Symptomatic Bone Langerhans Cell Histiocytosis Treated at Diagnosis or After Reactivation With Indomethacin Alone Jorge Braier, MD,* Diego Rosso, MD,* Daniel Pollono, MD,w Guadalupe Rey, MD,z Eduardo Lagomarsino, PhD,y Antonio Latella, MD,8 and Pedro Zubizarreta, MD* Summary: This study evaluated the outcome of patients with symptomatic bone Langerhans cell histiocytosis (LCH) treated with indomethacin alone, either at diagnosis or after reactivation (after recurrence with previous therapies). We evaluated the non- randomized use of oral indomethacin (2 mg/kg/d) in patients with symptomatic single-system bone LCH. From 1997 to 2012, 38 sequential patients were treated for a median of 4 months. Criteria of nonactive disease (NAD) after initial treatment (8 wk) were: no pain, no soft tissue involvement, no increase of size, or no new bone lesions. Twenty-two patients were treated at diagnosis: 18 showed NAD after initial treatment (2 patients who had bone reactivations were retreated with indomethacin and remain with NAD). Three patients improved and they are with NAD after treatment with indomethacin, steroids, or radiotherapy. One patient developed progressive bone disease and he is with NAD after treatment with steroids and chemotherapy. Sixteen patients were treated after reactivation, and all were with NAD after initial treatment: 5 reactivated and 4 remain with NAD after retreatment with indomethacin. Toxicity was not significant. We conclude that indomethacin is a well tolerated and active drug in patients with symptomatic bone disease. The results support the concept that chemotherapy may not be necessary for limited bone disease. Key Words: indomethacin therapy, bone Langerhans cell histio- cytosis, outcome (J Pediatr Hematol Oncol 2014;36:e280–e284) L angerhans cell histiocytosis (LCH) is a rare disease with variable clinical manifestations. It may be self-limited in some patients, whereas in others intensive treatment is unsuccessful. The outcome depends on whether vital organ are compromised at diagnosis in which case the prognosis is poor. 1 The course of single-system LCH is usually benign. Bone is the commonest single organ involved in LCH. In bone disease, reactivations usually remain restricted to skel- eton and do not influence survival. However, reactivations have an impact on morbidity as permanent consequences are mostly related to the site of disease activity. 2 Many different strategies have been used for the treatment of bone LCH in children, 3,4 from minimal strategies such as observation only or steroid injections 5,6 to more aggressive approaches such as surgery, chemotherapy, or radiotherapy. 7,8 Treatment strategies with lower inci- dence of adverse events while ensuring a successful cure are desirable in this cohort of patients. Indomethacin is a nonsteroidal anti-inflammatory drug inhibitor of cyclo-oxygenase 1 and 2 enzymes that participate in prostaglandin synthesis from arachidonic acid. 9 Prostaglandins are hormone-like molecules normally found in the body where they have a wide variety of effects, some of which lead to pain, fever, and inflammation. The main use of indomethacin is as an anti-inflam- matory drug in rheumatologic conditions. Prostaglandins (PG) have been implicated in the pathogenesis of histiocytic disorders. Purified LCH cells from bony lesions of LCH produce interleukin 1 and PG E2 in vitro and LCH cells in a case of disseminated LCH have been shown to produce PG D2 and thromboxane. 10,11 On that basis Munn et al 9 used indomethacin in patients with symptomatic bone LCH and they concluded that indomethacin was a useful therapy for LCH involving the bony skeleton and may have a role as first-line treat- ment in single-system bone disease. Other subsequent study also showed that indomethacin seems to be effective for treating isolated bone LCH in children avoiding morbid- ities associated with other treatment approaches such as chemotherapy or surgery. 12 However, the systematic use of indomethacin in larger cohorts of children with LCH, including children with reactivation of the disease, has not been further explored. Therefore, the aim of this study was to evaluate the outcome of patients with symptomatic bone LCH treated with indomethacin alone, either at diagnosis or after reactivation. METHODS A retrospective analysis of 38 LCH patients with per- sistent symptomatic single-system bone involvement at diagnosis (after bone aspiration, biopsy, or curettage) or after reactivation was performed. Patients treated at diagnosis had a proven definitive diagnosis of LCH according to the His- tiocyte Society criteria. 13 Patients treated at reactivation were diagnosed according to the clinical symptoms/signs (pain, tumor) associated with new bone lesion(s) with or without adjacent soft tissue involvement showed by imaging. Received for publication May 17, 2013; accepted March 10, 2014. From the *Hematology/Oncology Department; yPharmacy Depart- ment; 8Pediatric Department, Hospital Nacional de Pediatrı´a Juan P Garrahan; wOncology Department, Hospital de Nin˜os Sor Marı´a Ludovica; and zOncology Department, Hospital de Nin˜os Ricardo Gutierrez, Buenos Aires, Argentina. The authors declare no conflict of interest. Reprints: Jorge Braier, MD, Hematology/Oncology Department, Hospital Nacional de Pediatrı´a Juan P Garrahan, Combate de los Pozos 1881 (1245), Buenos Aires, Argentina. (e-mail: jolubraier@ gmail.com). Copyright r 2014 by Lippincott Williams & Wilkins ORIGINAL ARTICLE e280 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 36, Number 5, July 2014