Jan 26, 2004 - Bone Marrow Transplantation (2004) 33, 875â876. ... insipidus and bone marrow suppression, massive hepatosplenomegaly, lung infiltration.
Bone Marrow Transplantation (2004) 33, 875–876 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $25.00
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Langerhans cell histiocytosis (LCH) is a rare disease of still unknown etiology1 characterized by the accumulation of abnormal Langerhans cells in locations where they are normally not found. Langerhans cells belong to a family of antigen-presenting cells called dendritic cells.2 LCH cells resemble normal Langerhans cells with regard to the expression of S-100 neuroprotein and CD1a antigen. They contain the characteristic Birbeck granules. In addition to LCH cells, skin and organ infiltrates contain T lymphocytes, multinucleated giant histiocytes and eosinophils. Langerhans cells produce various cytokines (eg prostaglandin E2, IL-1, IL-3, IL-4, IL-8, GM-CSF and TNFa), which are thought to play a pivotal role in the pathogenesis of LCH.3 Patients may suffer from local disease primarily involving skin and bone or from multisystem disease, which is typically seen in children younger than 2 years. This results in a plethora of symptoms ranging from skin lesions and bone fractures to diabetes insipidus and bone marrow suppression, massive hepatosplenomegaly, lung infiltration and wasting. To improve therapeutic regimens in this rare disease, patients should be enrolled in international randomized clinical treatment studies, such as those sponsored by the Histiocyte Society (www.histio.org/society/). We report umbilical cord blood transplantation from an unrelated donor with a single HLA-mismatch at the B locus and engraftment of donor hematopoiesis in a 15-month-old infant with severe multisystem LCH. Donor monocytederived dendritic cells (moDCs) could be cultured indicating engraftment of fully functional monocytes. A 6-week-old male infant with a history of Varicella zoster exposure on the second day of life was admitted to our hospital because of a vesiculopapular skin exanthema, fever, dyspnea, anemia and thrombocytopenia. A skin biopsy showed typical LCH infiltrates. The patient was diagnosed with severe multisystem LCH and enrolled in the LCH-III treatment protocol. Chemotherapy consisting of systemic prednisolone, vinblastine, methotrexate and VP16 was administered. During the course of treatment the infant suffered from severe secondary septic episodes associated with extended LCH skin lesions and bone marrow suppression that developed under chemotherapy. Since the disease could not be controlled by systemic chemotherapy, the decision was made to perform allogeneic hematopoietic stem cell transplantation with the rationale of replacing clonal host derived LCH cells by competing normal donor-derived Langerhans cells. In all, 6.27 107 nucleated cells/kg from an unrelated donor with a single
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Bone Marrow Transplantation (2004) 33, 875–876. doi:10.1038/sj.bmt.1704441 Published online 26 January 2004
HLA-mismatch at the B locus were infused. Cyclosporin A was commenced on day 1 for graft-versus-host disease (GvHD) prophylaxis. A neutrophil count consistently greater than 0.5 109/l was achieved by day þ 49. G-CSF (5 mg/kg) was commenced at day þ 42 and stopped at day þ 58. At day þ 78 the infant developed graft failure with a drop of the absolute neutrophil count (ANC) below 0.5 109/l. G-CSF (5 mg/kg) was recommenced at day þ 85 until day þ 92. A stable ANC above 0.5 109/l was achieved from day þ 89 onwards. The patient was erythrocyte and thrombocyte transfusion independent from day þ 220. Full chimerism of all cell lines in bone marrow aspirates and peripheral blood was achieved at day þ 33. The post-transplant clinical course was complicated by repeated septic episodes, compromised renal function and drug-induced hypertension. Hepatosplenomegaly decreased but was still detectable after transplantation. The patient developed grade III (Seattle criteria) acute GvHD involving primarily the gastrointestinal system, liver and skin. In addition, limited chronic GvHD of the skin arose for a short interval, but could be well controlled with immunosuppression. Skin biopsies taken 119 days after transplantation from formerly involved areas showed no signs of LCH infiltrates. To analyze differentiation plasticity and function of engrafted monocytes, moDCs were generated at day 253 post-transplantation. moDCs were of donor haplotype (HLA-B60) and could be fully matured (Figure 1). Immunosuppression with CSA and with MMF was stopped 360 and 400 days respectively after stem cell transplantation. At 4 months after discontinuation of immunosuppressive therapy the patient shows no signs of LCH or GvHD and is in a good clinical condition. Our data add evidence to the concept of treating refractory severe multisystem LCH with hematopoietic stem cell transplantation with either related or unrelated donors.4,5 Since many affected patients are infants and therefore need lower total cell numbers for transplantation,
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Unrelated cord blood transplantation in an infant with severe multisystem Langerhans cell histiocytosis: clinical outcome, engraftment and culture of monocyte-derived dendritic cells
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Figure 1 Monocyte-derived mature dendritic cells generated on day 253 after unrelated umbilical cord blood transplantation. mo-DCs display a mature phenotype (CD83 þ , HLA-ABC þ , CD14) and express the donor derived HLA molecule HLA-B60.
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umbilical cord blood transplants may represent a curative treatment option in spite of their lower cell content. F Meyer-Wentrup J Foell A Wawer S Burdach
Department of Pediatrics, Children’s Cancer Research Center/Biocenter, Martin-Luther-University Halle-Wittenberg, Halle, Germany
References 1 Laman JD, Leenen PJ, Annels NE et al. Langerhans-cell histiocytosis ‘insight into DC biology’. Trends Immunol 2003; 24: 190–196.
Bone Marrow Transplantation
2 Stingl G, Tamaki K, Katz SI. Origin and function of epidermal Langerhans cells. Immunol Rev 1980; 53: 149–174. 3 Annels NE, Da Costa CE, Prins FA et al. Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 2003; 197: 1385–1390. 4 Greinix HT, Storb R, Sanders JE, Petersen FB. Marrow transplantation for treatment of multisystem progressive Langerhans cell histiocytosis. Bone Marrow Transplant 1992; 10: 39–44. 5 Nagarajan R, Neglia J, Ramsay N, Baker KS. Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 2001; 23: 629–632.
