Medical Care
Optimal therapy for Langerhans cell histiocytosis (LCH), particularly in the case of multisystem organ disease, is emerging. The Histiocyte Society has conducted a number of prospective, randomized control trials to study the effect of various chemotherapeutic regimens in the treatment of LCH, which have resulted in recommendations by the Histiocyte Society.
Cobimetinib (Cotellic) was approved by the FDA for adults with histiocytic neoplasms (eg, LCH, Roasi-Dorfman, Erdheim-Chester disease) in October 2022. The National Comprehensive Cancer Network guidelines includes cobimetinib as a preferred regimen for treatment of Rosai-Dorfman disease, LCH with CNS lesions, multisystem or single-system lung LCH, and Erdheim-Chester disease. [93]
Generally, the choice of therapeutic regimen is based on disease severity. The International LCH Study of the Histiocyte Society proposes the stratification of LCH cases by the number of systems involved. They further categorize those cases with single-system involvement by the number of sites within that system (eg, monostotic vs polyostotic bone disease, solitary vs multiple lymph node involvement). In addition, the presence or the absence of risk-organ dysfunction is used to stratify patients with multisystemic disease; the presence of risk-organ dysfunction portends a poorer prognosis.
Notably, most trials for the treatment of LCH have been performed in pediatric populations, and their results have typically been extrapolated to adults. This has resulted in a call for more prospective, randomized trials looking specifically at the treatment of LCH in adults and whether changes in chemotherapeutic regimens and their duration may be appropriate. [62]
Single-system disease
Solitary bone lesions are treated locally with curettage or excision. Painful bone lesions may require intralesional steroid injection (triamcinolone acetonide). Bisphosphonates such as zoledronic acid can also be used to reverse bone destruction and mitigate the pain of bony lesions. [63] Early treatment with vinblastine and prednisolone has been suggested for bony lesions at vital anatomic locations requiring prompt resolution. [28] Rarely, lesions that are unusually large and painful occur in inaccessible sites or involve vital structures require radiation therapy (3-6 Gy [300-600 rad]).
Polyostotic bone lesions are best treated with indomethacin or a short course of systemic steroids. [64] A case report on pharmacologic management of single-system bony disease using naproxen indicates that multiple COX antagonists may be used in treating this form of LCH. [65]
Localized skin disease is best treated with moderate-to-potent topical steroids (eg, mometasone furoate [Elocon] cream 0.1%, triamcinolone [Kenalog] cream 0.1%, fluocinolone [Synalar] ointment 0.025%) or superpotent topical steroids (eg, clobetasol propionate 0.05%). In cases of severe cutaneous involvement, topical nitrogen mustard (20% solution) may be used. Acitretin may also be an effective agent for patients with primarily cutaneous manifestations of LCH. [66]
Psoralen plus ultraviolet A (PUVA) is another effective modality for cutaneous-only LCH or for cutaneous involvement in multisystemic disease. PUVA consists of photosensitizing psoralens (8-methoxypsoralen or 5-methoxypsoralen) either applied topically or ingested systemically 2 hours prior to treatment with long-wave ultraviolet A (320-400 nm). The purpose of this treatment is to induce remission of skin diseases by inducing a repeated and controlled phototoxic reaction. The photoconjugation of psoralens with DNA produces an antiproliferative reaction in the skin, generates programmed cell death (apoptosis), and induces down-regulation of the cutaneous immune system. [67]
Ultraviolet B excimer laser has been found in at least one case report to offer effective adjuvant therapy in the management of cutaneous LCH, and it may be particularly useful for patients with comorbidities who cannot tolerate more aggressive treatment. [68]
For single lymph node infiltration, excision is the treatment of choice. Regional lymph node enlargement can be treated with a short course of systemic steroids. Treatment-resistant nodes with sinus tracts to the skin may require systemic chemotherapy.
Smoking cessation is an important intervention in cases of pulmonary LCH. [40]
Single-agent chemotherapy with cladribine (2-chlorodeoxyadenosine/2-CdA) may be a promising treatment for single-system pulmonary LCH. [69, 70]
Multisystem disease
Systemic chemotherapy is indicated for multisystem disease and cases of single-system disease not responsive to other treatment. The combination of cytotoxic drugs and systemic steroids is generally effective. Low-to-moderate doses of methotrexate, prednisone, and vinblastine are used.
Efficacy differences in chemotherapeutic agents
Multiple large clinical trials have examined differences in efficacy between chemotherapeutic agents.
One cooperative clinical trial in Europe used vinblastine, etoposide, and prednisolone for 6 weeks, followed by mercaptopurine, vinblastine, and prednisolone for 1 year. If soft tissue was involved, treatment was supplemented with etoposide, and, if the patient has organ dysfunction, methotrexate was added. Initial complete resolution occurred in 86% of patients, with a mortality rate of 9% and a disease-free survival rate of 77% at a median follow-up time of 6 years. [71]
The LCH-I trial sponsored by the Histiocyte Society used etoposide or vinblastine for 24 weeks. These agents produced equivalent responses at week 6 and had similar effects on survival and disease recurrence. Lack of response at 6 weeks was associated with an increased likelihood of treatment failure and a worse prognosis. The survival rate was slightly better in the aforementioned European trial than in LCH-I, but the difference was not statistically significant. A greater probability of developing diabetes insipidus occurred in the LCH-I trial. [32]
The LCH-II randomized clinical trial compared the effectiveness of 24 weeks of combined therapy with vinblastine, oral prednisone, and mercaptopurine, versus the same combination with the addition of etoposide. The overall survival in patients treated with etoposide was marginally improved compared with treatment without it; this effect was more pronounced in those patients with risk-organ involvement. However, although the addition of etoposide produced slightly more favorable therapeutic responses, it did not decrease the likelihood of disease recurrence. [72] Ultimately, the Histiocyte Society concluded that early therapy intensification (when compared with the LCH-I trial) had a positive effect on survival. [72] However, the addition of etoposide appeared to be of minimal therapeutic benefit and it use was not included in the recommendations of the Histiocyte Society released in April 2009.
The LCH-III study, a prospective, randomized clinical trial, evaluated the efficacy of adding methotrexate to vinblastine and prednisone in the treatment of LCH in multisystem-risk patients. It also included evaluation of the optimal duration of treatment (6 mo vs 12 mo) using prednisone and vinblastine for multisystem low-risk patients. Finally, it includes a pilot study for patients with single-system multifocal bone disease and localized special sites, including the CNS. Results of LCH-III resulted in the following recommendations from the Histiocyte Society:
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Risk patients should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients who continue to have active disease should repeat this regimen for another 6 weeks. Patients who have no active disease after 6-week induction therapy should begin continuation treatment with oral 6-mercaptopurine daily, supplemented with pulses of oral prednisone and intravenous vinblastine, for 12 months of total treatment. The addition of methotrexate to LCH treatment is not recommended in current practice.
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Low-risk patients should be treated with oral prednisone and intravenous vinblastine for 12 months total.
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Patients with multifocal bone disease or CNS risk should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients should then be supplemented with pulses of oral prednisone and intravenous vinblastine for 6 months of total treatment.
LCH-IV, an international treatment protocol sponsored by Dana-Farber Cancer Institute for children and adolescents with LCH (ClinicalTrials.gov identifier NCT02205762), is currently recruiting participants. In this randomized, interventional study, patients who do not respond to standard first-line prednisone and vinblastine will be switched to the combination of cytosine arabinoside and 2-chlorodeoxyadenosine. Other stratifications of the study design include treatments with mercaptopurine and methotrexate, indomethacin, hematopoietic stem cell transplantation, and intravenous immunoglobulin.
Treatment of refractory disease
LCH-S-98, a prospective, phase II Histiocyte Society study evaluated 2-chlorodeoxyadenosine (2-CdA) as salvage monotherapy for patients with risk-organ involvement refractory to initial therapy with three agents (excluding 2-CdA) or patients with recurrent, low-risk LCH (ie, patients with non–risk-organ involvement, including multifocal bone disease). [73] The study concluded that 2-CdA is active as salvage therapy for LCH, but that it is more effective in low-risk patients or patients with multifocal bone disease. Those patients with risk-organ involvement who responded to 2-CdA therapy had a good prognosis, while those who were refractory typically had grim outcomes. Notably, patients older than 2 years and those with a longer time between diagnosis and 2-CdA therapy had better responses, presumably because their disease was less aggressive. [73]
Combination therapy with 2-chlorodeoxyadenosine and cytosine arabinoside (ARA-C) has been studied in patients with refractory, risk-organ‒positive LCH. The overall 5-year survival rate was 85%; thus, the combination of 2-chlorodeoxyadenosine and ARA-C appears to be an effective therapy for refractory multisystem LCH, albeit one associated with high toxicity. [74]
A retrospective study evaluating the efficacy of 2-CdA (+/- arabinoside) in treating refractory LCH in 17 Japanese patients similarly concluded that 2-CdA is effective for the treatment of refractory disease. [75] Notably, patients whose disease reactivated following the conclusion of their initial therapy had improved outcomes compared with those patients who had primary refractory disease or those who experienced reactivation during their initial chemotherapy. This same study also suggested that 2-CdA may be effective in the treatment of LCH with CNS involvement. [75]
In LCH patients with a very poor prognosis (rapid disease progression, refractory to conventional treatment, or with disseminated risk-organ involvement), bone marrow transplantation (BMT) or reduced-intensity condition stem cell transplantation has shown promise as effective salvage therapy. [76, 77, 78] A retrospective review of 87 instances of hematopoietic stem cell transplant (HSCT) for LCH provides cautious optimism about the benefits of this procedure. [79] Specifically, the authors note that survival after HSCT has improved with time, and almost 75% of children now survive following transplantation, which the authors attribute in part to better supportive care following HSCT. Comparing myeloablative condition regimens with reduced intensity conditioning (RIC) regimens, there appeared to be no differences in transplantation-related mortality, although those undergoing RIC had higher relapse rates. These findings may reflect a selection bias where patients at higher risk were more cautiously treated with RIC regimens. Although a hopeful option for patients refractory to typical chemotherapy, the authors caution that the ideal conditioning regimen remains undefined; timing of such transplantations have also not been rigorously evaluated. [79, 80]
Resistant LCH may also be treated with a combination of cyclosporin A, antithymocyte globulin, and prednisolone if patients do not have a matched donor for BMT.
Thalidomide has also been proposed as an agent for treating refractory/relapsing multisystem disease, but its efficacy appears to be limited to low-risk patients with only skin or bone involvement. Its use also is associated with significant toxicities, including pancytopenia and pulmonary failure. [81]
The discovery of oncogenic BRAF V600E mutation in more than half of LCH specimens [82] suggests that B-RAF inhibitors such as vemurafenib could be applied to treatment of those cases shown to bear that mutation. Vemurafenib was approved for Erdheim-Chester disease (ECD) with BRAF V600 mutation in November 2017. ECD is also known as polyostotic sclerosing histiocytosis. Early case reports describing use of vemurafenib to treat patients with multisystemic and refractory ECD carrying the BRAF V600E mutation showed positive results. Two of the patients also had skin or lymph node LCH involvement. In all three patients, vemurafenib treatment led to clinical and biologic improvement, which was maintained after 4 months of follow up (although persistent disease activity was still observed). [83] A phase 2 VE-BASKET study (n=22) confirmed use of vemurafenib for patients who have ECD with the BRAF V600 mutation. Results from a basket study in 2015 showed a response rate of 43% in the cohort with ECD or LCH. [84] Final results showed a best overall response rate of 54.5%. [85]
In phase 2 of the VE-BASKET trial, four BRAF V600E LCH patients showed a 2-year progression-free survival of 86%, with all patients achieving stable disease or better. Dose reduction was required for every patient, owing to adverse events, including a case of treatment-induced thyroid cancer that resulted in discontinuation of vemurafenib. [86] An international observational study of 54 patients showed vemurafenib to be effective in treating refractory multisystem LCH. At 8 weeks, 38 patients achieved complete responses. However, 24 of 30 patients experienced relapse after drug discontinuation. [36] Additional studies are needed to establish the optimal dosage and duration of vemurafenib treatment.
Finally, the MEK1/2 inhibitor cobimetinib has been found to be efficacious in treating a variety of multisystem or refractory histiocytic neoplasms, including LCH. A phase II study of 18 patients had an 89% response rate, with 95% progression-free at 1 year. [87]
Other treatment options
A paucity of clinical trials for the treatment of LCH in adults has lead to the report by Derenzini and colleagues of a monocentric, retrospective study on the use of intense MACOP-B therapy (a common therapeutic regimen in aggressive non-Hodgkin lymphoma) without continued maintenance therapy, in the treatment of adults with LCH. [57]
In this study, 7 patients were treated with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) weekly for 12 weeks. A retrospective analysis of these patients showed a complete response (defined as no evidence of active disease, plus a regression of signs and symptoms at physical examination and on imaging) in all 7 patients, although 3 patients subsequently had reactivation of their disease. Taken together, the authors conclude that more intense initial therapy may induce a better disease response in adults than alternative regimens that induce partial response to induction chemotherapy followed by a maintenance regimen. [57] However, these results require more formal evaluation.
Other potential treatments include monoclonal antibody targeting with indium–labeled anti-CD1a, cytokine inhibitors, alemtuzumab (anti-CD52), low-dose oral cyclophosphamide, and all-trans retinoic acid. [88, 89, 90] Imatinib has been proposed as a potential therapy for LCH, owing to its ability to inhibit signaling through the platelet-derived growth factor (PDGF), macrophage-colony stimulating factor (MCSF), and c-kit receptors, which are present on the surface of histiocytes. However, clinical application of this therapy has shown mixed efficacy. [91, 92]
Consultations
Referral to an orthopedic surgeon has important diagnostic and management implications when bone lesions are present.
An otolaryngologist may aid in the treatment of otitis media caused by destruction of the temporal and mastoid bones.
Consultation with an ophthalmologist is suggested for a vision check and an assessment of the need for decompression in patients with proptosis.
Consultation with a dentist is indicated if loose teeth result from infiltration of the mandibles.
Referral to an endocrinologist may help in the design of treatment of the endocrine abnormalities.
Long-term hearing loss can cause significant morbidity, owing to ear involvement by Langerhans cell histiocytosis (LCH), as well as to the use of other medications (ie, aminoglycosides) as adjuncts to chemotherapy. It has been proposed that all LCH patients with ear involvement have regular audiometry and CT/MRI of the petrous temporal bones, as well as long-term follow up with an audiologist to monitor for hearing loss. [58]
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Letterer-Siwe disease. Bilateral inguinal erosive plaques and erythematous papules on the abdomen. Courtesy of Dr Neil S. Prose.
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Abdominal area of an infant with multiple erythematous papules covered by scale and/or crust.
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Typical purpuric lesions in Langerhans cell histiocytosis (must be distinguished from seborrheic dermatitis).
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On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.
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High-power views. Marked epidermotropism is noted (left). The lesional cells are large, with abundant pink cytoplasm and reniform nuclei. An admixture of inflammatory cells, including occasional eosinophils, is present (right).
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High-power views. Diffuse immunoreactivity for S-100 protein (right). Langerhans cells and lymphocytes (left, hematoxylin and eosin).
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Widespread positivity for CD1a. Note the presence of epidermotropism (right). Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis (left, hematoxylin and eosin).
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Electron microscopy. Tennis racquet form of Birbeck granules with a small terminal expansion.
