Rao A, Kelly M, Musselman M, Ramadas J, Wilson D, Grossman W, Shenoy S. Safety, efficacy, and immune reconstitution after rituximab therapy in pediatric patients with chronic or refractory hematologic autoimmune cytopenias

Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
Pediatric Blood & Cancer (Impact Factor: 2.39). 04/2008; 50(4):822 - 825. DOI: 10.1002/pbc.21264

ABSTRACT Background
Autoimmune hematologic cytopenias in children often require therapeutic intervention. We report a prospective pediatric multicenter trial of rituximab for refractory or steroid-dependent patients.Methods
Four doses of rituximab (375 mg/m2/dose) were administered weekly. Patients without response after three doses were offered dose escalation to 750 mg/m2/dose/week × 3. Safety, efficacy, and immunologic tests were evaluated after therapy.ResultsTwenty-nine of 30 children (2–18 years) with thrombocytopenia (21), hemolytic anemia (6), Evans syndrome (2), and neutropenia (1) received at least four doses of rituximab. One developed anaphylaxis with the first dose. One patient was subsequently diagnosed with monosomy 7 myelodysplasia. Of 28 remaining patients, 9 received dose escalation. Responders discontinued other therapy following rituximab. The overall response rate was 72% with median follow-up of 18 months. Complete remission was observed in 14 (50%); all received four doses of rituximab. Partial remission (PR) was observed in six (22%); five had received dose escalation. Of four relapses, 4–24 months after therapy, two were retreated with rituximab and achieved second remission. No major infections were encountered. Circulating B-cells were depleted by 1 month and normalized by 1 year. IgM, Ig A, and IgG levels decreased 6, 9, and 12 months after therapy, respectively, but remained near normal range. Tetanus toxoid antibody titers remained detectable.Conclusions
Rituximab was well tolerated, and induced sustained remissions in children with refractory immune cytopenias. Dose escalation and re-treatment after relapse elicited additional responses. Rituximab therapy should be considered prior to potential interventions with higher toxicity. Pediatr Blood Cancer 2008;50:822–825. © 2007 Wiley-Liss, Inc.

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Available from: David B Wilson, Apr 23, 2015
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    • "Four were alive and responsive at 13 – 21 months follow - up , and two died at 19 and 40 d after rituximab was started , of continued haemolysis and of multiorgan failure due to respi - ratory syncytial virus ( RSV ) infection , respectively . Toxicity of rituximab in children with autoimmune cytopenias is mainly represented by transient neutropenia and thrombocytopenia , serum sickness or infusion related symptoms whereas infections related to B - cell depletion are very few ( Larrar et al , 2006 ; Giulino et al , 2007 ; Rao et al , 2008 ) . However , the occurrence of enteroviral meningoencephalitis in a child after rituximab ( Quartier et al , 2003 ) and progressive multifocal leukoence - phalopathy ( PML ) in two adults with systemic lupus erythe - matosus after rituximab ( FDA / Center for Drug Evaluation and Research , 2006 ) and one rheumatoid arthritis adult formerly treated with rituximab ( http : / / www . "
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    ABSTRACT: We report a case series of four infants with severe autoimmune haemolytic anaemia (AIHA) who responded to treatment with rituximab and cyclosporine after having failed first line therapy with high-dose steroid (prednisolone 4-8 mg/kg/d). Rituximab was started at 11-90 d from onset due to continued haemolysis; three infants also received cyclosporine A. Three of four infants reached complete response, defined as normal haemoglobin, reticulocytes and negative indices of haemolysis, at 7-21 months from diagnosis. In long-term follow-up two infants remained disease-free with normal immunology, one had undefined immunodeficiency and one had autoimmune lymphoproliferative syndrome.
    British Journal of Haematology 03/2009; 145(1):96-100. DOI:10.1111/j.1365-2141.2009.07594.x · 4.71 Impact Factor
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    • "The mechanism of action of rituximab raises unique safety concerns in children, especially in terms of vaccine responses and potential long-term effects of B-cell depletion. Studies of rituximab in children with conditions such as chronic autoimmune cytopenias, however, have provided preliminary evidence of safety and tolerability in children [34,35]. "
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    ABSTRACT: Juvenile idiopathic arthritis (JIA) is the most common autoimmune-autoinflammatory disease in childhood and affects approximately 1 in 1,000 children. Despite advances in diagnosis and treatment options, JIA remains a chronic condition for most affected children. Recent evidence suggests that disease control at onset may determine the tempo of subsequent disease course and long-term outcomes, and raises the concept of a therapeutic window of opportunity in patients with JIA. This underscores the importance of early aggressive treatment in patients with JIA. With the advent of novel biologic therapeutics, the repertoire of agents available for treatment of children with JIA has greatly increased. The present article will summarize recent developments in the medical treatment of children with JIA and will offer insights into emerging therapies.
    Arthritis research & therapy 03/2009; 11(1):216. DOI:10.1186/ar2619 · 3.75 Impact Factor
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    • "diseases (Garcia Hernandez et al, 2007; Garvey, 2008). Its efficacy and tolerability in the treatment of ITP have been shown in adults (Arnold et al, 2007) and children (Taube et al, 2005; Wang et al, 2005; Bennett et al, 2006; Parodi et al, 2006; Penalver et al, 2006; Rao et al, 2008), though its exact mechanism is still unknown. Few data are available regarding long-term follow-up analysis and prognostic factors in children. "
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    ABSTRACT: We report the long-term follow-up (median 39.5 months) of 49 paediatric patients (33 females and 16 males) with refractory symptomatic immune thrombocytopenic purpura (ITP) treated with rituximab. The overall response rate was 69% (34/49 patients). Twenty-one responders had a platelet count >50 x 10(9)/l at a median 20.2 months from treatment. Kaplan-Meier analysis showed a probability of relapse-free survival (RFS) of 60% at 36 months from the first rituximab infusion. The number of infusions and a previous splenectomy did not influence overall response rate. Patients who achieved complete response were significantly older at diagnosis and first rituximab infusion than partial responders (P = 0.027). Older children displayed a significantly greater probability of sustained response (RFS) at 36 months than younger children (88.9% vs. 56.7%, P = 0.037). Earlier responses (within 20 d from treatment) were significantly associated with both complete (P = 0.004) and sustained response (P = 0.002). Only mild and transient side-effects were observed in 9/49 children; no major infections nor delayed toxicities were recorded during the follow-up.
    British Journal of Haematology 12/2008; 144(4):552-8. DOI:10.1111/j.1365-2141.2008.07487.x · 4.71 Impact Factor
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