Thalidomide in Children Undergoing Bone Marrow Transplantation: Series at a Single Institution and Review of the Literature

Thalidomide has one of the most notorious drug histories because of its teratogenicity. Its widespread use in the 1960s led to a worldwide epidemic of phocomelia in inborns; this in turn led to its complete ban in most of the world. However, it has now been licensed for selected indications including graft-versushost-disease (GVHD) after bone marrow transplantation, wasting associated with tuberculosis and human immunodeficiency virus infection, and leprosy. Little is known, however, about its use in children in these settings. Therefore, we report our experience and review the literature on thalidomide in children for GVHD after bone marrow transplantation. We studied 6 patients, 2 with chronic GVHD, 2 with acute GVHD, and 2 with acute GVHD progressing into chronic disease. One patient with chronic GVHD had a complete response, whereas the other had a partial response. Side effects consisted primarily of sedation and constipation, which are reported previously and well known side effects. None had neuropathy. One patient had rash, eosinophilia, and early pancreatitis that began shortly after initiation of thalidomide, persisted, and resolved only after discontinuation of thalidomide. Eosinophilia and pancreatitis are both previously unreported side effects or associated findings of thalidomide treatment. Review of the literature reveals three major studies of thalidomide in GVHD; of these two included children and adults together, and one in which age range of patients was not mentioned. In addition, four series of children receiving only thalidomide are reported. These series contained 1 to 14 patients each. Results show efficacy in at least 50% of children with chronic GVHD and little or no efficacy in children with exclusively acute GVHD. Side effects are similar to those reported in adults and consisted mostly of sedation and constipation, both of which subsided over time and resolved after discontinuing the drug. We speculate on the reasons for which thalidomide is more effective in chronic, compared with acute, GVHD in children, and make recommendations for future study. Pediatrics 1999; 103(4). URL: http://www.pediatrics.org/cgi/content/full/ 103/4/e44; thalidomide, BMT, GVHD. ABBREVIATIONS. GVHD, graft-versus-host disease; ATG, antithymocyte globulin; SCIDS, severe combined immunodeficiency syndrome; WBC, white blood cell; HLA, human leukocyte antigen. Thalidomide has one of the most notorious drug histories in the United States. Its use in pregnant women leading to an epidemic of phocomelia among newborns remains a shocking chapter in medicine. Thus, the recent decision to lift the ban on thalidomide and to approve its use for selected indications has attracted great attention.1–4 Because thalidomide now has been licensed, it is necessary that all pediatricians become familiar with its indications, contraindications, and safety profile, apart from its teratogenicity. Little is known about thalidomide in children, precisely because it has been banned in the United States. Despite the ban, however, the drug has been used intermittently over the past 2 decades and has found a place as an inhibitor of tumor necrosis factor. The Food and Drug Administration estimates that there are at least 1000 patients in this country presently receiving thalidomide on a compassionate basis or in clinical trials.2 Most of the clinical indications for thalidomide are wasting associated with human immunodeficiency virus and tuberculosis, Behcets disease, leprosy, and chronic graft-versus-host disease (GVHD). However, little data are available on these or other patients, especially children. Although distribution of the drug will be strictly controlled, it will be used in selected children, particularly those with GVHD after bone marrow transplantation, those with cachexia from human immunodeficiency virus or tuberculosis, or those with leprosy. We therefore review here our experience with thalidomide in children suffering from acute or chronic GVHD after bone marrow transplantation and review case reports and series in which children, alone or with adults, have been studied. MATERIALS AND METHODS Experience at the University of Florida We studied thalidomide use in children undergoing bone marrow transplantation who developed GVHD. All patients were treated according to an institutional protocol. The protocol was approved by the University of Florida Institutional Review Board. All patients were treated first with front-line conventional antiGVHD therapy including steroids, tacrolimus, cyclosporine, and/or antithymocyte globulin (ATG). If they had no response after 2 weeks, they were started on thalidomide in doses of 12.5 to 25 mg/k per day; this was increased gradually as tolerated. Guidelines were written in a protocol approved by the University of Florida Institutional Review Board. A parent or legal guardian was required to sign informed consent before any therapy with thalidomide was started. Thalidomide was obtained from the manufacturer (Celgene Corp, Warren, NJ). Demographics of the children are shown Table 1. Briefly, 6 children were studied; of these 2 had chronic GVHD, 2 had acute GVHD progressing into chronic GVHD, and 2 had early acute GVHD. Children were between 1.5 and 17 years of age; all were males. Underlying diseases were severe combined immunodeficiency syndrome (SCIDS),1 acute myelogenous leukemia,2 chronic myelogenous leukemia,2 and non-Hodgkin’s lymphoma secondary to acute lymphoblastic leukemia.1 Patients had GVHD involving skin (all 6), gastrointestinal tract,3 liver,2 and joints.2 All had been treated with steroids, 1 had Received for publication Aug 7, 1998; accepted Nov 20, 1998. Reprint requests to (P.M.) University of Florida College of Medicine, UFHSC, Box 100296, Gainesville, FL 32610-0296. PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Academy of Pediatrics. http://www.pediatrics.org/cgi/content/full/103/4/e44 PEDIATRICS Vol. 103 No. 4 April 1999 1 of 5 by guest on July 17, 2017 Downloaded from received ATG, and all had received prophylaxis with cyclosporine and methotrexate as part of their prophylactic regimen for GVHD.