LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age < 18 years).

Study Overview

• Status: Active, not recruiting
• Conditions: Langerhans Cell Histiocytosis
• Intervention / Treatment: Drug: Prednisone; Drug: Vinblastine; Drug: mercaptopurine; Drug: INDOMETHACIN; Drug: Methotrexate; Drug: Cytosine Arabinoside; Drug: 2-chlorodeoxyadenosine; Procedure: hematopoietic stem cell transplantation (RIC-HSCT); Biological: Intravenous immunoglobulin

Detailed Description

The international efforts of the past 20 years have shown that combination therapy with vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in patients with and without risk organ involvement. It also showed that prolonged treatment in the latter group (treatment duration of 12 vs. 6 months) is superior in preventing disease reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV study seeks to tailor treatment based on features at presentation and on response to treatment, leading to seven strata:

• Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single system (SS)-LCH with multifocal bone or "Central Nervous System (CNS)-risk" lesions (Group 2)
• Stratum II: Second-line treatment for non-risk patients (patients without risk organ involvement who fail first-line therapy or have a reactivation after completion of first-line therapy)
• Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs who fail first-line therapy)
• Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk organs who fail first-line therapy)
• Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH
• Stratum VI: Natural history and management of "other" SS-LCH (patients who do not need systemic therapy at the time of diagnosis)
• Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be followed for reactivation or permanent consequences once complete disease resolution has been achieved and the respective protocol treatment completed)

• Study Type: Interventional
• Enrollment (Actual): 1400
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Madera, California, United States, 93636
      • Valley Children's Healthcare
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital of Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94158-0106
      • UCSF Helen Diller Family Cancer Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • St. Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta, Emory
  • Illinois
    • Chicago, Illinois, United States, 60611-2991
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children - Indiana University
  • Kansas
    • Kansas City, Kansas, United States, 64108
      • Children's Mercy Hospitals
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky A.B.Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville, Norton Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Minnesota
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New Hyde Park, New York, United States, 11040
      • Cohen Children's Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10032
      • Columbia University / Herbert Irving Cancer Center
    • New York, New York, United States, 10170
      • Memorial Sloan Kettering Cancer Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
    • The Bronx, New York, United States, 10467
      • Children's Hospital at Montefiore
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center, Levine Children's Hospital
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital, University Hospitals
    • Toledo, Ohio, United States, 43606
      • Russell J Ebeid Children's Hospital (Promedica)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
    • Greenville, South Carolina, United States, 29605
      • Greenville Health System BI-LO Charities Children's Cancer Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas, UT Southwestern
  • Washington
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Children's Hospital
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • American Family Children's Hospital University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Stratum I

  • Patients must be less than 18 years of age at the time of diagnosis.
  • Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1
  • Signed informed consent form

• Stratum II

  • Patients of Stratum I who have:
  • Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
  • AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2)
  • Disease progression (AD worse) in non-risk organs at any time during continuation treatment
  • Active disease at the end of Stratum I treatment
  • Disease reactivation in non-risk organs at any time after completion of Stratum I treatment

• Stratum III

  • Patients from Stratum I who fulfill the following criteria:
  • AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).

  • Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as

    • Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
    • PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have to be fulfilled) AND/OR
    • Liver dysfunction (or digestive involvement with protein loss)
    • Total protein <55 g/L or substitution dependency
    • Albumin <25 g/L or substitution dependency (at least one of the two criteria to be fulfilled)

• Stratum IV

  • Patients from Stratum I or Stratum III who fulfill the following criteria:
  • AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR
  • AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
  • Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as defined in Table XI (see Section 10.3.1).
  • Informed consent: All patients or their legal guardians (if the patient is <18 years of age) must sign an Ethics or institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study. When appropriate, younger patients will be included in all discussions in order to obtain assent.
  • Adequate organ function: Patients should have adequate hepatic, renal, cardiac and pulmonary function to undergo reduced intensity HCT based upon local institutional guidelines, or at a minimum meet requirements noted in eligibility checklist Appendix A-VIII_1. However, significant hepatic and pulmonary dysfunction, if secondary to underlying LCH disease activity, will not exclude patients from protocol enrollment and should be discussed with the National PI Coordinator and the Coordinating Principal Investigator.

• Stratum V

  • All patients with verified diagnosis of LCH and MRI findings consistent with ND-CNSLCH irrespective of previous treatments (also those not registered to other Strata ofLCH-IV).
  • Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis). In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study

• Stratum VI

  -- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.

• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as consent for longterm follow-up has not been withheld.

Exclusion Criteria:

• Stratum I

  • Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy)
  • LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease
  • Prior systemic therapy

• Stratum II

  • Patients with progressive disease in risk organs
  • Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations
  • No written consent of the patient or his/her parents or legal guardian

• Stratum III

  • The presence of any of the following criteria will exclude the patient from the study:
  • Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement.
  • Inadequate renal function as defined by serum creatinine > 3x normal for age

• Stratum IV

  • Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
  • Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
  • Uncontrolled active life-threatening infection.
  • Decreased renal function with a GFR of less than 50ml/1.73m2/min.
  • Pregnancy or active breast feeding
  • Failure to provide signed informed consent

• Stratum VI

  • Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible for Stratum V),
  • Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible for Stratum I, Group 2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stratum I; 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.	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban®; Vincaleukoblastine Sulfate; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol®; -6-MP
Experimental: Stratum II; 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).	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban®; Vincaleukoblastine Sulfate; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol®; -6-MP; Drug: INDOMETHACIN; Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.; Drug: Methotrexate; fixed dose weekly orally for total treatment duration of 24 months.; Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C
Experimental: Stratum III; 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.	Drug: 2-chlorodeoxyadenosine; Other Names: Leustatin®; 2-CdA; Cladribin®
Experimental: Stratum IV; 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).	Procedure: hematopoietic stem cell transplantation (RIC-HSCT)
Experimental: Stratum V; 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.	Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C; Drug: 2-chlorodeoxyadenosine; Other Names: Leustatin®; 2-CdA; Cladribin®; Biological: Intravenous immunoglobulin; Other Names: IVIG
Experimental: Stratum VI; 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.	Drug: Prednisone; Stratum I; Drug: Vinblastine; Stratum I; Other Names: Velban®; Vincaleukoblastine Sulfate; Drug: mercaptopurine; Stratum I; Other Names: -Purinethol®; -6-MP; Drug: Cytosine Arabinoside; Other Names: Cytarabine, Ara-C; Drug: 2-chlorodeoxyadenosine; Other Names: Leustatin®; 2-CdA; Cladribin®; Biological: Intravenous immunoglobulin; Other Names: IVIG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients with Reactivation Free Survival	Stratum I, II, VI	12 Months
Response Rate of Second Cycle	Stratum III	9 weeks
Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)	Stratum IV	3 Years
The cumulative incidence of radiological and clinical neurodegeneration in patients with isolated tumorous CNS-LCH, DI, anterior pituitary dysfunction, and those with CNS-risk lesions	Stratum V	2 Years
The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH	Stratum V	2 Years
Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc.	From all treatment stratum via long-term follow up in Stratum VII	2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Serious and Non-Serious Adverse Events		2 Years
Overall Survival	Stratum I	2 Years
Incidence of Permanent Consequences	All Stratum	2 Years
Cumulative incidence of reactivations in risk organs		2 Years
Time to complete disease resolution	Stratum III	2 Years
Response rate to the combination of prednisone, vincristine and cytarabine	Stratum II	2 years
The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration)	Stratum II	2 Years
Percentage of treatment-related toxicities	Stratum II	2 Years
Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.	Stratum II	2 years
The type of subsequent intensive and/or maintenance therapy utilized	Stratum III	2 Years
Early and late mortality	Stratum II	2 Years
Early and late toxicity	Stratum III	2 Years
d+100 transplant related mortality	Stratum IV	2 Years
Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT		2 Years
Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD	Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH	2 Years
Percentage of Participants with incidence of chronic GVHD	Stratum IV	2 Years
Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy	Stratum V	2 years
Response of isolated tumorous CNS-LCH to 2-CDA	Stratum V	2 Years
Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH	Stratum V	2 Years
Methods of early identification of ND-CNS-LCH	Stratum V - Exploration of the value of neurochemistry, neurophysiology, and neuropsychology methods in early identification of ND-CNS-LCH and in assessing its severity, and comparison to MRI findings.	2 Years
Need for systemic therapy later during disease course	Stratum VI	2 Years
Identify possible risk factors for permanent consequences (PC)		2 Years

Collaborators and Investigators

• Sponsor: North American Consortium for Histiocytosis
• Collaborators: Histiocyte Society
• Investigators: Study Chair: Milen Minkov, MD, Ph.D, Children's Cancer Research Institute / St. Anna Children's Hospital; Study Chair: Carlos Rodriguez-Galindo, MD, North American Consortium for Histiocytosis

Study record dates

Study Major Dates

• Study Start: November 2, 2016
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: July 7, 2014
• First Submitted That Met QC Criteria: July 30, 2014
• First Posted (Estimated): July 31, 2014

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Langerhans cell histiocytosis
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lymphatic Diseases; Lung Diseases, Interstitial; Histiocytosis; Hemic and Lymphatic Diseases; Histiocytosis, Langerhans-Cell; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Alkaloids; Polycyclic Compounds; Transplantation; Indoles; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Nucleosides; Ribonucleosides; Pterins; Pteridines; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Immunoglobulin Isotypes; Immunoglobulin G; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Deoxyribonucleosides; Stem Cell Transplantation; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Sulfhydryl Compounds; Methotrexate; Prednisone; Cytarabine; Mercaptopurine; Vinblastine; Immunoglobulins, Intravenous; Cladribine; Indomethacin; Hematopoietic Stem Cell Transplantation
• Other Study ID Numbers: 13-428; 2011-001699-20 (EudraCT Number); 042011 (Other Identifier: Children's Cancer Research Institute)