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