Autologous Transplant Followed by Allogeneic Transplant for High Risk Neuroblastoma

Despite the modest advances made over the past two decades with the addition of more
intensive chemotherapy and high dose myeloablative therapy with allogeneic or autologous
bone marrow transplantation, children with high-risk neuroblastoma continue to have an
unsatisfactory long-term survival. The current survival for a child > 1 year of age at
diagnosis with stage 4 neuroblastoma is only 20-35% 1,7. The overall treatment plan for
high-risk patients with neuroblastoma will be:

Induction Therapy Intensive induction chemotherapy with the cardioprotectant dexrazoxane
(Zinecard), vincristine, doxorubicin (Adriamycin), and cyclophosphamide (ZVAC), alternating
with cisplatin and etoposide (CiE). Patients who receive induction chemotherapy on an
alternate protocol and achieve a CR, VGPR, or PR will also be eligible for entry to receive
consolidation therapy and AlloSCT immunotherapy after discussion and approval of the
Principal Investigators ).

Consolidation Therapy with AutoSCT Consolidation therapy with a myeloablative preparative
regimen of carboplatin, thiotepa, and topotecan (CaTT) followed by AutoSCT with PBSCs (CD34+
selection optional).

Immunotherapy with Non-myeloablative AlloSCT Immunotherapy with a non-myeloablative
preparative regimen of busulfan and fludarabine followed by AlloSCT with either: (Arm A) a
related donor (5/6 or 6/6 HLA matched); or (Arm B) an umbilical cord blood donor (unrelated
4/6, 5/6, or 6/6 HLA matched, or related 3/6, 4/6, 5/6, or 6/6 HLA matched). Patients with
an umbilical cord blood donor will also receive Thymoglobulin (ATG-rabbit) during the
preparative regimen. GVHD prophylaxis will consist of Tacrolimus and mycophenolate mofetil
(MMF).

Maintenance Therapy Patients with a related donor who have persistent disease detected prior
to NAT/AlloSCT will be assigned to Arm A1 and will receive two courses of DLI, followed by
cis-RA for 6 cycles. Patients with a related donor with no persistent disease detected prior
to NAT/AlloSCT will be assigned to Arm A2 and receive cis-RA for 6 cycles. Patients with an
umbilical cord blood donor will receive cis-RA for 6 cycles.

Radiation Therapy Due to the potential risk of increased GVHD following radiation therapy,
local radiation therapy to the primary tumor site (21 Gy) and metastatic sites, will be
given after NAT/AlloSCT for patients on Arm A2 and Arm B, and prior to cis-RA therapy.
Radiation therapy will be given following DLI in Arm A1, and prior to cis-RA therapy.

Inclusion Criteria:

- Age be < 30 years of age at the time of initial diagnosis.

- Patients must have a diagnosis of neuroblastoma (ICD-O morphology 9500/3) verified by
histology and/or demonstration of clumps of tumor cells in bone marrow with elevated
urinary catecholamine metabolites. Patients with the following disease stages at
diagnosis are eligible, if they meet the other specified criteria. The revised
International Neuroblastoma Staging System (INSS) will be used to stage all patients
58. (See 14.3 for risk assignment).

- Patients with newly diagnosed neuroblastoma and age > 547 days with the following:

- INSS Stage 4 neuroblastoma regardless of biologic factors

- INSS Stage 2A/2B with MYCN amplification (> 10)

- INSS Stage 3 with MYCN amplification (> 10) OR Unfavorable histology

- Patients with newly diagnosed neuroblastoma and age < 365 days with the following:

* INSS Stage 3, 4, OR 4S neuroblastoma AND MYCN amplification (> 10).

- Patients with newly diagnosed Neuroblastoma and age 365 - <547 days with the
following:

- INSS Stage 3 with MYCN amplification (> 10)

- INSS Stage 4 with MYCN amplification (> 10) OR with deoxyribonucleic acid (DNA)
Index (ploidy) = 1 OR with Unfavorable histology

- Patients > 365 days with INSS Stage 1, 2, and 4S who have progressed to Stage 4.

- Newly Diagnosed patients should be entered on this study within 4 weeks of diagnosis,
or after receiving only one cycle of intermediate dose chemotherapy for patients
initially treated on/according to the low or intermediate risk Children's Oncology
Group (COG) neuroblastoma studies, or within 4 weeks of progression to Stage 4 for
INSS Stage 1, 2, 4S.

- Patients treated with alternative induction regimens and/or consolidation regimens
(AutoSCT) who were not enrolled at diagnosis but who achieve a complete response
(CR), very good partial response (VGPR), partial response (PR), or minimal response
(MR) and meet all other criteria will be eligible for either the consolidation
MAT/AutoSCT and NAT/AlloSCT immunotherapy or NAT/AlloSCT, which ever is clinically
appropriate after discussion with the Principal Investigators.

- Liver Function: alanine aminotransferase (ALT) and bilirubin < 3x normal

- Cardiac Function: Shortening fraction > 27%, or ejection fraction > 47%, no clinical
congestive heart failure.

- Renal Function: Creatinine clearance and/or glomerular filtration rate (GFR) > 60
ml/min/1.73m2.

- Hematologic Function: Patients must have adequate hematopoietic function (absolute
neutrophil count (ANC) > 1000/mm3 and platelets > 100,000/mm3) unless inadequate
hematopoiesis documented to be due to bone marrow involvement with tumor (> 10% tumor
infiltration).

Exclusion Criteria:

- Patients who are pregnant. Patients of childbearing potential must practice an
effective method of birth control while participating on this study.