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Published on: May 4, 2017
Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL
O Middleton1, E Cosimo1, E Dobbin2
1Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Insights
Complement defects in chronic lymphocytic leukemia (CLL) patients reduce complement-dependent cytotoxicity (CDC) during anti-CD20 monoclonal antibody (MAb) therapy. Supplementing with fresh-frozen plasma may improve treatment efficacy in these patients.
Area of Science:
- Immunology
- Hematology
- Pharmacology
Background:
- Monoclonal antibodies (MAbs), such as rituximab (RTX) and ofatumumab (OFA), are crucial in treating chronic lymphocytic leukemia (CLL).
- The efficacy of anti-CD20 MAbs relies on complement-dependent cytotoxicity (CDC).
- Complement deficiencies in CLL patients may impair MAb-induced CDC responses.
Purpose of the Study:
- To investigate the impact of complement defects on CDC induction by anti-CD20 MAbs in CLL patients.
- To compare the CDC-inducing capabilities of ofatumumab and rituximab in CLL.
- To explore strategies for restoring CDC in CLL patients with complement deficiencies.
Main Methods:
- Patient serum samples were analyzed for complement component levels and CDC activity.
- CDC was measured using anti-CD20 MAbs (rituximab and ofatumumab) against CLL cells.
- Complement activity was assessed after secondary challenge with MAbs, with and without serum supplementation.
Main Results:
- Ofatumumab induced higher CDC than rituximab, particularly in poor-prognosis CLL subgroups.
- 38.1% of CLL patients exhibited deficiencies in one or more complement components, correlating with reduced CDC.
- Complement components were exhausted in CLL patients post-treatment, and supplementation with normal human serum or C2 restored CDC.
- High CLL cell counts led to rapid complement exhaustion.
Conclusions:
- Complement deficiencies and exhaustion significantly impair anti-CD20 MAb efficacy in CLL patients.
- Ofatumumab demonstrates superior CDC induction compared to rituximab in CLL.
- Supplementation with fresh-frozen plasma or specific complement components may enhance CDC and improve therapeutic outcomes in CLL patients with complement defects or high tumor burden.
Abstract:
Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q- and 17p-). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy.
