Which medications are used as monotherapy in the treatment of Langerhans cell histiocytosis (LCH)?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Purine analogs with activity for treatment of Langerhans cell histiocytosis (LCH) include 2-chlorodeoxyadenosine (2CdA; cladribine [Leustatin]) and 2-deoxycoformycin (2CDF; pentostatin; [295, 296, 297, 298, 299, 300, 301] 2CdA has been found to be particularly toxic to monocytes. [296, 297] Justification for the use of 2CdA is that some histiocytes are derived from monocytes. [208] In a review of 15 patients with multiorgan involvement receiving 2CdA and 2 receiving 2CDF, 6 had complete responses, 3 had partial responses, 5 had no response, and 1 died early. Fourteen had previously received significant treatments. [295]

As a single agent, cyclosporine has been used in pretreated patients with advanced Langerhans cell histiocytosis. Cyclosporine, a cyclic undecapeptide immunosuppressant of fungal origin, inhibits immune responses. The proposed mechanism of action is blockage of the transmission and synthesis of lymphokines, such as IL-2 and INF (ie, INF-alpha inhibition of the accessory cell function of Langerhans cells and reduced capacity of dendritic cells to enhance mitogenic stimulation of lymphocytes). Cyclosporine is postulated to disrupt abnormal cytokine-dependent activation of lymphocytes and histiocytes in the liver, spleen, lymph nodes, and bone marrow. The activation of lymphocytes is presumed to be secondary to uncontrolled proliferation of Langerhans cells. Furthermore, cyclosporine can inhibit cytokine-mediated cellular activation that potentially contributes to phagocytosis and disease progression. [286]

Cytosine arabinoside (cytarabine, ARA-C, Cytosar U), an antimetabolic chemotherapy agent, has been used for treatment of children and adults with Langerhans cell histiocytosis. The mechanism of action of this agent, has been used for treatment of children and adults with LCH. The mechanism of action of this agent is conversion to cytosine arabinoside triphosphate (Ara-CTP) by deoxycytidine kinase and other nucleotide kinases which results in cellular arrest in the S phase of inhibits RNA and DNA polymerases and nucleotide reductase enzymes necessary for DNA synthesis.

Cytosine arabinoside is converted to its inactive form, uracil arabinoside, by pyrimidine nucleoside deaminase. Because of its capability to cross the blood brain barrier, has efficacy in cases with CNS involvement. Cytosine arabinoside converts to uracil arabinoside (ARA-U) by pyrimidine nucleoside deaminase and is excreted mostly (80%) in the urine. This agent has been successfully used in single form or in combination in treatment of children and adults with LCH, including CNS involvement. [302, 303, 304, 305]


This agent is a purine nucleoside metabolic inhibitor. Clofarabine is metabolized intracellularly to the 5’-monophosphate metabolism by deoxycytidine kinase and monokinase and diphosphokinase to the active 5’-triphosphate metabolite. This agent inhibits DNA synthesis by several mechanisms. This includes decreasing cellular deoxynucleotide substrate and deoxycytidine. Clofarabine inhibits DNA synthesis by reducing cellular deoxynucleotide phosphate pool via inhibition of ribonucleotide reductase and termination of DNA chain elongation.

Furthermore, it inhibits DNA repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. Clofarabine 5’-triphosphate disrupts repair by incorporation into the DNA chain during the repair process. It also disrupts integrity of mitochondrial membrane resulting in release of the proapoptotic mitochondrial proteins, cytochrome C, and apoptosis-inducing factor. This results in programmed cell death. After intravenous administration, clofarabine becomes bound to plasma proteins (47%) mainly albumin. The half-life of this agent, in pediatric patients, is 5.2 hours. Approximately, 49-60% of clofarabine is excreted in the urine unchanged.

Clofarabine, as a single agent and in combination, appears to be active in treatment of LCH, including advanced forms, not responding to the conventional therapies. [306]

In one study of 6 pediatric patients with multisystem LCH, this agent had shown promising results with significant side effects. In another report of 18 refractory patients who had previously received a median of three chemotherapeutic agents for Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease, 17 responses were noted after two to four cycles of therapy with clofarabine. These patients were treated with two to eight cycles of 25 mg/m2 for 5 days of clofarabine. Complete responses were seen in 61% and partial response in 22% with the remaining patients being on therapy at the time of the report. Neutropenia, vomiting, and infections were the major short term toxicities.

Partial and complete responses have been recorded in a small number of patients. Patients with partial response had achieved a complete response with prednisone and vinblastine chemotherapy. Cyclosporine A has also been used in familial erythrophagocytic lymphohistiocytosis (FEL). In one report of 2 children whose disease was resistant to steroids and etoposide, durable remission was obtained with this agent. [307]

INF-alpha had some effect in anecdotal cases of Langerhans cell histiocytosis. [287, 308]

Treatment of multifocal relapsing and resistant bone lesions in LCH is challenging. Langerhans cells are capable of releasing cytokines, which are potent activators of osteoclasts and can result in the lytic lesions seen in the disease. Pamidronate, a bisphosphonate agent, has been reported to induce response or result in disease stability in a small group of patients. [309]

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