A phase II trial using thalidomide for Langerhans cell histiocytosis

Baylor College of Medicine, Texas Children's Cancer Center/Hematology Service, Houston, Texas, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 01/2007; 48(1):44-9. DOI: 10.1002/pbc.20578
Source: PubMed


Few new drugs for treatment of Langerhans cell histiocytosis (LCH) have been studied. Tumor necrosis factor-alpha (TNF-alpha) is a prime therapeutic target since it appears to be present in elevated amounts in LCH lesions. Thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other anti-cytokine effects.
A Phase II trial of thalidomide for treatment of LCH patients who had failed primary and at least one secondary regimen was conducted. Sixteen patients were enrolled: nine males and seven females ranging in age from 19 months to 45 years. Six patients were high risk (HR) because of spleen, liver, lung, or bone marrow involvement. The low risk (LR) patients included six with bone/skin LCH, one with multiple bone, one with skin/bone/pituitary, one with skin/bone/brain, and one with skin only disease involvement. Fifteen patients remained on treatment from 3 weeks to over 1 year.
Among the LR patients there were four complete responses, three partial responses, and two with no response to thalidomide. No HR patient responded to thalidomide and all died of pulmonary, liver, or bone marrow failure. Thalidomide may have played a role in the pulmonary failure. Other toxicities that required stopping therapy included neutropenia, peripheral neuropathy, and fatigue.
Thalidomide is an effective therapy for some LR patients with LCH, but showed no significant responses in HR patients. Dose-limiting toxicities may reduce its efficacy in LR patients. Additional trials with improved anti-TNF therapies would appear warranted.

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    • "Thalidomide: is a TNF-α antagonist and has been shown to be effective in treating cutaneous LCH [33] but gives poor responses in high risk multisystem disease [34]. Dose of 100mg/day in adults is generally used but toxicity with peripheral neuropathy must be monitored (Grade C2). "
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    ABSTRACT: Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.
    Orphanet Journal of Rare Diseases 05/2013; 8(1):72. DOI:10.1186/1750-1172-8-72 · 3.36 Impact Factor
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    • "Targeted therapeutic possibilities in this context include metformin to : 1. Activate AMPK with inhibition of TGF-β{Smad3}-associated Gli2 and IL-11 signaling [26] [27] [28] [29] [30] [31] [62] [63] and in turn, inhibition of PTHrP and RANKL signaling [46] [64] [65] with reduced osteoclastogenesis; 2. Downregulate FASN [66] leading to reduced substrate for the PLD1/PKC-α/TGF-β signaling axis; and 3. Inhibit STAT3 activation at tyrosine 705 [67]. Moderators of TGF-β pathway signaling related to immune dysregulation include: thalidomide, which has shown efficacy in blocking the TGF-β pathway [16] [17] [18] [19] and clinically, in treating osteolytic LCH [15]; and metronomic cyclophosphamide , which targets T regulatory cells [68]. *Indicates protein analytes identified in osteolytic LCH. "
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    ABSTRACT: Langerhans cell histiocytosis (LCH) has a challenging and still unclear pathogenesis. A body of literature points to impaired maturation of the lesional dendritic cells, and to immune dysregulation in the form of increased FoxP3 cells. Various cytokine abnormalities such as expression of transforming growth factor (TGF)-β have been reported, as well as abnormalities in lipid content in LCH cells. Morphoproteomic techniques were applied to identify the signal transduction pathways that could influence histogenesis and immune regulation in osteolytic LCH. Five pediatric cases of osteolytic LCH were examined, using antibodies against CD1a, S100, CD68, CD8, FoxP3, phosphorylated (p)-STAT3 (Tyr705), protein kinase C (PKC)-α, phospholipase (PL)D1, fatty acid synthase (FASN), and zinc finger protein, Gli2. Positive and negative controls were performed. A FoxP3(+)/CD8(+) cell ratio was calculated by counting the FoxP3+ and CD8+ cells in 10 high power fields for each case. There is induction of sonic hedgehog (SHH) mediators consistent with TGF-β signaling pathway through Smad3-dependent activation of Gli2, findings supported by the plasmalemmal and cytoplasmic expression of PKC-α and PLD1, and nuclear expression of Gli2, in lesional cells. The FoxP3+/CD8+ cell ratio is increased, ranging from 1.7-7.94. There is moderate cytoplasmic expression of FASN in most of the Langerhans cells, a finding that supports previously published phospholipid abnormalities in LCH and is consistent with PKC-α/PLD1/TGF-β signaling. With our study, we strongly suggest that the TGF-β cell signaling pathway is a major player in the pathogenesis of LCH, leading to non-canonical induction of nuclear Gli2 expression, thereby contributing to osteoclastogenesis in LCH histiocytes. It could also cause a state of immune frustration in LCH, by inducing the transformation of CD4(+)CD25(-) cells into CD4(+)/FoxP3(+) cells. This coincides with the clinical evidence of a response to thalidomide in patients with osteolytic LCH, given its reported ability to reduce TGF-beta 1 and FoxP3 cells. Such TGF-β signaling in osteoclastogenesis and immune dysregulation, and the presence of FASN in the majority of cells, have additional therapeutic implications for osteolytic LCH.
    International journal of clinical and experimental pathology 09/2012; 5(6):503-11. · 1.89 Impact Factor
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    ABSTRACT: A 57-year-old woman presented with a 1-year history of non-healing inguinal and perianal ulcers as well as a 2-year history of polydipsia. The clinical picture and histology suggested Langerhans cell histiocytosis, which was confirmed by immunohistochemistry and electron microscopy. Magnetic resonance imaging of the brain revealed hypothalamic-pituitary axis involvement. Treatment was started with thalidomide and desmopressin. The skin lesions resolved over 2 months. Over the next 24 months of continued therapy, the cerebral involvement remained stable and the skin lesions did not recur.
    American Journal of Clinical Dermatology 02/2007; 8(5):311-4. · 2.73 Impact Factor
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