SALVAGE THERAPY FOR MULTISYSTEMIC LANGERHANS CELL HISTIOCYTOSIS WITH RISK ORGAN INVOLVEMENT: A REVIEW OF THE PEDIATRIC LITERATURE

Clinton M. Carroll, BA1 and James A. Whitlock, MD2

1Vanderbilt School of Medicine, Nashville, TN; 2Department of Pediatric Hematology/Oncology, Monroe Carell, Jr. Children’s Hospital at Vanderbilt, Nashville, TN.

Background: Langerhans cell histiocytosis (LCH) is a rare, heterogeneous disorder of childhood and beyond characterized by proliferating histiocytes that resemble Langerhans cells of the epidermis. LCH may be localized or diffuse, monosystemic or multisystemic, and may remit spontaneously or progress rapidly, ending in organ failure and death despite aggressive therapy. Prior to 1987, the disorder was known by a number of names, including histiocytosis X, eosinophilic granuloma, Hand-Schuller-Christian disease, Letterer-Siwe disease, and type II histiocytosis, among others. There were few diagnostic or risk stratification criteria in place at the time, making comparison of therapeutic studies difficult, if not impossible. Then, in 1987, the Histiocyte Society coined the broad term “Langerhans cell histiocytosis” and set-forth diagnostic and risk stratification guidelines, thus enabling investigators to assign presumptive or definitive diagnoses to patients, and to place patients in low-risk and high-risk groups. This latter group, especially children with multisystemic LCH with risk organ involvement (hematopoietic, pulmonary, hepatic, or splenic involvement), is of special interest to clinicians. Children with multisystemic LCH with risk organ involvement are often treatment-refractory, and many succumb to disease. Unfortunately, the evidence for how to best treat these high-risk children is lacking. Most of the literature prior to 1987 is unreliable, and most subsequent literature consists of small case reports and anecdotal treatment recommendations. Nevertheless, there is value in gathering what evidence does exist, so that preliminary observations may be made to aid and direct future therapeutic trials. Objectives: To review the pediatric literature on salvage therapy for multisystemic LCH with risk organ involvement, and to compare and analyze all pertinent studies to aid and direct future therapeutic research. Materials and Methods: All articles used in this review were English language articles obtained from PubMed using the search terms “Langerhans cell histiocytosis”, “infant(s)”, “neonate(s)”, “children/child”, “adolescent(s)”, “young adult(s)”, “twin(s)”, and “treatment” in various combinations. Articles published prior to 1988 were included only if a definitive diagnosis of LCH was made. Articles published after 1987 were included if any diagnosis of LCH, presumptive or definitive, was made. Children were included in this review if they had multisystemic LCH with risk organ involvement at the time of diagnosis, prior to salvage therapy, or at any point in between. Children were included only if they failed at least one course of systemic treatment prior to salvage therapy. Children were excluded if they were 18 years of age or older at the time of salvage therapy, if they underwent liver or lung transplantation at any time, if they had any type of malignancy prior to or subsequent to LCH, if they suffered from a specific co-morbid disorder, such as a second histiocytic disorder, if they had special-site LCH involvement, including CNS disease (with the exception of isolated pituitary involvement), or if their disease or treatment trajectories could not be followed. One hundred and thirty two children met the above criteria, and were divided according to disease profile, the aggressiveness of treatment prior to salvage therapy, and whether remission was achieved prior to salvage therapy. This gave twelve groups: children with low-risk disease at the time of LCH diagnosis and high-risk disease at the time of salvage therapy with non-aggressive or aggressive prior treatment with or without remission (groups 1-4), children with high-risk disease at the time of LCH diagnosis and low-risk disease at the time of salvage therapy with non-aggressive or aggressive prior treatment with or without remission (groups 5-8), and children with high-risk disease at the time of LCH diagnosis and high-risk disease at the time of salvage therapy with non-aggressive or aggressive prior treatment with or without remission (groups 9-12). High-risk disease was defined as multisystemic LCH with risk organ involvement. Low-risk disease was defined as monosystemic LCH with or without risk organ involvement or multisystemic LCH without risk organ involvement. Non-aggressive prior treatment was defined as any localized treatment such as radiation therapy, single-agent chemotherapy with or without steroids, or monotherapy with a non-steroidal immunosuppressive agent such as etanercept. Aggressive prior treatment was defined as multiagent chemotherapy, either single regimens or sequential agents, or any sort of bone marrow or stem cell transplantation. Finally, remission was defined as any period following the diagnosis of LCH during which the child was disease free. Each child’s salvage therapy and latest follow-up information were recorded for interstudy comparison. Results: One hundred and thirty two children met the above criteria, and were divided according to disease profile, the aggressiveness of treatment prior to salvage therapy, and whether remission was achieved prior to salvage therapy.

The largest group (n=58) were those patients with multisystemic involvement and risk organ involvement at both diagnosis and recurrence. An analysis of specific treatment medications and protocols for this group of patients is in progress. Conclusions: (1) LCH patients with multisystemic involvement and risk organ involvement at both diagnosis and recurrence represent the largest subset of LCH patients with recurrent disease in the English literature. (2) An analysis of responses to specific treatment protocols will lay the groundwork for future clinical interventions in this high-risk group of patients. (3) Prospective, randomized trials are needed in this patient population. References: References are available upon request.

Clint Carroll

2006-01-31T22:54:00