Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification

Abstract

Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO ؉)or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/ 71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO ؊ ) had 100% survival and uniformly high (> 80%) rapid response, (2) RO ؉ patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO ؉ patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI ‫؍‬ 0.29-1.00 IntroductionLangerhans cell histiocytosis (LCH) is a reactive clonal proliferation of dendritic cells 1-3 that comprises a wide range of clinical presentations, from localized disease (single-system disease) with excellent outcome to disseminated disease involving 2 and more organs or systems (multisystem disease, MS-LCH). [4][5][6] Treatment has varied from conservative to intensive combination chemotherapy. 7-10 When the systems involved are "risk organs" and/or the patient is younger than 2 years at diagnosis, MS-LCH has been considered particularly devastating, and as carrying a potentially fatal prognosis. 11,12 In 1991, the Histiocyte Society initiated LCH-I, a randomized international clinical trial for MS-LCH, comparing the efficacy of 6-month single-agent therapy with either vinblastine or etoposide (VP-16). 13 The drugs did not differ in disease response, reactivation, permanent consequences, survival, or toxicity. However, the results were inferior in some respects to previous reports based on more aggressive therapy. 8,13 That suggested that therapy for MS-LCH patients should be intensified. We therefore designed the next randomized controlled trial, LCH-II, to evaluate combining vinblastine and VP-16, in an intensified 6-month regimen. Methods Patient entry and randomizationEligible patients (confirmed histopathology, multisystem [MS] disease, age younger than 18 years, and no prior specific therapy) were entered, with informed consent obtained in accordance with the Declaration of Helsinki, from 98 pediatric institutions through 7 study subcenters and stratified into 2 groups, risk and low risk. 14,15 The study and study protocol have been approved by the Institutional Review Board of each institution participating in the trial. The risk patients, the subject of this report, either had involvement of risk organs (RO ϩ ; ie, liver, lung, and hematopoietic system or spleen) or had disease onset at younger than 2 years of age. 11,12 Low-risk MS-LCH patients...

Langerhans Cell Histiocytosis in Children: A Single Center Experience from Turkey.

“…Three clinical trials (LCH-I, -II, and -III) have tested this regimen and showed that it provides an increased survival rate in risk organnegative patients, even in infants. 5,11 However, despite this treatment, the mortality rates of ROpositive patients remain high at 16-38%. 5,11 In our study, patients without risk organ involvement had excellent outcome, but 3 of 4 patients with ROpositive MS disease had died.…”

“…5,11 However, despite this treatment, the mortality rates of ROpositive patients remain high at 16-38%. 5,11 In our study, patients without risk organ involvement had excellent outcome, but 3 of 4 patients with ROpositive MS disease had died. However, this high International Journal of Hematology and Oncology mortality rate may be related to the small number of cases.…”

“…Patients with risk organ involvement who do not respond within the first 6 weeks of therapy -especially those with evident clinical progression -have a negative prognosis. 5,15 Early therapy intensification is justified for such patients. Patients with multifocal bone disease are known to have an excellent prognosis (survival of 100%), but have a high tendency for reactivation (30-50%) and permanent outcomes.…”

Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan

“…[1][2][3] Although the risk factors for LCH have not been fully elucidated, patients younger than 2 years of age at onset, with risk organ involvement, including the hematopoietic system, liver, spleen, or lung, and disease refractory to conventional chemotherapy have a very poor outcome, with survival rates of about 20%. [4][5][6][7][8] The treatment strategy for these high-risk LCH patients has not yet been established. Recently, it was reported that a combination of 2-chlorodeoxyadenosine (2-CdA) and cytarabine (Ara-C) was effective for refractory LCH.…”

Oksipital kemik yerleşimli langerhans hücreli histiyositoz: Olgu sunumu

“…Hastalığın doğal seyri, spontan iyileşebilen lezyonlardan organ birikimleri ile giden ve hayatı tehdit eden sonuçlara kadar geniş bir yelpazede heterojenite göstermekle birlikte kalıcı sekellere de neden olabilir. Hastalık nadir görüldüğü ve litaratürde sınırlı sayıda vaka olduğu için bir çok tedavi yöntemi belirsiz ve tartışmalı olarak kalmıştır [7][8][9][10][11]. EG, LHH grubu hastalıkların lokalize formu olup, diğerlerine göre daha iyi prognoza sahiptir.…”