Pilot Study of Non-Myeloablative, HLA-Matched Allogeneic Stem Cell Transplantation for Pediatric Hematopoietic Malignancies

Background:

- Allogeneic blood and marrow stem cell transplantation (BMT) plays an important role in
the curative treatment of a number of pediatric malignancies. Unfortunately, the success
of conventional allogeneic BMT is limited in part by the multiple toxicities associated
with myeloablative preparative regimens.

- Non-myeloablative pre-transplant regimens are associated with less toxic side effects
than standard BMT. Recently, a novel immunosuppressive, non-myeloablative pre-transplant
chemotherapy regimen has been shown to facilitate complete donor engraftment in an adult
trial at the NCI.

Objectives:

The primary objective of this protocol is to evaluate the efficacy and safety of this
treatment approach in pediatric patients with hematopoietic malignancies

Eligibility:

Inclusion Criteria

Age: Patient must be greater than or equal to 5 years and less than 22 years of age.

Diagnosis:

- Hodgkin s and Non-Hodgkin s Lymphoma: Refractory disease or relapse after salvage
regimen.

- Acute Myelogenous Leukemia: History of bone marrow relapse in remission (CR) #2 or
greater.

- Acute Lymphocytic Leukemia: History of bone marrow relapse in CR #2 or greater (CR#1
with Philadelphia chromosome positive or prior induction failure).

- Acute Hybrid Leukemia including mixed lineage, biphenotypic and undifferentiated:
History of bone marrow relapse in CR #2 or greater (CR#1 with Philadelphia chromosome
positive or prior induction failure).

- Myelodysplastic Syndrome: RAEB or RAEB-t with less than 10% blasts in marrow and blood.

- Chronic Myelogenous Leukemia: Chronic phase or accelerated phase with less than 10%
blasts in marrow and blood.

- Juvenile Myelomonocytic Leukemia: less than 10% blasts in marrow and blood.

Prior Therapy: Chemotherapy to achieve above criteria allowed. Prior BMT allowed as long as
at least day 100+ post-prior BMT, no evidence of GVHD, and no detectable residual donor
chimerism.

Donor: First degree related donors, who are HLA matched (single HLA-A or B locus mismatch
allowed), weight greater than or equal to 15 kilograms, and who meet standard donation
criteria will be considered. The same donor from a prior BMT is allowed.

ECOG Performance Status: 0, 1, or 2. and life expectancy: greater than 3 months.

Liver Function: Serum direct bilirubin less than 2.0 mg/dL and serum ALT and AST values less
than or equal to 2.5x upper limit of normal. (Values above these levels may be accepted if
due to malignancy.)

Renal Function: Age adjusted normal serum creatinine or Cr clearance greater than or equal to
60 mL/min/1.73 m(2).

Pulmonary Function: DLCO greater than or equal to 50%.

Cardiac Function: LVEF greater than or equal to 45% by MUGA or LVSF greater than or equal to
28% by ECHO

Exclusion Criteria

- Active CNS malignancy: Tumor mass on CT or leptomeningeal disease. (Patients with a
history of CNS involvement and no current evidence of CNS disease are allowed.)

- HIV infection, active hepatitis B or C infection: HbSAg or HCV seropositive and elevated
liver transaminases.

- Fanconi Anemia.

- Lactating or pregnant females.

Design:

Pilot Study

- Initial evaluation: Patient and donor will be screened for eligibility. G-CSF primed
bone marrow derived stem cells will be collected from the donor.

- Induction/Consolidation chemotherapy: 1 to 3 cycles will be given every 22 days
depending on disease response, CD4 count, and toxicities.

- Lymphoma: fludarabine, etoposide, doxorubicin, vincristine, cyclophohamide, prednisone,
and filgrastim (EPOCH-fludarabine).

- Leukemia and MDS: Fludarabine, cytarabine, and filgrastim (FLAG).

- Transplantation: Fludarabine and cyclophosphamide will be administered over 4 days
followed by bone marrow transplant. Patients will remain hospitalized until bone marrow
recovery. Patients will be monitored closely at the NIH for at least 100 days post-BMT.

- Post-transplant CNS prophylaxis for ALL: Standard post-transplant CNS prophylaxis will
be employed with intrathecal methotrexate to decrease the risk of CNS relapse for all
patients with ALL.

- Total number of recipient and donors to be accrued is 56.

- INCLUSION CRITERIA PATIENTS:

Patients with the following diagnoses will be considered:

- Hodgkin's and Non-Hodgkin's Lymphoma: Refractory (non-CR) to primary treatment
regimen; Refractory (non-CR) to or relapse after salvage regimen.

- Acute Myelogenous Leukemia (AML): History of bone marrow relapse it CR number 2 or
greater.

- Acute Lymphocytic Leukemia (ALL): History of bone marrow relapse in CR number 2 or
greater; complete remission #1 with Philadelphia chromosome positive or prior
induction failure (subsequent induction regimen required to achieve CR).

- Acute hybrid leukemia including mixed lineage, biphenotypic, and undifferentiated
(AUL): History of bone marrow relapse in CR number 2 or greater; Complete remission #1
with Philadelphia chromosome positive or prior induction failure (second induction
regimen required to achieve (CR).

- Myelodysplastic Syndrome (MDS) excluding refractory anemia (RA) and RA with ringed
sideroblasts (RARS): blasts less than 10% in marrow and blood.

- Chronic Myelogenous Leukemia (CML): Chronic Phase; Accelerated Phase with blasts less
than 10% in marrow and blood.

- Juvenile Myelomonocytic Leukemia (JMML, J-CML): Blasts less than 10% in marrow and
blood.

Patients must be greater than or equal to 4 years and less than 22 years of age.

Prior chemotherapy: Chemotherapy to achieve above noted criteria allowed. Prior autologous
BMT allowed. Prior allogeneic BMT allowed as long as at least day +100 post-prior BMT, and
no evidence of ongoing active GVHD.

Availability of 5 or 6 antigen genotypic HLA-matched first-degree relative donor (single
HLA-A or B locus mismatch allowed).

Performance status of 0,1, or 2.

Life expectancy greater than 3 months.

Liver function: serum direct bilirubin less than 2.0 mg/dL, and serum ALT and AST values
less than or equal to 2.5 times the upper limit of normal. Values above these levels may be
accepted, at the discretion of the PI, if such elevations are thought to be due to
malignancy (excluding acute leukemia).

Renal function: age-adjusted normal serum creatinine or a creatinine clearance greater than
or equal to 60 mL/min/1.73 m(2).

Pulmonary function: DLCO corrected for hemoglobin and alveolar volume greater than or equal
to 50% of predicted.

Left ventricular function: Ejection fraction greater than or equal to 45% by MUGA or
shortening fraction greater than or equal to 28% by ECHO.

Ability to give informed consent. For patients less than 18 years old their legal guardian
must give informed consent. Pediatric patients will be included in age appropriate
discussion in order to obtain verbal assent.

Durable power of attorney form completed (patients greater than 18 years of age only).

Patients must not have an active CNS malignancy as defined by: lymphoma (tumor mass on CT
scan or leptomeningeal disease), Leukemia (CNS 2 or CNS 3 classification), or NB (History
of CNS involvement with no current evidence of CNS malignancy is NOT an exclusion).

Patients must not be HIV positive.

Patients must not have active hepatitis B or C infection as defined by seropositive for
hepatitis B (HbSAg) or hepatitis C and elevated liver transaminases.

Female patients must not be lactating or pregnant (due to risk to fetus or newborn).

Patients must not have high risk of inability to comply with transplant protocol as
determined by principal investigator, social work, and BMT team.

Patients must not have Fanconi Anemia (FA): patients with MDS must have a negative FA test.

INCLUSION CRITERIA DONOR:

First degree relative with genotypic identity at 5 or 6 HLA loci (single HLA-A or B locus
mismatch allowed).

Weight of greater than or equal to 15 kilograms.

Adequate venous access for peripheral apheresis, or consent to use a temporary central
venous catheter for apheresis (on Cohort #2, for possible future cell collection if
needed).

Ability to give informed consent. For donors less than 18 years of age, he/she must be the
oldest eligible donor, their legal guardian must give informed consent, the donor must give
verbal assent, and he/she must be cleared by social work and a mental health specialist to
participate.

Donor selection criteria will be in accordance with NIH/CC Department of Transfusion
Medicine standards.

EXLCUSION CRITERIA PATIENT:

Active CNS malignancy as defined by:

- Lymphoma: tumor mass on CT scan or leptomeningeal disease

- Leukemia: CNS 2 or CNS 3 classification

- NB: History of CNS involvement with no current evidence of CNS malignancy is NOT an
exclusion.

HIV positive.

Active hepatitis B or C infection as defined by seropositive for hepatitis B (HbsAg) or
hepatitis C and elevated liver transaminases.

Lactating or pregnant females.

High risk of inability to comply with transplant protocol as determined by principal
investigator, social work, and BMT team.

Fanconi Anemia (FA): Patients with MDS must have a negative FA test.

EXCLUSION CRITERIA DONOR:

History of medical illness which in the estimation of the PI or DTM physician poses
prohibitive risk to donation including, but not limited to stroke, hypertension that is not
controlled by medication, or heart disease. Individuals with symptomatic angina or a
history of coronary artery bypass grafting or angioplasty will not be eligible. History of
congenital hematologic, immunologic, or metabolic disorder which in the estimation of the
PI poses prohibitive risk to the recipient.

Anemia (Hb less than gm/dl) or thrombocytopenia (less than 100,000/ul).

Lactating or pregnant females.

HIV positive.

Seropositive for hepatitis B (HbsAg) or hepatitis C.

High risk of inability to comply with transplant protocol as determined by principal
investigator, social work, and BMT team.