Department of Pediatrics, College of Medicine at the University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Pediatric Hematology and Oncology, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
Cancer. 2024 Jul 15;130(14):2416-2439. doi: 10.1002/cncr.35301. Epub 2024 Apr 30.
Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.
朗格汉斯细胞组织细胞增生症(LCH)是一种髓系肿瘤性疾病,其特征为病变组织中有 CD1a 阳性/朗格汉斯细胞(CD207)阳性的组织细胞和炎症浸润,可导致局部组织损伤和全身炎症。临床表现范围从单一的、影响较小的病变到危及生命的播散性疾病。系统性 LCH 的治疗是通过一系列临床试验经验性地测试不同的化疗药物和治疗持续时间来建立的。然而,目前的标准治疗方案(长春碱/泼尼松/(巯嘌呤))仅能治愈少于 50%的播散性疾病患者,且治疗失败与长期发病率相关,包括 LCH 相关神经退行性变的风险。历史上,LCH 的性质(是一种反应性疾病还是一种肿瘤/恶性疾病)尚不确定。在过去的 15 年中,开创性的发现广泛定义了 LCH 的发病机制;具体而言,髓系前体细胞中的丝裂原活化蛋白激酶通路突变(最常见的是 BRAFV600E)驱动病变形成。因此,LCH 是一种克隆性肿瘤性疾病,尽管继发性炎症特征也参与了疾病的发生。这些改变范式的见解为基于个体突变、克隆储库和疾病程度为患者提供合理治疗提供了希望。然而,临床试验发展的速度落后于转化发现的速度。在这篇综述中,作者讨论了目前对 LCH 生物学、临床特征、治疗策略的理解,以及通过协调药物优先级和临床试验努力改善每位患者预后的机会。