Haematologica 2002; 87:(12)ECR45
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Life-threatening complication of rituximab in a child
Brigitte Bader-Meunier,* Martine Gabolde, Nicole Casadevall, Guy Seguin, Gil Tchernia
*Département de Pédiatrie, Hôpital de Bicêtre, Assistance Publique des Hôpitaux de Paris, 94270 Le Kremlin Bicêtre, France; laboratoire d'Hématologie , Hôpital de Bicêtre, 94270 Le Kremlin Bicêtre, France; laboratoire d'Hématologie, Hôpital Hôtel-Dieu, 75 001 Paris, France ; and Centre Hospitalier, 49325 Chollet, France
Correspondence: Dr. Brigitte Bader-Meunier, MD, Département de Pédiatrie, Hôpital de Bicêtre, Assistance Publique des Hôpitaux de Paris, 94270 Le Kremlin Bicêtre, France. E-mail: brigitte.bader-meunier@bct.ap-hop-paris.fr

Successful treatment of childhood autoimmune hemolytic anemia with rituximab, without any severe adverse events has been recently reported. In contrast, we report a life-threatening complication of rituximab in a 4-year-old boy treated for relapsing immune-mediated pure red cell aplasia (PRCA). The two first episodes of PRCA occurred at age 11 months and 3 years respectively, and were initially associated with a diffuse rash. The blood counts showed normochromic-normocytic anemia (hemoglobin: 4 g/dL) with reticulopenia and normal white blood cell and platelet counts. Direct and indirect Coombs' tests were negative, and serum haptoglobin value was normal. Serologic tests for parvovirus B19, human cytomegalovirus and Epstein-Barr virus were negative. On bone marrow smears myeloid and megakaryocyte lineages were found to be normal, while cells of the erythroid lineage were nearly absent. Anemia resolved spontaneously within 4 months the first time, and within one month after the initiation of a treatment with steroids the second time. At the time of the third relapse of the PRCA, the bone marrow aspirate was unchanged; in vitro cultures of the patient's bone marrow cells2 demonstrated that the patient's plasma profoundly inhibited growth of CFU-E from both healthy control and his own bone marrow, suggesting the existence of soluble serum factors responsible for PRCA. The search for anti-erythropoietin antibodies was negative.1,2 Serum levels of IgG, IgA and IgM were normal. Prednisone (1 mg/kg per day) then intravenous immunoglobulin infusions were ineffective in increasing reticulocyte count, and repeated administration of red blood cell concentrates was required. Rituximab was administered intravenously at the dose of 375 mg/m2 diluted in a glucose solution (1mL =1mg of rituximab) at an initial rate of 25 mg/h, after a pre-medication with diphenhydramine. Within one hour of infusion, a collapse occurred with a severe drop in systolic blood pressure to 30 mm Hg associated with chills and fever (40°C) ; rapid volemic expansion with colloids and administration of methylprednisolone was needed. Physical examination returned to normal within one hour.
Rituximab has been introduced a few years ago for treatment of B-cell lymphomas: 85 to 94% of patients reported adverse events during clinical trials. However, 90% of these events were mild or moderate, including flu-like symptoms such as headache, fever, sweats, skin rash, shortness of breath, hypotension, nausea, and asthenia that occurs with the first infusion. Severe side effects, such as hypotension, bronchospasm, hypoxia and even death have been rarely reported, especially when treating patients with high numbers of circulating antigen-expressing cells. Ref 3. More recently, rituximab has been successfully used for the treatment of immune-mediated cytopenia, including pure red cell aplasia 1,4,5 and was well tolerated in all patients. Our report underlines the need for careful monitoring of rituximab infusions, even in the absence of an increased number of cells expressing the CD20 antigen.

References

  1. Quartier P, Brethon, B, Philippet P, Landman-Parker J, Le Deist F, Fisher A. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001;358:1511-3.
  2. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002 ;46:469-75.
  3. Onrust SV, Lamb HM, Balfour JA. Rituximab. Drugs 1999;58:79-88.
  4. Stasi R, Pagano A, Stipa E, Arnadori S. Rituximab chimeric anti CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98:952-7.
  5. Zecca M, De Stefano P, Nobili B, Locatelli F. Anti-CD20 monoclonal antibody for the treatment of severe immune-mediated, pure red cell aplasia and hemolytic anemia. Blood 2001; 97:3995-7.