Vinblastine/Prednisone Versus Single Therapy With Cytarabine for Langerhans Cell Histiocytosis (LCH)

To be eligible to participate in this study, patients physician must have determined that
they have LCH which is not treatable by surgical intervention or observation alone. If
patient chooses to participate in this study, they will be assigned randomly (like flipping a
coin) to one of two LCH chemotherapy treatment groups. A computer will randomly determine if
they will begin to receive vinblastine/prednisone treatment or cytarabine treatment. Patient
will have an equal chance (50%) to receive vinblastine/prednisone or to receive cytarabine.
Neither the patient nor their doctor will be able to choose the group assignment, but the
patient and their study doctor will know which treatment they are receiving.

The patient will need to have the following tests, exams, or procedures. Most of these are
part of regular cancer care and may be done even if the patient does not want to join this
study. Some of them may not need to be repeated if they have had them done recently. The
patient's doctor will tell them which ones they need to repeat.

- History and Physical

- Blood tests

- Urine tests

- Biopsy to confirm diagnosis

- Bone Marrow biopsy/aspirate (if patient is less than 2 years old or for any patient
clinical concern for bone marrow disease)*

- Lumbar puncture for spinal fluid tests (if patient has disease in pituitary gland or
brain)

- The bone marrow sample procedure is as follows: The skin above the hipbone will be
made numb. This area will then be sterilized and a small incision will be made. A
bone marrow needle will be inserted into the hipbone and bone marrow will be
withdrawn. Patient will sign a separate consent that explains this procedure in
more detail.

We will also do x-rays and scans of the inside of the body. These scans may include chest and
bone x-rays, ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI)
and/or positron emission tomography (PET). The specific tests depend on age, sites of LCH and
other clinical factors. An ultrasound is a sound wave machine that uses a computer to make
pictures of the tissues of the body. A CT is an x-ray machine that uses a computer to make
pictures of the organs of the body. An MRI is a scan which uses a magnetic machine to make
pictures of the inside of the body. A PET scan is an x-ray technique that uses a sugar
solution that you drink to see activity inside the body. The PET and CT scans will look at
where the LCH is in the body.

If tests show that the patient can participate in this study and they choose to participate,
treatment will begin based on randomization to either the cytarabine ("experimental") arm or
the vinblastine/prednisone ("standard") arm as described below.

Patient will have a history and physical and blood tests before each cycle. The cancer drugs
will be given to the patient intravenously (IV). An IV is a tube placed inside a vein to give
medicine to the patient. If at anytime during the study the cancer gets worse, the patient
will be taken off the study treatment.

1. Cytarabine ("experimental") arm

Initial therapy I (Weeks 1-6)

• Cytarabine for five consecutive days. This five-day cycle will be repeated every 21
days for a total of two cycles.

Patient will have scans to see how the LCH responded to the treatment during week 6. If
the patient had LCH in their bone marrow (BM) at the beginning of the study, they will
have another BM biopsy. If the cancer is stable and does not respond to therapy by Week
6, the patient will be taken off the study treatment. If the disease is only partly gone
or unchanged the patient will receive additional therapy with Initial therapy II.

Initial therapy II (Weeks 7-12)

• Cytarabine for five consecutive days. This five-day cycle will be repeated every 21
days for a total of two cycles.

Patient will have scans to see how the LCH responded to the treatment during week 12
(unless they had no active disease at week 6). If the patient had LCH in their bone
marrow (BM) at the beginning of the study, they will have another BM biopsy. If the
cancer is stable and does not respond to therapy by Week 12, the patient will be taken
off the study treatment. If the patient has no evidence of active disease at this time
they will proceed to Continuation therapy.

Continuation therapy (Weeks 13-52)

• Cytarabine for five consecutive days. This five-day cycle will be repeated every 28
days for 10 additional cycles to complete one year of therapy

Patient will have scans to see how the LCH responded to the treatment at Week 24 and at
the end of therapy. If the patient had LCH in their bone marrow (BM) at the beginning of
the study, they will have another BM biopsy.

2. Vinblastine/prednisone ("standard") arm

Initial therapy I (Weeks 1-6)

- Prednisone given by mouth two times a day daily on days 1-28 AND

- Vinblastine will be given IV (into a vein) one day a week for 6 weeks

Patient will have scans to see how the LCH responded to the treatment after week 6. If the
patient had LCH in their bone marrow (BM) at the beginning of the study, they will have
another BM biopsy. If the disease is completely gone by Week 6, patient will proceed to
Continuation therapy. If the disease is only partly gone or unchanged patient will receive
additional therapy with Initial therapy II.

Patient will have scans to see how the LCH responded to the treatment during Week 12 and if
they had LCH in their bone marrow (BM) at the beginning of the study, they will have another
BM biopsy.

Initial therapy II (Weeks 7-12, given only if the patient does not have evidence of active
disease by Week 6)

- Prednisone by mouth on the first three days of each week during weeks 7-12 AND

- Vinblastine IV weekly during weeks 7-12

If the disease is gone or better after this additional therapy Continuation therapy will
begin.

Continuation therapy

- Prednisone by mouth twice daily day on days 1-5 every 3 weeks AND

- Vinblastine IV once every 3 weeks

- 6-Mercaptopurine by mouth daily NOTE: Only high risk patients will receive
6-Mercaptopurine

Patient will have scans to see how the LCH responded to the treatment at Week 24 and at the
end of therapy. If the patient had LCH in their bone marrow (BM) at the beginning of the
study, they will have another BM biopsy.

STUDY FOLLOW-UP: Patient will be in this study for 5 years after completion of their therapy.
The doctors will exam the patient at 1 month, 3 months, 6 months, 9 months, 12 months, then
at 18 and 24 months, then yearly until 5 years after the patient is taken off treatment. At
these visits the patient may have routine blood tests, scans, and the biology tests.

Inclusion Criteria:

1. Patient must have biopsy-confirmed diagnosis of Langerhans cell histiocytosis.

2. Patient must be between 0-21 years of age.

3. Patient must have a Karnofsky performance score ≥ 50% or Lansky performance score ≥
50%.

Exclusion Criteria:

1. Patient may not have received prior systemic chemotherapy for LCH or other malignant
disorder. Systemic steroids equivalent to prednisone 1 mg/kg/day can not have been
given for more than 7 days in the 30 day period prior to study enrollment. However,
patients who have only received surgical or radiation therapy, intralesional injection
of steroids, or topical steroids may be enrolled.

2. Patient may not have disease limited to a single skin or bone site, with the following
exceptions:

- Central Nervous System (CNS) risk lesions/special site disease: patients with
single bone sites that are CNS-risk (sphenoid, mastoid, orbital, zygomatic,
ethmoid, maxillary, or temporal bones, the cranial fossa, pituitary gland or
neurodegenerative disease) or are "special sites" (odontoid peg, vertebral lesion
with intraspinal soft tissue extension) require systemic therapy as standard of
care and thus are eligible for the study.

- Functionally critical lesions: A single lesion not described above which may
cause "functionally critical anatomic abnormality" wherein attempts at local
therapy (such as surgical curettage or radiation) would cause unacceptable
morbidity. These patients may be enrolled with written approval of the
Coordinating Center PI or Vice-Chair and documentation of the rationale
justifying systemic therapy.

3. Patient may not have severe renal disease (creatinine greater than 3 times normal for
age OR creatinine clearance < 50 ml/m2/1.73m^2).

4. Patient may not have severe hepatic disease (direct bilirubin greater than 3 mg/dl OR
aspartate aminotransferase (AST) greater than 500 IU/L), unless hepatic injury is due
to LCH.

5. Female patients may not be pregnant or breastfeeding.

6. Patients of reproductive potential must use birth control or abstain from sexual
activity.

7. Patients with HIV who are unable or unwilling to stop antiretroviral therapy for the
duration of therapy may not be enrolled.

NOTE: Patients excluded for laboratory abnormalities or performance score only may be
enrolled on the study with written approval from the Coordinating Center PI or Vice-Chair.