A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia
Su W. Maung,1,2 Maeve Leahy,1 Hilary M. O’Leary,1 Irfan Khan,3 Mary R. Cahill,3 Oonagh Gilligan,3 Philip Murphy,4 Suzanne McPherson,5 Fred Jackson,5 Mary Ryan,5 Brian Hennessy,5 Johnny McHugh,2 Matthew Goodyer,6 Larry Bacon,6 Peter O’Gorman,6 Aisling Nee,7 Michael O’Dwyer,7 Helen Enright,2 Jean Saunders8 and Denis O’Keeffe1 1
Department of Haematology, University
Hospital Limerick, Limerick, 2Department of Haematology, Tallaght Hospital (AMNCH), Dublin, 3Department of Haematology, Cork University Hospital, Cork, 4Department of Haematology, Beaumont Hospital, Dublin, Department of Haematology, Waterford
Regional Hospital, Waterford, 6Department of Haematology, Mater Misericordiae University Hospital, Dublin, 7Department of Haematology, University College Hospital, Galway, and 8
Statistical Consulting Unit/CSTAR @ UL,
University of Limerick, Limerick, Ireland Received 15 April 2013; accepted for
Summary This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m2 weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 706% (24/34) with 265% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 875% (21/24) and 3 months in 125% (3/24) of patients. The median duration of follow-up was 36 months (range 6–90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 165 months (range 6–60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response. Keywords: autoimmune haemolytic anaemia, safety, retrospective, multicentre, rituximab.
publication 17 June 2013 Correspondence: Dr Denis O’Keeffe, Department of Haematology, University Hospital Limerick, Dooradoyle, Limerick, Ireland. E-mail: [email protected]
Autoimmune haemolytic anaemia (AIHA) in adults is characterized by severe haemolysis due to the development of auto-antibodies directed against patient’s own red cells. AIHA is classified into warm (WAIHA) and cold reactive antibody types and can be divided into primary and secondary types. WAIHA can occur secondary to lymphoproliferative disorders, infections, immunodeficiency and primary autoimmune syndromes (Lechner & Jager, 2010). Patients with WAIHA will respond to steroid therapy in 80% of cases, but approximately 30% of patients will need second line therapy due to primary refractory disease or First published online 2 August 2013 doi: 10.1111/bjh.12486
relapse post-steroid treatment (Murphy & LoBuglio, 1976; Gehrs & Friedberg, 2002). Splenectomy has been the standard second line therapy for nearly 50 years (Chertkov & Dacie, 1956). However, a number of alternative immunosuppressive treatments have been tried with varying success rates for patients who cannot undergo splenectomy or have persistent disease post-splenectomy (Crowther et al, 2011). Rituximab is a chimeric IgG 1/K monoclonal antibody that specifically depletes B cells by targeting CD20 antigen expressed on both immature and mature B lymphocytes. ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2013, 163, 118–122
Rituximab in the Treatment of Autoimmiune Haemolytic Anaemia The efficacy of rituximab has already been proven in the treatment of B cell lymphoproliferative disorders and various autoimmune diseases, including Immune Thrombocytopenic Purpura (ITP) and AIHA (Barcellini & Zanella, 2011). A number of studies have suggested that rituximab, given at the standard dose of 375 mg/m2 on days 1, 8, 15 and 22, is effective in a significant number of patients with WAIHA (Bussone et al, 2009; Dierickx et al, 2009). A more recent study has indicated that low dose rituximab (100 mg/m2) may be equally effective in treating WAIHA (Barcellini et al, 2012). However, it remains unclear as to whether this response is sustained. Recent studies assessing rituximab treatment in ITP suggest that a significant number of patients will relapse within three years (Medeot et al, 2008; Patel et al, 2012). Rituximab has been extensively used as second line treatment for WAIHA in Ireland over the last 6 years. This study retrospectively collected data in seven haematology centres in the Republic of Ireland to assess initial response, time to response, durability of response and complications of this treatment.
Patients and methods Seven haematology centres across the Republic of Ireland participated in this study. Patients included in this study were defined as having WAIHA based on evidence of a haemoglobin concentration (Hb) of