Recurrent Langerhans Cell Histiocytosis Research Articles

Langerhans Cell Histiocytosis or Acute Cellular Rejection?

Langerhans cell histiocytosis (LCH) is a rare malignant disorder of epidermal antigen presenting cells. It is characterized by infiltration of various tissues with dendritic cells (Langerhans cells, LC) that express CD1a or CD207 (langerin), often leading to organ dysfunction. A patient with LCH required liver transplantation (LT) for LCH-associated biliary-tract disease. Cholangiopathy developed after LT. The question arose: In this patient, did LC in damaged liver-allograft biliary epithelium signify acute cellular rejection (ACR) or recurrent LCH? We evaluated immunohistochemical identification of LC (CD1a, CD207) in the proposita and in 14 ACR patient samples as distinguishing between ACR and recurrent LCH. Among 15 patient samples, 3 (20%) marked with neither antibody. Among the remaining 12 samples (80%), 4 (26.7%)-including that from the proposita-had cells marking for both antigens within bile-duct epithelium as well as in surrounding portal-tract connective tissue, 2 (13.3%) had cells marking for both antigens in one region or the other, but not in both, and 6 (40%) had cells marking for only one antigen in one region or the other. Immunostaining for CD1a and CD207/langerin in the setting of ACR without suspicion of LCH identifies LC in damaged bile ducts. This biomarker pairing proved not to be LCH-specific. Our findings indicate that the presence of these cells alone is insufficient to identify recurrent LCH in the allograft liver.

Multisystemic recurrent Langerhans cell histiocytosis misdiagnosed with chronic inflammation at the first diagnosis: A case report

BACKGROUND Langerhans cell histiocytosis (LCH) is characterized by diabetes insipidus and is an uncommon occurrence. Pathological biopsies still have a certain degree of diagnostic probability. We present a case in which LCH initially affected the pituitary gland. This resulted in a misdiagnosis of chronic inflammation upon pathological examination. CASE SUMMARY A 25-year-old female exhibited symptoms of diabetes insipidus. Magnetic resonance imaging revealed an enhanced foci in the pituitary gland. After surgical resection of the pituitary lesion, the pathological diagnosis was chronic inflammation. However, the patient later experienced bone destruction in the skull and lower limb bones. After the lower limb bone lesion was compared with the initial pituitary lesion, the final diagnosis was modified to LCH. The patient was treated with multiple chemotherapy courses. However, the patient’s condition gradually worsened, and she eventually passed away at home. CONCLUSION LCH should be considered when patients exhibit diabetes insipidus and absence of high signal intensity in the pituitary gland on sagittal T1-weighted image and abnormal enhancement in the pituitary region.

99mTc-MDP Bone Scan Findings of Recurrent Langerhans Cell Histiocytosis in an Adult Involving Femur After Joint Replacement.

Langerhans cell histiocytosis (LCH) is a rare proliferative histiocytic disorder. It mainly occurs in children and is rare in adults. We reported 99mTc-MDP bone scan findings of recurrent LCH in an adult, which involved the right femur after right-side total hip arthroplasty. This case emphasizes that the possibility of LCH should be considered in osteolytic lesions in adults, especially after joint replacement. In addition, LCH should be included in the differential diagnosis of prosthetic joint pain and abnormal 3-phase bone scan after prosthesis arthroplasty.

Pilot study to estimate the safety and effectiveness of hydroxyurea and methotrexate recurrent langerhans cell histiocytosis (LCH-HU-pilot).

This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH.

Recurrent and Refractory Langerhans Cell Histiocytosis in Children Treated with the Combination of Cladribine and Cytarabine

To observe the efficacy and prognosis of cladribine (2-CdA) combined with cytarabine (Ara-C) regimen in the treatment of relapsed refractory Langerhans cell histiocytosis (LCH) in children. Nine patients with relapsed refractory LCH treated with the 2-CdA combined with Ara-C regimen in the Department of Hematology and Oncology of Wuhan Children's Hospital from July 2014 to February 2020 were retrospectively analyzed, and the efficacy and disease status were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009) and the Disease Activity Score (DAS), the drug toxicity were evaluated according to the World Health Organization（WHO） grading criteria for chemotherapy. All patients were followed up for survival status and disease-related sequelae. Before the treatment combining 2-CdA and Ara-C, 7 of 9 patients were evaluated as active disease worse (ADW), and 2 as active disease stable (ADS) with a median disease activity score of 8 (4-15). Of 9 patients, 6 cases achieved non active disease (NAD) and 3 achieved active disease better (ADB) with a median disease activity score of 0 (0 to 5) after 2-6 courses of therapy. All 9 patients experienced WHO grade IV hematologic toxicity and 3 patients had hepatobiliary adverse effects (WHO grade I～II) after treatment. The median follow-up time was 31(1 to 50) months with all 9 patients survived, 3 of the 9 patients experienced sequelae to the disease with 2 combined liver cirrhosis as well as cholestatic hepatitis and 1 with oral desmopressin acetate tablets for diabetes insipidus. 2-CdA combined with Ara-C is an effective regimen for the treatment of recurrent refractory LCH in children, and the main adverse effect is hematologic toxicity, which is mostly tolerated in children. Early treatment with this regimen may be considered for patients with multisystem LCH with risky organ involvement who have failed first-line therapy and for patients with relapse.

A study of pathological characteristics and BRAF V600E status in Langerhans cell histiocytosis of Vietnamese children.

BackgroundLangerhans cell histiocytosis (LCH) is more common in children than adults and involves many organs. In children, the BRAF V600E mutation is associated with recurrent and high-risk LCH.MethodsWe collected paraffin blocks of 94 pediatric LCH patients to detect BRAF_V600E mutation by sequencing. The relationship between BRAF V600E status and clinicopathological parameters were also critically analyzed.ResultsBRAF V600E mutation exon 15 was detected in 45 cases (47.9%). Multiple systems LCH showed a significantly higher BRAF_V600E mutation rate than a single system (p=.001). No statistical significance was evident for other clinical characteristics such as age, sex, location, risk organs involvement, and CD1a expression.ConclusionsIn Vietnamese LCH children, the proportion of BRAF V600E mutational status was relatively high and related to multiple systems.

NFB-05. AN UNUSUAL PRESENTATION OF RECURRENT LANGERHANS CELL HISTIOCYTOSIS OF THE CRANIOFACIAL BONES IN A PATIENT WITH NEUROFIBROMATOSIS TYPE I

Neurofibromatosis type 1 (NF1), predisposes patients to benign and malignant tumors due to lack of suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Langerhans cell histiocytosis (LCH) manifests in numerous ways, from localized lesions to multisystem organ involvement secondary to a constitutively active MAPK signaling cascade often driven by BRAF mutations. While both LCH and NF1 are characterized by overactive MAPK signaling, there are few reports of the two diseases occurring simultaneously. We report a novel case of a patient with underlying NF1 and recurrent LCH without a BRAFV600E mutation. She initially presented at 2 years of age with an aggressive appearing mass of the left temporal bone found on surveillance imaging. Pathology was consistent with Langerhans histiocytosis and she was treated with the LCH-III protocol for patients with high-risk LCH due to the location of her lesion. Five years after completion of therapy, MRI demonstrated development of a calvarial mass consistent with relapsed LCH in a new risk site. Lesional curettage was performed and pathology confirmed recurrence of LCH with juvenile xanthogranulomatous features. BRAF testing of blood and the lesion were negative for any BRAF alterations. Further genomic evaluation of the tumor is in progress at this time to evaluate for other known mutations associated with LCH. The patient is currently receiving monthly cytarabine treatment which she has tolerated to date. Our patient represents a unique presentation of recurrent LCH in a patient with NF1 and further molecular evaluation may help identify other drivers of LCH activation.

Langerhans cell histiocytosis associated with lymphoma: an incidental finding that is not associated with BRAF or MAP2K1 mutations

Langerhans cell histiocytosis is characterized by a localized or systemic proliferation of Langerhans cells. BRAF mutations have been reported in 40–70% of cases and MAP2K1 mutations have been found in BRAF-negative cases, supporting that Langerhans cell histiocytosis is a true neoplasm, at least in mutated cases. In a small subset of patients, Langerhans cell histiocytosis is detected incidentally in a biopsy involved by lymphoma. These lesions are usually minute and rarely have been assessed for mutations. We assessed for BRAF and MAP2K1 mutations in seven cases of Langerhans cell histiocytosis detected incidentally in biopsies involved by lymphoma. We performed immunohistochemical analysis for phosphorylated (p)-ERK. There were four men and three women (median age, 54 years; range, 28–84). The biopsies included lymph nodes (n=6) and chest wall (n=1). The lymphomas included five classical Hodgkin lymphoma, one mantle cell lymphoma, and one angioimmunoblastic T-cell lymphoma. All cases were negative for BRAF V600E and MAP2K1 mutations. Nevertheless, three of seven cases showed ERK activation as shown by expression of p-ERK. We performed mutation analysis using a panel of 134 commonly mutated genes (including BRAF and MAP2K1) by next-generation sequencing on three cases, including two cases positive for p-ERK by immunohistochemistry. No mutations were detected in any of the three cases assessed. Six patients received therapy appropriate for their lymphoma. With a median follow-up of 21 months (range, 6–89), no patients developed disseminated or recurrent Langerhans cell histiocytosis. We conclude that lymphoma-associated Langerhans cell histiocytosis is a clinically benign process that is not associated with BRAF V600E or MAP2K1 mutations and, as suggested by others, the designation Langerhans cell hyperplasia may be more appropriate. Nevertheless, the expression of p-ERK in three cases suggests that the RAS–RAF–MAP2K–ERK pathway is activated, perhaps by non-mutational mechanisms induced by the presence of lymphoma or lymphoma–microenvironment interactions.

Efficacy and Toxicity Profile of Clofarabine in Patients with Recurrent/Refractory Langerhans Cell Histiocytosis and Other Histiocytic Disorders

Introduction: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder. Patients with recurrent or refractory LCH are at increased risk of mortality and long-term morbidity. The standard of care for high-risk LCH patients who are refractory to vinblastine/prednisone or who relapse is very high dose While mostly cytarabine/cladribine. While effective, this strategy also has very high treatment-related mortality. Clofarabine is a nucleoside analog with efficacy in other myeloid malignancies. Case reports have suggest that is has activity in LCH and other histiocytic disorders at moderate doses. The purpose of this study was to report the efficacy and toxicity profile of a restrospective cohort of patients with histiocytic disorders treated with clofarabine.Methods: Medical records were retrospectively reviewed for 26 pediatric patients with histiocytic disorders who were treated with clofarabine. Twenty-one of these patients had LCH and had failed at least one prior systemic therapy, while the remaining 5 patients had other histiocytic disorders (JXG, Rosai-Dorfman disease or mixed histiocytic disease). Patients were treated for a minimum of 6 months of with clofarabine (25 mg/m2/day x 5 days every 28 days), were reassessed for response at the end of therapy and monitored for relapse or progression post-treatment.Results: All patients in this series started treatment under the age of 18 years old (median=1.5 years; range: 0.3-16.3). Patients with LCH had received a median of 3 prior treatments (range:1-5). A majority of the patients (n = 17, 65%) were received all clofarabine infusions in an outpatient clinic. The most common adverse event was fever requiring hospital admission (n = 18; 69%), followed by Grade 3 neutropenia (n = 12; 46%), and intractable nausea/vomiting (n = 7; 27%). Additional adverse events included Grade 3 anemia, Grade 2 dehydration, Grade 3 cytopenias, and Grade 3 infection. Overall survival was 100%. LCH patients who completd 6-months of clofarabine had an 85% overall response (33% complete response, 52% partial response); 10% progressed on therapy and 5% had stable disease. Relapse occurred in 5 (28%) patients with LCH after completion of treatment (median time to relapse=22 months; range: 1-42). The odds of relapse was approximately 4-times greater in LCH patients with CNS involvement (n=16) compared to those without (n=4), and also in those with high risk disease (n=5) relative to standard risk (n=10). One of the patients who experienced disease recurrence received an additional 12 cycles of clofarabine and is currently doing well with no active disease.Conclusions: Clofarabine may be an effective and relatively safe salvage therapy for LCH and other histiocytic disorders. Future prospective trials for patients with refractory histiocytic disorders will directly compare efficacy and toxicity relative to other current salvage strategies with cytotoxic nucleoside analogs or targeted inhibitors. DisclosuresNo relevant conflicts of interest to declare.

Treatment and Rehabilitation of Repetitively Recurrent Langerhans Cell Histiocytosis: A Case Report

Langerhans cell histiocytosis (LCH) is characterized by proliferation of histiocyte-like cells (Langerhans cell histiocytes) with characteristic Birbeck granules, accompanied by other inflammatory cells. Treatments of LCH include surgery, chemotherapy, and radiotherapy. One of the representative forms of chemotherapy is intralesional injection of steroids. Surgical treatment in the form of simple excision, curettage, or even ostectomy can be performed depending on the extent of involvement. Radiotherapy is suggested in case of local recurrence, or a widespread lesion. This article shows the case of repetitively recurrent LCH of a 56-year-old man who had been through surgical excision and had to have marginal mandibulectomy and radiotherapy when the disease recurred. After the first recurrence occurred, lesions involved the extensive part of the mandible causing pathologic fracture, so partial mandibular bone resection was performed from the right molar area to the left molar area followed by the excision of the surrounding infected soft tissues. The resected mandibular bone was reconstructed with a segment of fibula osteomyocutaneous free flap and overdenture prosthesis supported by osseointegrated implants.

Cladribine for 13 cases refractory high-risk children Langerhans cell histiocytosis

To observe the efficacy and adverse reaction of the improvement program of cladribine combined with cytarabine (2-CdA+Ara-C) in treatment of children with refractory high-risk Langerhans cell histiocytosis (LCH). 13 patients with refractory high-risk LCH or recurrent LCH were treated by combined 2-CdA+Ara-C chemotherapy. The treatment efficacy and the disease state in the process were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009). The drug toxicity was evaluated according to the Common Terminology Criteria Adverse Events Version 4.0 (CTCAE v4.0, 2009). Of 13 patients, 10 cases achieved non active disease (NAD); 2 patients with liver cirrhosis before the improvement program with CIP-LCH-2012 gave up the treatment after 1 course of therapy; 1 patient died of infectious shock after chemotherapy with severe pulmonary infection and intestinal infection. All 13 patients had grade 3 of blood and lymphatic system toxicity; 10 patients had grade 1 of hepatobiliary and gastrointestinal side effects; 3 patients with liver cirrhosis before the improvement program had grade 2 or grade 3 of hepatobiliary system and gastrointestinal system side effects, including 1 patient of death. The improvement program of CIP-LCH-2012 had significant efficacy for children with refractory high-risk and relapsed LCH. The cladribine-associated toxicity was of significant myelosuppression, which may be tolerated in the most children patients. The program could be considered as a recommended salvage therapy for multi-system LCH (MS-LCH) after failure of first-line therapy, and as a first-line therapy for MS-LCH with risk organ injury. The program should be used with caution or dose-adjustment consideration for pre-treatment of severe organ damage exist, especially cirrhosis.

Adult multisystem langerhans cell histiocytosis presenting with central diabetes insipidus successfully treated with chemotherapy.

We report the rare case of an adult who was diagnosed with recurrent multisystem Langerhans cell histiocytosis (LCH) involving the pituitary stalk and lung who present with central diabetes insipidus and was successfully treated with systemic steroids and chemotherapy. A 49-year-old man visited our hospital due to symptoms of polydipsia and polyuria that started 1 month prior. Two years prior to presentation, he underwent excision of right 6th and 7th rib lesions for the osteolytic lesion and chest pain, which were later confirmed to be LCH on pathology. After admission, the water deprivation test was done and the result indicated that he had central diabetes insipidus. Sella magnetic resonance imaging showed a mass on the pituitary stalk with loss of normal bright spot at the posterior lobe of the pituitary. Multiple patchy infiltrations were detected in both lung fields by computed tomography (CT). He was diagnosed with recurrent LCH and was subsequently treated with inhaled desmopressin, systemic steroids, vinblastine, and mercaptopurine. The pituitary mass disappeared after two months and both lungs were clear on chest CT after 11 months. Although clinical remission in multisystem LCH in adults is reportedly rare, our case of adult-onset multisystem LCH was treated successfully with systemic chemotherapy using prednisolone, vinblastine, and 6-mercaptopurine, which was well tolerated.

Treatment of recurrent Langerhans cell histiocytosis of the vulva with lenalidomide.

e16555 Background: Langerhans cell histiocytosis (LCH) of the female genital tract is an extremely rare disease. We report a 14 year follow up of a patient with LCH successfully treated with lenalidomide in the relapsed setting. Methods: N/A. Results: A 43 year old Ethiopian woman initially presented to another institution with a nodular lesion on her left vulva with biopsy consistent with LCH. Metastatic workup at the time did not reveal evidence of distant disease. The patient was initially treated with radiotherapy to the vulva and 2 years later she was diagnosed with recurrent disease in the vulva and underwent a wide local excision. Six months afterwards she developed a lesion on her right labium majus consistent with disease recurrence. She was treated with radiotherapy again and underwent a wide radical vulvar excision. She recurred only 3 months later and was started on salvage therapy with thalidomide, 3 years after the initial diagnosis. Within 2 months of starting thalidomide therapy, the patient experienced resolution of vulvar lesions and symptoms. She remained symptom free for 8 years while on thalidomide but then presented to our institution with a new central vulvar lesion after being off therapy for 4 months. Vulvar biopsy confirmed the presence of LCH. She was subsequently restarted on thalidomide and achieved symptom control for an additional 18 months before developing worsening pain and neuropathy associated with therapy. Imaging revealed no evidence of metastatic disease. We then started lenalidomide therapy at dose of 10 mg daily for 21 days in a 28 day cycle and subsequently increased the dose to 25 mg daily continuously. She achieved marked improvement in vulvar symptoms within a month of initiation of lenalidomide. She has tolerated therapy well with no neuropathy or cytopenias. Conclusions: Primary vulvar LCH is a rare disease with no standard therapies. Thalidomide has been described in the literature as an effective treatment option. We describe the use of lenalidomide as an alternative and well tolerated therapy in the relapsed setting. Further investigation is required to determine whether lenalidomide is a viable first line therapy for this rare disease.

Spontaneous remission of 2-chlorodeoxyadenosine (2-CdA)-related secondary myelodysplastic syndrome in a patient with refractory Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is sometimes resistant to conventional chemotherapies, and treatment with 2-chlorodeoxyadenosine (2-CdA) is gaining importance as a salvage treatment for refractory or recurrent LCH. Secondary malignancies such as acute myelogenous leukemia and myelodysplastic syndrome (MDS) due to 2-CdA have recently been reported. However, there have been no reports to date of cases of 2-CdA-related secondary MDS in which spontaneous remission was achieved. Here, we report the case of a 1-year-old boy with an occipital tumor who was diagnosed with LCH by biopsy and underwent chemotherapy. However, the disease relapsed and became refractory to chemotherapy. He received 2-CdA treatment, which was effective. However 6months after the start of treatment, he developed MDS with chromosomal abnormality of 7q-. After 1-year observation without any intervention, his hematological findings had returned to normal, and the chromosomal abnormality had also disappeared. To our knowledge, this is the first report of 2-CdA-related MDS with spontaneous hematological remission.

Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan

Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs). However the efficacy and safety of BPs therapy for childhood LCH is unknown. Data on children with LCH who had received BPs therapy were collected retrospectively from hospitals participating in the Japanese Pediatric Leukemia/Lymphoma Study Group. Twenty-one children with histologically proven LCH were identified. Of these, the case histories of 16 children who had been treated with pamidronate (PAM) for disease reactivation were analyzed in detail. The median post-PAM therapy follow-up period was 2.8 years (range: 0.9-9.3 years). The median age at commencement of PAM therapy was 9.4 years (range: 2.3-15.0 years). All children had one or more bone lesions but none had risk organ (RO) involvement. In the majority of the children, six courses of PAM were administered at a dose of 1.0 mg/kg/course at 4-week intervals. In 12 of the 16 children, all active lesions including lesions of the skin (n = 3) and soft tissues (n = 3) resolved. Of these children, eight children had no active disease for a median of 3.3 years post-PAM therapy (range: 1.8-9.3 years). Progression-free survival (PFS) was 56.3 ± 12.4% at 3 years. PFS was significantly higher in children with a first reactivation compared with children experiencing a second or subsequent reactivation. PAM may be an effective treatment for reactivated LCH with bone lesions. A prospective trial of the efficacy of PAM in recurrent pediatric LCH is warranted.

2′‐chlorodeoxyadenosine (2‐CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH‐S‐98 protocol of the histiocyte society

A prospective phase II Histiocyte Society study, LCH-S-98, evaluated the efficacy of 2-chlorodeoxyadenosine (2-CdA) monotherapy as salvage therapy in Langerhans cell histiocytosis (LCH). Patients with poor and intermediate risk LCH not responsive to initial therapy and patients with low-risk chronic recurrent LCH were evaluated for response and survival after treatment with 2-6 courses of 2-CdA. Forty-six patients (55%) had involvement of risk organs; lung, liver, spleen, or hematopoetic system (RO+), 37 (45%) were RO-. Twenty-two percent of RO+ patients had a good response while 44% progressed, 62% RO- patients responded, and 11% progressed. Two-year predicted survival is 48% for RO+, 97% for RO- patients, 100% for RO+ patients reactivating in non-risk organs, 67% for RO- patients reactivating in risk organs. Two-year pSU for the entire group is 68%. Seventy-three percent of patients with a poor response to 2-CdA died. Sixty-five percent patients >2 years old and 30% <2 years old survived. There was a median of 26 months from diagnosis to 2-CdA for responders compared to a median of 5 months for non-responders. Twenty-one percent of patients treated <12 months and 57% treated >12 months from diagnosis responded. 2-CdA is active in LCH. It produces a higher response rate in patients with low-risk multisystem or multifocal bone disease than those with risk organ involvement. "Risk" patients who fail to respond to 2-CdA have a high mortality. Patient age at 2-CdA therapy and length of time from diagnosis to 2-CdA significantly affect response and survival.

Treatment of Refractory Langerhans Cell Histiocytosis (LCH) With a Combination of 2-Chlorodeoxyadenosine and Cytosine Arabinoside

The combination of 2-chlorodeoxyadenosine (2-CDA) and cytosine arabinoside (Ara-C) has been shown to be effective in children with refractory Langerhans cell histiocytosis (LCH). We have treated 5 patients with recurrent LCH with 2-CDA/Ara-C chemotherapy and closely followed immune and hematopoietic function. These patients display a decline in the absolute CD4, CD8, and natural killer cell number, decrease in the CD4/CD8 ratio. Septic events, including pneumocystis infection were present after most of the treatment courses (15/21). These data suggest that 2-CDA /Ara-C, should be considered in resistant and relapsed pediatric patients with LCH with high-risk multiorgan involvement. Consequent profound prolonged combined immune deficiency and myelosupression should be anticipated.

Bortezomib Alone or in Combinination with Doxil Is Active in Adult Refractory Multi-System Langerhans Cell Histiocytosis (LCH).

Langerhans cell histiocytosis (LCH) is a clonal disorder of activated Langerhans cells. LCH is characterized by increased proliferation index, Ki-67, as a result of dysregulation of anti-apoptotic pathways (Bcl-2) and cell cycle regulators (p53-p21 and p16-Rb pathways). Although current available therapies are very effective at inducing remission, treatment of LCH remains problematic due to multiple recurrences and eventual fatalities in a significant proportion of young patients. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of Bortezomib, a proteosome inhibitor with a reported antiproliferative effect on plasma cells and lymphocytes, in a heavily pre-treated patient with recurrent multi-system LCH involving lungs, bones, skin and pituitary gland and who was previously treated with and progressed on Vinblastine, Steroids, Peg-Interferon, Methotrexate/ 6MP. The patient received Bortezomib initially at 1.3 mg/m2 days 1, 4, 8, 11 Q 21 days (cycles 1&2) which was reduced to 1.0 mg/m2 days 1, 4, 8, 11 Q21 days (cycles 3&4) and then to 1.0 mg/m2 weekly for cycle#5 due to grade 3 exacerbation of his baseline Vinblastine induced peripheral neuropathy. Patient's skin disease achieved very early response after cycle 1 with PR as maximum response after cycle 2. Such response was maintained until the patient was switched to weekly dose. Stable disease was observed at other sites especially the pituitary mass. Upon flaring of his skin disease, patient was started back on Bortezomib 1.0 mg/m2 days 1, 4, 8, 11 along with Doxil 30mg/m2 on day 4 Q21 days, to explore their reported synergy. After cycle 1, patient achieved a very good PR as far as his skin disease and CR after the 3rd cycle. His pituitary LCH mass was also noted to decrease by 20% with visual improvement. Unfortunately, due to grade 3 fatigue and anorexia, therapy was stopped. However, responses are still maintained for 3 months so far. Hematologic toxicities were limited to Grade 1 neutropenia, anemia, and thrombocytopenia. Bortezomib has activity on its own and synergies with Doxil in recurrent and heavily pre-treated multisystem LCH. Its incorporation into front-line treatment of patients with multi-system LCH needs further study.

Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine

The objective of this study was to evaluate the efficacy of 2-chlorodeoxyadenosine (2-CdA), a purine nucleoside analog, in treating recurrent Langerhans cell histiocytosis (LCH) in children. This study retrospectively analysed the clinical records of 13 patients who were seen in the department for recurrent LCH. These patients were treated consecutively with 2-CdA chemotherapy between July 1997 and May 2005. Median age at diagnosis was 4 years 7 months and median pre-treatment duration of disease was 16.4 months. Four children received 0.1 mg kg−1 per day for 7 days and nine patients 5 mg m−2 per day for 5 days, repeated every 21 days. The maximum number of courses of 2-CdA per patient was limited to six. Seventy-six courses of 2-CdA were administered without difficulty. All 13 patients (100%) had a clinical response documented by radiographic investigation. Nine patients did not require additional therapy and remain in complete remission (CR). Four remaining children are currently disease-free after receiving other therapy as irradiation (two cases) or maintenance chemotherapy (vinblastine, prednisone and 6-mercaptopurine) (one case) or chemothery (vinblastine) + irradiation (one child) (). Hematologic toxicity was minimal and no infectious complications were documented. Median follow-up after initiation of 2-CdA treatment was 4 years 3 months (range 7 months – 8 years 2 months). This experience confirms the reported efficacy of 2-CdA in the treatment of LCH. However, further studies are needed to determine the role of this agent in high-risk patient who did not achieve complete remission after 2-CdA administration.

OCCURRENCE OF ACUTE NONLYMPHOBLASTIC LEUKEMIA IN TWO GIRLS AFTER TREATMENT OF RECURRENT, DISSEMINATED LANGERHANS CELL HISTIOCYTOSIS

The occurrence of Langerhans cell histiocytosis (LCH) and acute leukemia in one individual has rarely been observed. Despite few exceptions, two distinct patterns of association appear evident: acute lymphoblastic leukemia preceding LCH and LCH preceding acute nonlymphoblastic leukemia (ANLL). The latency of ANLL after the diagnosis of LCH is suggestive of a therapy-related process. This report describes two new cases in whom ANLL was diagnosed 7 years 8 months and 5 years 8 months after the start of initial treatment of disseminated recurrent LCH. Morphology showed blasts from FAB-type M4/M5 in the first patient, who died due to progression of leukemia. The second patient showed myelodysplastic syndrome (refractory anemia with excess of blasts in transformation; RAEB-t) and is now in remission from leukemia 3 years 11 months after allogeneic bone marrow transplantation. The review of a total of 26 patients with ANLL after LCH suggests that the disease has a poor prognosis and allogeneic BMT seems to be the treatment of choice.