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

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)

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)