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m² prednisone on days 1–5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424.

Findings

150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80–95). After a median follow-up of 20 months (range 0–45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49–67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4–7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38–56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients).

Interpretation

R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients.

Funding

Groupe d'Etude des Lymphomes de l'Adulte (GELA).

Introduction

Diffuse large B-cell lymphoma is the most common lymphoid malignancy worldwide.¹ Its incidence steadily increases with age and about 40% of cases occur in patients aged over 70 years.1, 2 However, few prospective data are available on the outcome of patients aged over 80 years. Retrospective analyses have shown that the outcome of elderly patients is worse than that of younger patients but that some elderly patients do have a complete response to treatment and long-term survival.3, 4, 5, 6

Whether diffuse large B-cell lymphomas in the elderly differ intrinsically from those in younger patients is not clear. Although there is no specific histological characteristic or genetic abnormality of diffuse large B-cell lymphoma in elderly people, the distribution of gene-expression profile subtypes with distinct prognosis might differ with age.⁷ Lymphoma in elderly patients is not substantially less responsive to treatment than in younger patients, and the main reason for the poor outcome of very old patients is their decreased ability to tolerate treatment.⁸ Impaired bone-marrow function, altered drug metabolism, and presence of comorbid diseases can increase the number of treatment-related complications. Several attempts to decrease doses of the standard chemotherapy regimen CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) or to substitute less toxic drugs in the combination have decreased toxicity but did not improve survival.9, 10, 11

Over the past 10 years, since the introduction of the chimeric anti-CD20 monoclonal antibody rituximab as the standard treatment, the treatment outcome of patients with diffuse large B-cell lymphoma has changed dramatically. In a randomised open-label trial by the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) in patients aged 60–80 years, the association of CHOP and rituximab was significantly superior to CHOP alone in terms of complete response rate and survival, without a clinically significant increase in toxicity.12, 13, 14 This study did not include patients aged over 80 years but did show a similar benefit for patients aged 60–70 years, 71–75 years, and 76–80 years.¹³ These results have since been replicated by two randomised trials in a similar patient population,15, 16 but no prospective study of this association has been done for patients aged over 80 years.

After the results of a small retrospective study⁶ that showed that rituximab could help maintain efficacy of a dose-reduced regimen in patients over 80 years old who had non-Hodgkin lymphoma, we decided to assess the efficacy and safety of the combination of a standard dose of rituximab and an attenuated dose of chemotherapy in this patient population.