Treatment Of Langerhans Cell Histiocytosis Research Articles

A phase II trial using thalidomide for Langerhans cell histiocytosis

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.

Drug therapy for the treatment of Langerhans cell histiocytosis

Langerhans cell histiocytosis results from the abnormal accumulation of a class of dendritic cells normally found in the skin, which proliferate in many organ systems along with lymphocytes, macrophages and eosinophils. Standard therapy for Langerhans cell histiocytosis includes vinblastine and prednisone with or without methotrexate and mercaptopurine, depending on the extent of disease. Effective therapies for patients unresponsive to the above include cytosine arabinoside and cladribine. Thalidomide has proven useful for patients with Langerhans cell histiocytosis of the skin and/or bone. Emerging therapies include the use of monoclonal antibodies against the CD1a or CD52 epitopes found on Langerhans cells. Specific therapies directed against the cytokines that are apparently critical to the abnormal proliferation have not yet been defined.

A single‐centre study can improve our knowledge of a rare disease! As exemplified by studies in Langerhans' cell histiocytosis

The main contribution of this clinical study of Langerhans' cell histiocytosis (LCH) is that it provides information on the adult outcome of patients diagnosed during childhood. The authors show that most patients, sometimes despite their sequelae, undertake higher education and live as independent adults. This study also offers evidence that some sequelae are due to radiotherapy, which should therefore be excluded from the treatment of LCH. The analysis of causes of death shows the important role of haematological dysfunction.

Spontaneous regression of Langerhans cell histiocytosis: a case report

Background Spontaneous regression of Langerhans cell histiocytosis (LCH) has been reported in skin, bone, and pulmonary lesions. However, such phenomena in the central nervous system (CNS) have not been described previously. Case description A case of LCH in the CNS with spontaneous regression is reported. A 2-year-old boy presented with general convulsion followed by frequent vomiting and diabetes insipidus. Magnetic resonance imaging (MRI) scan revealed numerous multifocal nodules predominantly in the left frontal lobe. The patient underwent surgery to remove part of the frontal lesion. Subsequent to surgery, residual lesions showed regression without any additional treatment, and clinical symptoms also subsided. The multiple lesions disappeared completely and did not relapse during 5-year observation. Conclusion Surgical resection and/or adjuvant therapy such as radiation and chemotherapy has been performed for the treatment of LCH in the CNS. However, there may be a subgroup of patients with multifocal brain LCH that regress spontaneously. Further clinical study is required to establish the natural course and prognostic factors of this disease.

90Y-DOTA-lanreotide shows potential in the treatment of Langerhans cell histiocytosis,

90Y-DOTA-lanreotide shows potential in the treatment of Langerhans cell histiocytosis,

Endocrine involvement in pediatric-onset langerhans' cell histiocytosis: a population-based study

Objective To document the frequency and outcome of endocrine involvement in pediatric-onset Langerhans' cell histiocytosis (LCH), and the association with other types of organ involvement. Study design This retrospective nationwide multicenter study involved 589 patients with pediatric-onset LCH, 148 of whom had endocrine dysfunction. Median follow-up was 11.6 years. Results Pituitary dysfunction was present in 145 patients, and 141 had diabetes insipidus (DI). The estimated 10-year risks of pituitary involvement were 24.2% ± 1.8%. GH deficiency occurred in 61 patients. Median age at onset was 2.8 years for LCH, 3.9 years for DI, and 7.7 years for GH deficiency. The risk of cranial involvement; ear, nose, and throat involvement; pneumothorax; and cholangitis was significantly higher in patients with endocrinopathy. The chronology of episodes did not support a causal link between pituitary involvement and involvement of other organs. Systemic treatment of LCH did not prevent pituitary involvement. The most severe complication was a neurodegenerative syndrome, which affected 4.3% and 10.8% of patients, respectively, 5 and 15 years after initial diagnosis, and appeared to be linked to pituitary involvement. Conclusion Patients who develop endocrine LCH disorders are at a high risk of neurodegenerative LCH and require long-term follow-up.

Atypical Cellular Disorders

Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similarities in that abnormal proliferations of lymphocytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, and Castleman's disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expression or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chromosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the "inflammatory response" camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don't have a "malignant" morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collaborations of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome. In Section II, Dr. Yasodha Natkunam reviews the features of SHML, which most often presents as painless cervical lymphadenopathy, although many patients can have extranodal involvement as well. These sites include the skin, respiratory tract, bone, lung, gastrointestinal tract, and brain. The diagnosis rests on finding intact lymphocytes in the cytoplasm of activated macrophages as well as accumulation of mature plasma cells. Hemolytic or non-hemolytic anemias, hypergammaglobulinemia, and elevated erythrocyte sedimentatin rate (ESR) are often found with SHML. An intriguing finding of human herpesvirus (HHV)-6 viral proteins in SHML has been reported in several patients, but needs further study. SHML associated with lymphoproliferations triggered by defects in apoptosis are discussed since this mechanism may provide a clue to the etiology. Therapy for SHML varies greatly in reported case series. Many patients have spontaneous regression or resolution after surgical removal of isolated node groups. Others with systemic involvement may benefit from chemotherapy, but no clinical trials have been done. In Section III, Dr. Steven Swerdlow clarifies key features of the four types of CD. Localized cases are divided into the hyaline vascular type and plasma cell type. Both are usually cured by surgical excision and have symptoms mainly of a mass lesion, although the latter often also has constitutional symptoms. The two types are distinguished largely by the nature of the follicles and the number of interfollicular plasma cells. Interleukin (IL)-6 expression is increased in the plasma cell type. Multicentric CD of the plasmablastic type is most often found in HIV-positive patients with coincident HHV-8 infection. Many have lymphomas or Kaposi sarcomas. Other cases of multicentric CD are also most like the plasma cell type, however, with disseminated disease and constitutional symptoms. A wide variety of anti-neoplastic drugs, radiation therapy, anti-IL-6 and rituximab or atlizumab have been used with varying success in patients with multicentric CD. Clinical trials are needed for SHML and CD and registration of adult and pediatric patients on current LCH trials are encouraged.

2-Chlorodeoxyadenosine Therapy for Disseminated Langerhans Cell Histiocytosis

To evaluate the efficacy of 2-chlorodeoxyadenosine (2-CDA), a purine nucleoside analogue, in treating disseminated Langerhans cell histiocytosis (LCH). We retrospectively reviewed the clinical records of 5 patients who were seen at our institution for histologically confirmed disseminated LCH, including 1 patient with central nervous system parenchymal involvement. These patients were treated consecutively with 2-CDA chemotherapy between December 1994 and January 2001. The patients ranged in age from 19 to 81 years, and the median pretreatment duration of disease was 23 months. Median follow-up after initiation of 2-CDA treatment was 33 months. 2-Chlorodeoxyadenosine was used as frontline therapy for 1 patient and as salvage therapy for the other patients. Patients generally received 0.7 mg/kg over 5 or 7 days; the median number of courses was 4. Complete responses were achieved in 3 patients, including the patient with central nervous system disease, which, to our knowledge, has not been described previously. Two other patients achieved partial responses. The overall response rate was 100%. Toxic effects consisted mainly of myelosuppression; 1 patient developed dermatomal herpes zoster infection. Our experience confirms the reported efficacy of 2-CDA in the treatment of LCH; however, the optimal timing and schedule of therapy remain to be determined.

Treatment of Langerhans cell histiocytosis with 2′-deoxycoformycin(2′-DCF)

Treatment of Langerhans cell histiocytosis with 2′-deoxycoformycin(2′-DCF)

Atypical Cellular Disorders

Atypical cellular disorders are commonly considered part of the gray zone linking oncology to hematology and immunology. Although these disorders are relatively uncommon, they often represent significant clinical problems, provide an opportunity to understand basic disease mechanisms, and serve as model systems for the development of novel targeted therapies. This chapter focuses on such disorders. In Section I, Dr. Arceci discusses the pathogenesis of Langerhans cell histiocytosis (LCH) in terms of the hypothesis that this disorder represents an atypical myeloproliferative syndrome. The clinical manifestations and treatment of LCH in children and adults is discussed along with possible future therapeutic approaches based upon biological considerations. In Section II, Dr. Longley considers the molecular changes in the c-Kit receptor that form the basis of mastocytosis. Based on the location and function of c-Kit mutations, he develops a paradigm for the development of specific, targeted therapies. In Section III, Dr. Emanuel provides a review of the "mixed myeloproliferative and myelodysplastic disorders," including novel therapeutic approaches based on aberrant pathogenetic mechanisms. Taken together, these chapters should provide an overview of the biological basis for these disorders, their clinical manifestations, and new therapeutic approaches.

Histiocitosis de células de langerhans en o.r.l.

Langerhans's cell histiocytosis (LCH) is an uncommon disease characterized by an accumulation of abnormal histiocytes, together lymphocytes and eosinophils in various organs and tissues. The head and neck are frequent sites of initial presentation. We present two cases of LCH with otorhinolaryngologic symptoms. Current recommendations for diagnosis, evaluation and treatment of LCH are also discussed.

Radiotherapy in the Treatment of Langerhans Cell Histiocytosis

To further clarify the role of radiotherapy (XRT) for the treatment of Langerhans cell histiocytosis (LCH) we retrospectively analysed 13 patients treated with megavoltage irradiation. Localisation of LCH, radiation doses and techniques, and treatment results were determined. XRT alone was used in 9 patients with localised LCH. In 8 patients a complete remission was induced with doses between 10 - 20 Gy. Two relapses occurred but were controlled after a second radiation course. One patient developed systemic LCH. Four patients with systemic LCH were irradiated to treat local problems. Complete remissions were achieved in two patients, frequent relapses occurred in the other two patients. Five patients had evidence of cerebral LCH causing diabetes insipidus. In two patients a cerebral LCH-tumour was detectable. Tumour growth was abrogated in these cases. XRT could not revert diabetes insipidus but no progression of tumour growth and the associated hormonal dysfunction occurred.

Abundant expression of CD40 and CD40-ligand (CD154) in paediatric Langerhans cell histiocytosis lesions

The pathogenesis of Langerhans cell histiocytosis (LCH) is obscure, partly because the events leading to activation of Langerhans-like lesional cells (LCH cells) and associated T cells, and the excessive cytokine production by these cells are unknown. The interaction between CD40 on antigen-presenting cells (APC) like Langerhans cells and CD40 ligand (CD40L) (CD154) expressed by activated CD4+ T cells, is essential for the activation of both the APC and the T cells and results in upregulation of APC functions and initiation of immunoreactivity. The effects of CD40–CD40L interaction include increased expression of co-stimulatory and adhesion molecules, proliferation, and production of pro-inflammatory cytokines and proteolytic enzymes, all features of LCH. Using immunohistochemistry, we analysed the in situ presence of the co-stimulatory molecules CD40 and CD40L in 15 fresh frozen biopsies of LCH lesions in children. The cells producing these molecules were identified by double staining for CD1a on LCH cells and CD3 on T cells. Prominent expression of CD40 by LCH cells and CD40L by T cells was found in all 15 specimens regardless of the source of specimen or characteristics of the patient. The findings of high expression of CD40 and CD40L in all specimens imply a key role for the CD40–CD40L adhesion pathway in the pathogenesis of LCH. Since this interaction is an accessible and realistic target for immunotherapy, these findings prompt speculation on the use of blocking antibodies to CD40 or to CD40L in the treatment of LCH.

Treatment of Langerhans Cell Histiocytosis with 2 Chlorodeoxyadenosine

Langerhans—cell histiocytosis (LCH) is a rare condition with a wide clinical spectrum and variable prognosis. Patients with multisystem LCH have been treated with a variety of agents but may develop resistant and progressive disease. Based on a preliminary encouraging report on the activity of 2 chlorodoxyadenosine in this disease, we administered this agent to a patient with LCH which was resistant to corticosteroids and etoposide. After 4 courses of treatment the patient achieved a complete remission which is currently ongoing for 12 months. 2 CdA appears to be effective in patients with resistant LCH and warrants investigation in previously untreated patients with poor risk disease.

Treatment of Relapsed Langerhans Cell Histiocytosis by Cyclosporin a Combined with Etoposide and Prednisone

Optimal treatment for Langerhans cell histiocytosis (LCH) has not yet been established. High-risk patients with systemic LCH may have a fatal course of the disease despite intensive treatment. New approaches using cyclosporin A (CSA) showed promising results. Here, we report on a 4-year-old boy who presented with systemic LCH of skin, liver, bone, bone marrow, and soft tissue infiltrates. The patient was refractory to conventional therapy including VP16, prednisone, 6-mercaptopurine, methotrexate, and vinblastine. Therefore the patient was treated with CSA as continuous therapy (serum levels were kept between 300 and 400 ng/mL) as well as intensification with VP16 and prednisone every 4 weeks. As early as 4 months after starting this treatment, clinical symptoms completely disappeared except for a slightly enlarged liver. During the next 12 months all clinical symptoms except a limited skin involvement vanished although treatment with VP16 and prednisone was stopped and CSA serum levels were kept between 100 and 150 ng/mL. In conclusion, intensive therapy using high-dose CSA combined with VP16 and prednisone might be a therapeutic option for patients with otherwise refractory LCH.

Digestive tract involvement in Langerhans cell histiocytosis

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease with a wide clinical spectrum. Although little is known of gastrointestinal involvement in LCH, it may be a major clinical problem. We investigated clinical, pathologic, and immunohistochemical features of digestive tract LCH involvement in children. PATIENTS: Selection criteria consisted of the presence of LCH with digestive symptoms, and histologic confirmation of gastrointestinal involvement. Seven children (2%) met the criteria among 348 cases of LCH in a French national retrospective survey from 1983 to 1993. Two children whose LCH was diagnosed in 1994 were also selected. RESULTS: Nine children with LCH and digestive tract involvement were studied. Clinical features at presentation included skin (9/9) and mucosal (4/9) involvement, failure to thrive (5/9), diarrhea (7/9), bloody stools (4/7), vomiting (4/9), and hypoalbuminemia (8/9). Five of the nine children died; factors associated with a poor prognosis included young age, organ dysfunction (stage 4), and need for parenteral nutrition. Unlike control biopsy specimens, LCH cells of children with digestive tract involvement disclosed expression of the mucosal homing receptor integrin α4β7 on frozen skin and digestive tract biopsy specimens. CONCLUSION: Cutaneous, mucosal, and digestive tract involvement in LCH is a clinicopathologic entity. The prognosis and treatment of LCH depend on the extent of the disease; therefore the treatment of these disseminated forms should not be delayed. Thus children with cutaneous LCH and digestive symptoms should undergo digestive tract biopsies. Studies of homing receptors may contribute to our understanding of the mechanisms of dissemination in LCH. (J Pediatr 1996;129:836-45)

Etoposide in Langerhans cell histiocytosis in children: a preliminary experience.

Treatment of Langerhans cell histiocytosis (LCH) is yet to be established. We treated seven patients with etoposide alone at a dose of 100 mg/m2/day for 3 days given every 3 to 4 weeks for six cycles. Three patients had received prior chemotherapy, two patients were less than 2 years of age, and two had liver dysfunction. A positive response to therapy was seen in five patients. There was no major toxicity. Etoposide therapy is safe and effective in the treatment of LCH.

Cyclosporine therapy for refractory Langerhans cell histiocytosis.

Optimal treatment for Langerhans Cell Histiocytosis (LCH) has not yet been established. Preliminary reports suggest some effect of cyclosporine (CSA), both alone or in combination with steroids and/or vinblastine, in untreated cases. Twelve children (6 females and 6 males, age at diagnosis 3 months to 4 years) with biopsy proven, systemic LCH received oral CSA (12 mg/kg/day in two divided doses given daily) as a second-line therapy following chemotherapy including vinblastine and/or etoposide (10 cases) or steroid alone (one case); one child was not pretreated. A total of 16 CSA courses were administered to the 12 patients: 8 were completed, 4 were interrupted as unsuccessful, and 4 are still ongoing. CSA related toxicity consisted of hypertrichosis and transient hypertension and was never limiting. Treatment was associated with a clinical response in 8/12 patients: 3 had a complete response and are off therapy, and 5 had a partial response; disease reactivation following first favorable response required additional CSA courses in 3 patients. Four patients failed to respond to CSA: two died of progressive disease, while two had a favorable response to CSA + VP16. Favorable response to CSA was not related to CSA trough and peak levels and was usually observed during the first 2 weeks of CSA therapy. CSA is effective for treatment of LCH also in pretreated children with progressive disease including life-threatening organ dysfunction. Long-lasting complete remission may be achieved after 6 to 12 months of CSA therapy. When disease reactivation occurs after treatment withdrawal, a second course may be followed by favorable response. As minimal or no adverse effects are observed during or after prolonged CSA therapy, this may also be safely used in young patients.

Langerhans' cell histiocytosis of the head and neck in children.

This is a retrospective analysis of a 29-year institutional experience with Langerhans' cell histiocytosis (LCH) in children. Cases of LCH were categorized by disease extent into three groups: group 1, with a solitary focus of LCH; group 2, with multiple non-vital organ foci; and group 3, with vital organ disease. Sixteen patients averaging 7.3 years of age and with 11.0 years of follow-up presented in group 1. One child experienced a spontaneous remission; all other children responded to local treatment. The skull was the most common site of involvement. Eight children averaging 4.6 years in age and with 8.0 years of follow-up presented in group 2; 3 children had diabetes insipidus. Treatment included radical surgery, radiotherapy, and chemotherapy; however, disease persisted in all patients. Iatrogenic complications were a significant cause of morbidity and mortality. Only 1 patient, 1 year of age, presented with lung and liver involvement (group 3). He died after a fulminant course. Current recommendations for diagnosis, evaluation, and treatment of LCH are discussed.

Treatment of Langerhans-cell histiocytosis in children. Experience at the Childrenʼs Hospital of Nancy.

Forty children who had Langerhans-cell histiocytosis were followed for an average of six years (range, excluding patients who died of the disease, two to fifteen years). The patients were divided into two diagnostic groups: those who had localized disease (involving one bone or more only) and those who had multifocal disease (an osseous lesion and a soft-tissue mass, a skin rash, diabetes insipidus, or generalized disease). Methods of treatment included curettage, bone-grafting, chemotherapy, local or systemic corticosteroids, and radiotherapy. Nineteen of the thirty patients who had localized disease had a complete response to the therapy, four had a partial response, and seven had no response. Twenty-one of these thirty patients had not had a recurrence by the time of the latest follow-up examination; nine had a local recurrence within four years after the initial therapy but had no additional recurrences after treatment of the local recurrence. No recurrence occurred more than four years after the time that the initial diagnosis had been made. Five of the ten patients who had multifocal disease had a complete response to the therapy, two had a partial response, and three had no response. Six patients had a recurrence; four did not. Two patients died of the disease. As a result of this study, we recommend the avoidance of intensive measures of treatment, if possible, and we advise long-term follow-up of these patients.