Refractory Langerhans Cell Histiocytosis Research Articles

Nationwide Study of Factors Impacting Survival Outcome and Consequences in Children with Reactivation/Refractory Langerhans Cell Histiocytosis.

Disease reactivation/refractory remains a major challenge in managing Langerhans cell histiocytosis (LCH). Outcomes and late sequelae should be explored. A multi-institutional retrospective study was conducted to describe clinical characteristics, predictive factors, outcomes and late sequelae of pediatric reactivation/refractory LCH in Thailand. In all, 47 patients were studied, 25 (53.2%) patients had disease reactivation and 22 (46.8%) patients had refractory LCH. The median reactivation and refractory time were 1.59 and 0.33 years from diagnosis, respectively (p <0.001). The most common site of reactivation/refractory was the bone (n = 26, 55%), and 20 (42.6%) patients developed late sequelae. The 5-year overall survival (OS) was 76.1%. Patients with reactivation and refractory LCH performed similarly in 5-year OS (88% vs. 63%, p = 0.055). Prognostic factors associated with mortality were liver, spleen, hematopoietic system and lung reactivation (p <0.05). Lung reactivation was the only independent risk factor associated with the survival outcome (p = 0.002). The outcomes of pediatric patients between reactivation and refractory LCH in Thailand were similarly desirable and mortality was minimal although late sequelae may evolve. Pulmonary reactivation/refractory was an independent risk factor associated with survival.

From mutation to management: Advancing Langerhans cell histiocytosis treatment through combination therapies.

The treatment landscape for relapsed Langerhans cell histiocytosis (LCH) is fraught with uncertainty due to a scarcity of data. Karri etal.'s study provides promising evidence that combining MAPK pathway inhibitors with chemotherapy could improve outcomes, even for patients with multiple relapses. Although larger studies are needed, this approach suggests a shift towards more aggressive, potentially curative strategies in the management of LCH. Commentary on: Karri etal. Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis. Br J Haematol 2024;204:1882-1887.

Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Adult‐onset BRAF V600E‐related multisystem Langerhans cell histiocytosis treated with vemurafenib

AbstractWe report a case of a 65‐year‐old female with 1‐year history of dental pain and oral ulcers. A diagnosis of Langerhans cell histiocytosis (LCH) was made by oral biopsy and CD207 (Langerin) stain, and BRAF V600E mutation was identified. PET/CT revealed an enhancing lesion in the hard palate with extension into the maxillary sinus. Chemotherapy with cytarabine failed, and LCH progressed to affect additional organ systems. Treatment with vemurafenib was started, resulting in a dramatic improvement of painful mucocutaneous ulcers since the first month of treatment. Vemurafenib is effective in children with refractory BRAF V600E‐mutated LCH, and recent data support the use of vemurafenib in adults with refractory multisystem LCH harbouring the same mutation.

Efficacy and safety of intermediate-dose cytarabine in the treatment of children with refractory high risk Langerhans cell histiocytosis

Objective: To analyze the efficacy, safety, and long-term prognosis of intermediate-dose cytarabine (Ara-c) regimen in the treatment of children with refractory risk organ involvement Langerhans cell histiocytosis (LCH). Methods: Clinical data of 17 children with multisystem and risk organ involvement LCH who failed the first-line therapy and were treated with intermediate-dose Ara-c (250 mg/m2, twice daily) regimen in the Hematology Center, Beijing Children's Hospital from January 2013 to December 2016 were analyzed retrospectively. In addition to the basic treatment of vindesine and dexamethasone, the patients received two regimens: regimen A: the intermediate-dose Ara-c combined with cladribine and regimen B: the intermediate-dose Ara-c alone. The efficacy, safety and prognosis of the two regimens were analyzed. Results: Among all 17 patients, there were 11 males and 6 females, with the diagnosis age of 2.1 (1.6, 2.7) years. Ten children received regimen A, all of them achieved active disease-better (AD-B) after 8 courses of induction therapy. The disease activity scores (DAS) decreased from 5.5 (3.0, 9.0) to 1.0 (0, 2.3). Seven children received regimen B, and 6 of them achieved AD-B after 8 courses of induction therapy. The DAS decreased from 4.0 (2.0, 4.0) to 1.0 (0, 2.0). The follow-up time was 6.2 (4.9,7.2) and 5.2 (3.7,5.8) years in group A and B. The 5-year overall survival rate was 100.0% in both groups, and the 5-year event free survival rate was (88.9±10.5)% and (85.7±13.2)% in group A and B. Grade 3 or 4 myelosuppression was observed in 8 patients in group A and 2 patients in group B. Conclusions: The intermediate-dose Ara-c regimen (with or without cladribine) is effective and safe for patients with refractory high-risk LCH, with a good long-term prognosis.

Responses to Combination Chemotherapy with MAPK Pathway Inhibition in Relapsed and Refractory LCH

MAPK pathway inhibition (MAPKi) is associated with high response rates in patients with Langerhans cell histiocytosis (LCH), but monotherapy may not be curative and efficacy in LCH-associated neurodegeneration (LCH-ND) is not known. Based on upregulation of Bcl-xL by MAPK activation, we hypothesize that MAPKi may render LCH cells more sensitive to chemotherapy-induced cytotoxicity. We assessed the safety and efficacy of combination therapy in 10 patients with refractory systemic disease and LCH-ND. Records of patients treated with combination therapy at Texas Children's Hospital from October 2018 to July 2023 were reviewed for clinical responses as well as peripheral blood/tissue BRAFV600E mutation status, ataxia rating scores, and toxicity. The median age at the start of combination therapy was 6.82 years (range, 0.48-20.45 years) with a median of 4 treatments prior to this therapy regimen (range, 1-14). Almost all Clofarabine was administered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK inhibitors included BRAFV600E inhibitors (50%) and MEK inhibitors (50%). Overall response was 8/10 (80%), with 5/5 (100%) objective response rate (ORR) for systemic disease. Further, 5/6 (83%) demonstrated reduced or extinguished peripheral BRAFV600E+ fraction by the end of combination therapy. Ataxia rating scores were improved in 2/3 (67%) individuals with clinical neurodegeneration. Common toxicities during treatment included fever, skin rash, arthralgia, and cytopenia. Combining therapy was well-tolerated and associated with clinical and molecular improvement in most patients with highly refractory systemic LCH and LCH-ND. Further prospective multi-center trials are required to optimize this approach, determine potential for combination therapy to achieve cure, and compare risks and benefits to chemotherapy or MAPK inhibitor monotherapy.

Cladribine and cytarabine in children refractory high risk multisystem Langerhans cell histiocytosis

There is no uniform regimen for refractory Langerhans cell histiocytosis (LCH). We retrospectively described patients with refractory multisystem and risk organ involvement LCH treated with the low-dose (Ara-c, 100 mg/m2/d × 5day; 2-CDA, 5 mg/m2/d × 5day) chemotherapy (LDC) and the intermediate-dose (Ara-c, 500 mg/m2/d × 5day; 2-CDA, 9 mg/m2/d × 5day) chemotherapy (IDC). 26 patients and 10 patients receiving the LDC and IDC regimen from January 2013 to December 2016 were included in the study. The overall response rate exhibited no significant difference between the LDC and IDC groups after four courses (76.9% vs 90%, P = 0.375) and eight courses (80.8% vs 100%, P = 0.135) of treatment. No statistical differences in the overall survival rate were observed between the two groups, but 5-year event-free survival rate of patients in the IDC group was higher than that in the LDC group at the median follow-up of 6.16 and 5.07 years (88.9% vs 52.9%, P = 0.033). The patients in the IDC group had more severe myelosuppression than those in the LDC group (grade 3/4 myelosuppression, 80% vs 19.2%, P = 0.001). The intermediate-dose regimen of 2CDA and Ara-c had a higher event-free survival rate and a similar overall survival rate compared with the low-dose regimen.

Targeted therapy with trametinib in infantile refractory langerhans cell histiocytosis: A case report

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by a clonal proliferation of Langerhans-like cells. LCH affects all ages and in children with a frequency ranging from 4.1 to 8.9/million/year with an increased incidence in children &lt;1 year of age. Infantile LCH refractory to frontline therapy is difficult to treat but targeted therapies in patients with BRAF mutations are promising. We treated an infant of refractory multisystem LCH with risk organ involvement with MAP kinase inhibitor (trametinib) with excellent outcomes.

MEK-inhibitors in treatment of Langerhans cell histiocytosis

Background. There are increasing data of targeted therapy efficacy of different types of Langerhans cell histiocytosis (LCH) with inhibitors of BRAF-specific serin-threonine kinase (BRAF-inhibitors) in cases with BRAF V600E mutation published last years. At the same time there are no published data of use of inhibitors of MAPK/ERK pathway (MEK-inhibitors) in pediatric patients with BRAF-negative forms of LCH.Purpose of the study is to evaluate efficacy and safety of MEK-inhibitor (cobimetinib) in eight pediatric BRAF V600E-negative refractory LCH patients.Materials and methods. The study included 8 children with various forms of LCH. All patients received therapy according to the LCH-IV protocol and were diagnosed with progression of LCH during or after termination of the treatment. The response to the therapy was assessed in accordance with the international scale Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). The assessment of the toxicity was performed in accordance with the international scale of Common Terminology Criteria for Adverse Events (CTCAE v.5.0).Results. Complete response was not achieved in any patient. Partial response was established in 5 cases. One patient was diagnosed with disease progression in three months after termination of the therapy. The incidence of adverse events was high.Conclusion. Cobimetinib therapy is effective in BRAF V600E-negative refractory pediatric LCH patients. The response to the treatment can be delayed. All cases of the toxicity were dose depended and successfully resolved after dose correction. Further research is needed to define duration of treatment and optimal dosage.

Biomodulatory therapy induces durable remissions in multi-system Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is rare hematological neoplasia originating from the aberrant proliferation of CD207-positive dendritic cells. Refractory multi-system LCH is difficult to treat necessitating the continuous development of different salvage therapies. At our medical center, eleven patients (age 11 months to 77 years) with multi-system LCH were treated on a compassionate use basis with metronomic biomodulation therapy (MBT) involving the daily oral application of low-dose trofosfamide, etoricoxib, pioglitazone and low-dose dexamethasone. Overall, four patients including two heavily pretreated pediatric patients achieved ongoing complete remission. Moreover, partial disease remission was observed in three patients, and four patients attained stable disease. MBT demonstrated high activity against multi-system LCH even in patients, refractory to multiple systemic chemotherapies. Further confirmation of efficacy should be systematically evaluated in prospective trials.

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.

18F-fluorodeoxyglucose-positron emission tomography/computed tomography delineates involved sites in the cervical spine in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH), a granulomatous tumorous lesion consisting of CD1a-positive clonal immature dendritic cells in association with various inflammatory cells, develops in tissues including bone, skin, lungs, and lymph nodes. When bone LCH exhibits osteolytic lesions, the spine is often involved, and each part of the vertebral body, vertebral arch, and vertebral spinous process can be affected. Such vertebral LCH can occur at the onset of disease and in relapse. To confirm pathological sites, a computed tomography (CT) scan is generally used to characterize lytic lesions of vertebrae, while MRI is suitable for delineating marrow and soft tissue. Additionally, to identify specific locations, 18F-fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) is useful. We describe three LCH cases showing characteristic cervical spinal involvement. Case 1: A 39-year-old woman complained of right temporal pain and was found to have osteolytic lesions of right temporal/sphenoid/petrous bones. She also had central diabetes insipidus (CDI). After the diagnosis of LCH from biopsied tissue, she was treated with chemotherapy and attained remission. Four years later, she complained of neck/shoulder pain associated with herpes zoster in the right arm. PET/CT revealed a cervical spine (C3)-vertical body lesion (Figure 1A). With a revised chemotherapy regimen, she attained a second remission. Case 2: A 70-year-old man, a heavy smoker for more than 40 years, complained of shortness of breath, and a chest X-ray revealed characteristic honeycomb lungs. PET/CT showed hot lesions in the lungs, cervical spine (C3) right vertebral arch (Figure1B), and ribs. Lung lesion biopsy confirmed the diagnosis of LCH. He had no CDI and was treated with irradiation to the cervical spine and with chemotherapy. Case 3: A 40-year-old man who had severe atopic dermatitis since the age of 20 complained of nuchal pain after a traffic accident. He was also noted to have lymphadenopathy in the bilateral axillary and inguinal areas. PET/CT revealed hot signals at the spinous process of the cervical spine (C6) (Figure 1C) and lymph node lesions. Biopsy of the C6 lesion confirmed LCH. He attained a remission treated with chemotherapy and zoledronic acid. Three years later, relapse at the lymph nodes was noted, but not in the C6 lesion. He was treated with chemotherapy for refractory LCH and attained a second remission. An analysis of 76 cases of vertebral LCH by Huang et al. [1] consisted of 40 children and 36 adults, with a male to female ratio of 55:21. Lesions were predominantly in the cervical spine, followed by the thoracic and lumbosacral spines. In an analysis of 30 LCH patients with cervical spine involvement by Jiang et al. [2], 14 had atlantoaxial lesions (C1 and C2), and 16 had sub-axial (C3–C7) lesions. Chemotherapy is recommended for the management of cervical spine lesions in cases of multifocal LCH. In our three cases, two patients had spinal involvement at onset while the other developed it at relapse. All received chemotherapy because of multifocal LCH lesions. In summary, as an imaging study of cervical spine involvement in LCH, PET/CT seems to be useful for pinpointing the involved sites of vertebrae. None The authors declare no conflict of interest.

Miraculous recovery in an infant with refractory langerhans cell histiocytosis using trametinib based targeted therapy

Miraculous recovery in an infant with refractory langerhans cell histiocytosis using trametinib based targeted therapy

CONDITIONING REGIMEN FOR LANGERHANS HISTIOCYTOSIS

Langerhans cell histiocytosis (LCH) is a rare disease, with an estimated incidence of 0.5 per 100,000 children in the United States of America1. HCL occurs due to differentiation of myeloid precursors into CD1a+ / CD207+ cells and is characterized by constitutional activation of the MAPK2 signaling pathway, leading to a spectrum of organ involvement and dysfunction. Treatment of HCL is risk-adjusted: single lesions may respond to local treatment whereas multisystem disease requires systemic therapy. Although survival for patients without organ dysfunction is excellent3, mortality in those with compromised organs at risk (hematopoietic system, liver, and/or spleen) reaches 20%2,4. Despite the progress made in the treatment of HCL, disease reactivation rates remain above 30% and the best second-line treatment has not yet been established. Treatment failure is associated with increased morbidity and mortality, including an association with neurodegeneration2.&#x0D; As it is a rare disease and generally has a good prognosis, few scientific studies are evaluating the role of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of this disease.&#x0D; In 2015 Veys et al5 published retrospective results of 87 high-risk patients transplanted between 1990 and 2013. Myeloablative conditioning regimens (MAC) based on total body irradiation or busulfan6 were the most used until the 2000s, and reduced-intensity conditioning regimens (RIC) – predominantly a combination of Melphalan and Fludarabine – were most used between 2000 and 2013. Transplant-associated mortality rates in 3 years were similar between RIC and MAC conditioning regimens (21% versus 15%, respectively). Recurrence was higher in the RIC group compared to the MAC group (28% versus 8%, respectively), however, the 3-year overall survival (OS) was similar (77% versus 71%, respectively), since the patients who relapsed after RIC transplantation could be rescued with chemotherapy.&#x0D; More recently, Kudo et al7 published a retrospective study with 30 patients with refractory LCH who underwent HSCT between 1996 and 2014. Eleven patients received myeloablative conditioning regimen based on total body radiotherapy (RCT) with a dose equal to or greater than 8 Gy or busulfan, and 19 of reduced intensity based on Fludarabine and Melphalan, associated or not with low dose of RCT. There was no significant difference between the conditioning regimen modalities, with OS of 56.8% for the RIC group and 63.6% for the MAC group. Disease status was the main prognostic factor, with a 5-year OS of 100% for patients who arrived at HSCT with disease in remission or with partial remission, versus 54.5% for those who had active disease at the time of the procedure.&#x0D; Regarding the type of donor used and the source of stem cells, there is great variation, with greater frequency for unrelated and extensive use of bone marrow and umbilical cord, and apparently, there is no impact on survival rates.5, 6&#x0D; There are few case reports and extremely restricted performance of autologous HSCT in HCL.

Salvage therapy with cladribine and cytarabine in refractory multisystem langerhans cell histiocytosis – A single centre experience

Salvage therapy with cladribine and cytarabine in refractory multisystem langerhans cell histiocytosis – A single centre experience

Results of TETimaX Trial of Langerhans Cell Histiocytosis Treatment and Perspectives on the Role of Imatinib Mesylate in the Era of MAPK Signaling

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

Treatment advances in pediatric relapsed and refractory Langerhans cell histiocytosis

朗格罕细胞组织细胞增生症（LCH）是儿童受累为主的组织细胞病，部分患儿对一线治疗反应不佳。目前阿糖胞苷、吲哚美辛、克拉屈滨、氯法拉滨、靶向药物及造血干细胞移植等可用于复发难治性LCH的治疗。现就复发难治性LCH的治疗进展进行综述。.

Recent advances in the understanding of the molecular pathogenesis and targeted therapy options in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder caused by the clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in the lesion. Advances in genomic sequencing techniques have improved our understanding of the pathophysiology of LCH. Activation of the mitogen-activated protein kinase (MAPK) pathway is a key molecular mechanism involved in the development of LCH. Recurrent BRAF mutations and MAP2K1 mutations are the major molecular alterations involved in the activation of the MAPK pathway. Recent studies have supported the “misguided myeloid differentiation model” of LCH, where the extent of disease is defined by the differentiation stage of the cell in which the activating somatic MAPK mutation occurs, suggesting LCH. Several studies have advocated the efficacy of targeted therapy using BRAF inhibitors with a high response rate, especially in patients with high-risk or refractory LCH. However, the optimal treatment scheme for children remains unclear. This review outlines recent advances in LCH, focusing on understanding the molecular pathophysiology, emerging targeted therapy options, and their clinical implications.

Three year experience of targeted therapy with BRAF inhibitor in refractory multisystem Langerhans Cell Histiocytosis with excellent response from a tertiary care unit

Three year experience of targeted therapy with BRAF inhibitor in refractory multisystem Langerhans Cell Histiocytosis with excellent response from a tertiary care unit