Langerhans Cell Histiocytosis
Conditions
Keywords
Langerhans cell histiocytosis
Brief summary
The LCH-IV is an international, multicenter, prospective clinical study for pediatric Langerhans Cell Histiocytosis LCH (age \< 18 years).
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)
Interventions
DRUGPrednisone
Stratum I
DRUGVinblastine
Stratum I
DRUGmercaptopurine
Stratum I
DRUGINDOMETHACIN
Indomethacin fixed dose given daily orally in two divided doses with gastric protection for total treatment duration of 24 months.
DRUGMethotrexate
fixed dose weekly orally for total treatment duration of 24 months.
PROCEDUREhematopoietic stem cell transplantation (RIC-HSCT)
BIOLOGICALIntravenous immunoglobulin
Sponsors
Histiocyte Society
North American Consortium for Histiocytosis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate of Second Cycle | 9 weeks | Stratum III |
| Percentage of Patients with Reactivation Free Survival | 12 Months | Stratum I, II, VI |
| Overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT) | 3 Years | Stratum IV |
| 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 | 2 Years | Stratum V |
| The time interval and cumulative incidence of progression of radiological neurodegeneration to clinically manifested ND-CNS-LCH | 2 Years | Stratum V |
| Cumulative incidence of specific Permanent Consequences e.g. diabetes insipidus (DI), growth hormone deficiency (GHD), neuropsychological impairment, etc. | 2 Years | From all treatment stratum via long-term follow up in Stratum VII |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response rate to the combination of prednisone, vincristine and cytarabine | 2 years | Stratum II |
| The proportion of patients alive and free of disease without permanent consequences (e.g. diabetes insipidus, anterior pituitary dysfunction, radiological or clinical neurodegeneration) | 2 Years | Stratum II |
| Percentage of treatment-related toxicities | 2 Years | Stratum II |
| Reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX. | 2 years | Stratum II |
| The type of subsequent intensive and/or maintenance therapy utilized | 2 Years | Stratum III |
| Early and late mortality | 2 Years | Stratum II |
| Early and late toxicity | 2 Years | Stratum III |
| d+100 transplant related mortality | 2 Years | Stratum IV |
| Identify possible risk factors for permanent consequences (PC) | 2 Years | — |
| Record all occurrence of skin, GI or liver abnormalities fulfilling criteria of Grades II-IV acute GVHD | 2 Years | Stratum IV: Hematopoetic Stem Cell Transplantation for Risk LCH |
| Percentage of Participants with incidence of chronic GVHD | 2 Years | Stratum IV |
| Response Rate to ND-CNS-targeted therapy at 12 and 24 months after start of therapy | 2 years | Stratum V |
| Response of isolated tumorous CNS-LCH to 2-CDA | 2 Years | Stratum V |
| Frequency of ND-CNS-LCH in patients with isolated tumorous CNS-LCH | 2 Years | Stratum V |
| Methods of early identification of ND-CNS-LCH | 2 Years | 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. |
| Need for systemic therapy later during disease course | 2 Years | Stratum VI |
| Incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT | 2 Years | — |
| Overall Survival | 2 Years | Stratum I |
| Number of Participants with Serious and Non-Serious Adverse Events | 2 Years | — |
| Incidence of Permanent Consequences | 2 Years | All Stratum |
| Cumulative incidence of reactivations in risk organs | 2 Years | — |
| Time to complete disease resolution | 2 Years | Stratum III |
Countries
United States
Contacts
Primary ContactAdrienne English, BSN, RN
Backup ContactSara G Hastings, MBA
Outcome results
None listed