What is the mechanism of action of this treatment?

The most common treatments for Langerhans Cell Histiocytosis (LCH) involve chemotherapy agents that target rapidly dividing cells. These cytotoxic agents, such as vincristine, methotrexate, and cyclophosphamide, work by interfering with cell division and DNA replication, leading to cell death. This is particularly important for LCH patients as the disease is characterized by the proliferation of abnormal Langerhans cells. By targeting these rapidly dividing cells, chemotherapy can help control the spread of the disease and alleviate symptoms, improving patient outcomes.

What side effects are associated with this type of intervention?

Common treatments for Langerhans Cell Histiocytosis (LCH) include chemotherapy agents such as vinblastine, prednisone, and methotrexate. Vinblastine can cause myelosuppression, leading to decreased blood cell counts and increased risk of infections, anemia, and bleeding. Prednisone may result in weight gain, hypertension, hyperglycemia, and heightened infection risk. Methotrexate can cause mucositis, liver toxicity, and myelosuppression. These side effects require careful monitoring and supportive care.

What prior FDA approvals exist?

Langerhans Cell Histiocytosis (LCH) is often treated with chemotherapy agents that target rapidly dividing cells. Commonly used cytotoxic agents include vinblastine and prednisone, which have been standard treatments for LCH. Other agents like methotrexate and cytarabine are also used in various treatment protocols. While specific FDA approvals for LCH treatments are not detailed in the provided context, these drugs are part of the broader chemotherapy regimens employed in managing the disease.

What other types of research exist?

Promising novel alternatives to chemotherapy for Langerhans Cell Histiocytosis (LCH) patients include targeted therapies and immunotherapies. These may involve BRAF inhibitors (e.g., vemurafenib) for patients with BRAF V600E mutations, MEK inhibitors (e.g., cobimetinib) for those with MAPK pathway alterations, and immune checkpoint inhibitors (e.g., pembrolizumab) for refractory cases. These therapies target specific molecular pathways involved in LCH pathogenesis and offer a more personalized treatment approach.

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Chemotherapy

Combination Therapy for Langerhans Cell Histiocytosis

Phase 2 & 3

Recruiting

Research Sponsored by North American Consortium for Histiocytosis

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1

Stratum I: Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the specified criteria

Must not have

Stratum IV: Pulmonary failure not due to active LCH, isolated liver sclerosis or pulmonary fibrosis without active LCH, uncontrolled active life-threatening infection, decreased renal function, pregnancy or active breastfeeding, failure to provide signed informed consent

Stratum III: Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement, inadequate renal function

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial uses a combination of two drugs, vinblastine and prednisone, to treat children with Langerhans Cell Histiocytosis. The treatment works by stopping abnormal cell growth and reducing inflammation. Vinblastine and prednisone have been used in various combinations to treat Langerhans Cell Histiocytosis (LCH) with some success in managing symptoms and achieving remission.

Who is the study for?

This trial is for children and adolescents under 18 with Langerhans Cell Histiocytosis (LCH). They must have a confirmed diagnosis, not be pregnant or breastfeeding, and have no prior systemic therapy. Participants need consent from parents/guardians if underage. Certain severe organ dysfunctions or infections may disqualify them.

What is being tested?

The study tests various treatments including Prednisone, stem cell transplantation, immunoglobulin, INDOMETHACIN, mercaptopurine, Cytosine Arabinoside, Vinblastine, Methotrexate and 2-chlorodeoxyadenosine in young patients with LCH to find the most effective approach.

What are the potential side effects?

Potential side effects include immune system suppression leading to increased infection risk; liver toxicity; bone marrow suppression causing anemia or bleeding issues; nausea; hair loss due to chemotherapy drugs like Methotrexate and Vinblastine.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My diagnosis of Langerhans cell histiocytosis is confirmed by tissue examination.

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My diagnosis of Langerhans cell histiocytosis is confirmed by tissue analysis.

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My non-risk organs are at least intermediate AD or my risk organs are better AD after 12 weeks.

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I have newly diagnosed single-system Langerhans Cell Histiocytosis not in my bones, brain, or 'CNS-risk' areas.

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I was under 18 when I was diagnosed.

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I was diagnosed before turning 18.

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My condition has worsened in areas of my body not considered at high risk.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have lung failure, liver issues, or lung fibrosis due to LCH. I am not pregnant, breastfeeding, and I can sign consent.

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I have a specific liver condition without liver disease and poor kidney function.

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I am pregnant or have long-term effects from LCH without active disease, and have had prior systemic therapy.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.

Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)

Percentage of Patients with Reactivation Free Survival

+3 more

Secondary study objectives

Early and late mortality

Early and late toxicity

Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH

+15 more

Side effects data

From 2016 Phase 3 trial • 854 Patients • NCT00003389

98%

Anemia

93%

Leukocytes decreased

90%

Lymphopenia

84%

Neutrophils decreased

78%

Neuropathy-sensory

75%

Alopecia

74%

Fatigue

67%

Nausea

60%

Hyperglycemia

52%

Constipation

46%

Hypoalbuminemia

40%

Myalgia

34%

Stomatitis

33%

Insomnia

32%

Vomiting

27%

Platelets decreased

26%

Alkaline phosphatase increased

26%

Aspartate aminotransferase increased

23%

Dyspnea

20%

Dyspepsia

19%

Dysphagia

19%

Headache

16%

Anorexia

16%

Arthralgia

15%

Neuropathy-motor

15%

Abdominal pain

14%

Infection w/o neutropenia

14%

Cough

14%

Fever

13%

Rash/desquamation

13%

Diarrhea w/o prior colostomy

12%

Bone pain

11%

Weight gain

11%

Taste disturbance

11%

Anxiety/agitation

10%

Sweating

10%

Radiation dermatitis

Rigors/chills

Dizziness/lightheadedness

Injection site reaction

Dysphagia-esophageal radiation

Hypoglycemia

Blood bilirubin increased

Chest pain

Pain-other

Phlebitis

Creatinine increased

Edema

Pruritus

Hot flashes

Infection w/ grade 3 or 4 neutropenia

Weight loss

Muscle weakness

Depression

Mouth dryness

Transfusion: pRBCs

Pneumonitis/pulmonary infiltrates

Thrombosis/embolism

Febrile neutropenia

Irregular menses

Nail changes

Allergic rhinitis

Allergic reaction

Infection w/ unknown ANC

Syncope

Sinus tachycardia

Dehydration

Neuropathic pain

100%

80%

60%

40%

20%

Study treatment Arm

Arm B (Stanford V)

Arm A (ABVD)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Group I: Stratum VIExperimental Treatment6 Interventions

Natural history and management of "other" SS-LCH not eligible for stratum I group 2. * Treatment Options- Management (mostly "wait \& see" and topical treatment) is left to the discretion of the treating physician. All treatments and disease responses must be reported in the database. In the case of uncertainties please contact your National Coordinator. * Patients being followed on Stratum VI who have progression of disease to MSLCH, multifocal bone disease or CNS-risk bone lesions should be enrolled on Stratum I therapy. * Patients being followed on Stratum VI who develop isolated tumorous or neurodegenerative CNS-LCH should be enrolled on Stratum V.

Group II: Stratum VExperimental Treatment3 Interventions

Stratum V Monitoring and Treatment of isolated tumorous and neurodegenerative CNS-LCH - Special regimens will be offered to patients with isolated tumorous CNS-LCH (repeated 2-CdA courses) and to patients with clinically manifested ND-CNS-LCH (+/- extracranial LCH manifestations). For the last group monotherapy with Ara-C courses or (Intravenous immunoglobulin)IVIG will be offered depending on physician's choice.

Group III: Stratum IVExperimental Treatment1 Intervention

To determine the overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT). Salvage treatment option for MS-LCH patients with risk organ involvement, who fail to respond to front-line therapy (Stratum I) OR to the salvage 2- CdA/Ara-C regimen (Stratum III).

Group IV: Stratum IIIExperimental Treatment1 Intervention

Salvage treatment for risk LCH To assess the efficacy of the combination 2-CdA/Ara-C (Cytosine Arabinoside and 2-chlorodeoxyadenosine) in MS-LCH (patients with risk organ involvement, who fail to respond to front-line (Stratum I) therapy. The initial therapy consists of 2 courses of 2-CdA/Ara-C. Continuation of outlined treatment to be assessed at assigned intervals in each stratum.

Group V: Stratum IIExperimental Treatment6 Interventions

A uniform "intensive" 24-week course consisting of prednisolone, vincristine and cytosine-arabinoside will be introduced in Stratum II for eligible patients. It will be followed by a continuation therapy to total treatment duration of 24 months. Participants who after SL-IT (week 24) have a response (NAD or AD better) are eligible for randomization between the continuation arms "INDOMETHACIN" and "6-MP/MTX" (mercaptopurine and Methotrexate).

Group VI: Stratum IExperimental Treatment3 Interventions

Stratum I The combination of Prednisone and vinblastine is the standard first-line combination for patients needing systemic therapy (Stratum I). Patients with MS-LCH and involvement of risk organs, who do not respond to 6-12 weeks of standard therapy, will be immediately switched to alternative treatment approaches (Stratum III or Stratum IV). Further therapy prolongation (12 vs. 24 months) and intensification (± mercaptopurine) will further reduce the reactivation rate and the permanent consequences.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Prednisone

2014

Completed Phase 4

~2500

Intravenous immunoglobulin

2017

Completed Phase 3

~330

mercaptopurine

1999

Completed Phase 3

~13700

Cytosine Arabinoside

2003

Completed Phase 3

~500

Vinblastine

1998

Completed Phase 3

~5410

Methotrexate

2019

Completed Phase 4

~4400

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Langerhans Cell Histiocytosis (LCH) involve chemotherapy agents that target rapidly dividing cells. These cytotoxic agents, such as vincristine, methotrexate, and cyclophosphamide, work by interfering with cell division and DNA replication, leading to cell death. This is particularly important for LCH patients as the disease is characterized by the proliferation of abnormal Langerhans cells. By targeting these rapidly dividing cells, chemotherapy can help control the spread of the disease and alleviate symptoms, improving patient outcomes.

Inhibition of normal granulopoiesis by cytostatic agents.Selective restoration of immunosuppressive effect of cytotoxic agents by thymopoietin fragments.Therapy Effect: Impact on Bone Marrow Morphology.