Elsevier

The Lancet

Volume 385, Issue 9980, 9–15 May 2015, Pages 1873-1883
The Lancet

Articles
Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial

https://doi.org/10.1016/S0140-6736(15)60027-7Get rights and content

Summary

Background

Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options.

Methods

We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m2) on days 1–7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189.

Findings

We enrolled 447 patients, median age 69 years (range 35–92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0–25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6–13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45–0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group.

Interpretation

Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy.

Funding

GlaxoSmithKline, Genmab A/S.

Introduction

Treatment of patients with chronic lymphocytic leukaemia who are elderly or have comorbidities is challenging because these patients often cannot tolerate toxic chemotherapy and are therefore not suitable for purine-analogue-based therapies such as fludarabine, cyclophosphamide, and rituximab, the standard of care for young and healthy patients.1 Alternative approaches have included reduced-doses of fludarabine, cyclophosphamide, and rituximab,2, 3 and bendamustine alone or in combination with rituximab.4, 5 Although these regimens are more tolerable and are effective alternatives, little data exists for use of these treatments in elderly patients and toxic effects are more pronounced than with chlorambucil. Therefore, chlorambucil is the standard of care for many patients with chronic lymphocytic leukaemia.6, 7

Ofatumumab is a human monoclonal antibody that binds to a membrane-proximal epitope of CD20, distinct from the rituximab-binding site.8 Ofatumumab induces cell lysis mainly through complement-dependent cytotoxicity, but also through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.8, 9, 10, 11, 12, 13 In clinical trials, ofatumumab monotherapy was active in patients with chronic lymphocytic leukaemia who were refractory to fludarabine and alemtuzumab, irrespective of previous rituximab, and in those with bulky disease.14, 15 The COMPLEMENT 1 study investigated the efficacy and safety of ofatumumab added to chlorambucil compared with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia for whom fludarabine-based treatment regimens were considered inappropriate for reasons such as advanced age or presence of a comorbidity.

Section snippets

Study design

We planned a prospective, randomised, open-label, phase 3 study of patients in 109 centres in 16 countries (appendix). A short version of the protocol is online. At participating centres, we enrolled untreated patients of any age who were diagnosed with chronic lymphocytic leukaemia, had active disease that needed treatment,16 and for whom fludarabine-based therapy was considered inappropriate. We included only patients who had Eastern Cooperative Oncology Group (ECOG) performance status score

Results

Between Dec 22, 2008, and May 26, 2011, we randomly assigned 447 patients; 221 to chlorambucil plus ofatumumab and 226 to chlorambucil monotherapy (figure 1). Treatment groups were well balanced (table 1). Median age was 69 years (range 35–92), with 307 (69%) patients older than 65 years and 221 patients (49%) older than 70 years (table 1). Most (391 [87%]) patients reported at least one comorbidity; the most frequently affected organs classes were vascular (245 patients [55%]), metabolic (159

Discussion

COMPLEMENT 1 is a phase 3 trial for the potential benefit of adding ofatumumab, a CD20 monoclonal antibody, to front-line chlorambucil chemotherapy in patients with chronic lymphocytic leukaemia who cannot tolerate fludarabine-based regimens. Addition of ofatumumab led to a significant benefit in progression-free survival in most subgroups of patients without a major increase in toxic effects.

Baseline disease characteristics of the patients enrolled into COMPLEMENT 1 were representative of

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