Total-Body Irradiation and Chemotherapy Followed By Donor Bone Marrow Transplant in Treating Young Patients With Hematologic Cancer

OBJECTIVES:

• Determine the efficacy of hyperfractionated total body irradiation, thiotepa, and cyclophosphamide followed by T-cell-depleted allogeneic bone marrow transplantation in children with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, or myelodysplastic syndromes.
• Correlate the progenitor cell dose and dose of clonable T cells with the incidence and quality of engraftment, extent of chimerism, incidence and severity of acute and chronic graft-versus-host disease, characteristics of hematopoietic and immunologic reconstitution, and overall and disease-free survival at 2 years in patients treated with this regimen.

OUTLINE: Patients undergo total body irradiation three times daily on days -9 to -7 and twice on day -6. Patients receive thiotepa IV over 4 hours on days -5 and -4 and cyclophosphamide IV over 30 minutes on days -3 and -2. Patients who cannot receive cyclophosphamide, due to prior hemorrhagic cystitis or exposure to high-dose cyclophosphamide or ifosfamide, receive fludarabine IV over 30 minutes on days -5 to -1. Patients planning to receive family member HLA-mismatched or unrelated bone marrow transplantation receive horse anti-thymocyte globulin IV once daily on days -5 and -4. Patients undergo allogeneic T-cell-depleted bone marrow transplantation on day 0. Patients receive filgrastim (G-CSF) IV every 12 hours beginning on day 7 and continuing until blood counts recover.

Patients are followed every 2-4 weeks for the first 100 days post-transplantation, every 6 weeks for 6 months, every 3 months for 1 year, and then every 3-6 months until 2 years post-transplantation.

PROJECTED ACCRUAL: A total of 50 patients (25 with HLA 6/6 antigen-matched related donors and 25 with HLA 5/6 antigen-matched related donors or HLA 5/6 or 6/6 antigen-matched unrelated donors) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• One of the following diagnoses:

• Histologically confirmed good-risk acute myeloid leukemia (AML) in first remission with an HLA-compatible related donor

• Ineligible for unrelated bone marrow transplantation unless failed first-line induction chemotherapy or have molecular evidence of disease at time of transplantation
• Histologically confirmed high-risk AML in first remission

• High risk defined by cytogenetics, biphenotypic and undifferentiated leukemia phenotype, secondary AML, or AML after myelodysplastic syndromes (MDS)
• Eligible for related or unrelated donor transplantation
• Histologically confirmed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) in first remission with high risk for relapse or in second or third remission

• High risk for relapse defined by hypodiploidy, pseudodiploidy with translocations t(9;22) or infant t(4;11), or failure to achieve remission after four weeks of induction therapy
• Eligible for related or unrelated donor transplantation
• Histologically confirmed chronic myelogenous leukemia (CML) in at least first chronic phase or acceleration with an HLA-compatible related donor
• Histologically confirmed CML in first chronic phase if failed conventional therapy or in at least second chronic phase or acceleration with an HLA-compatible unrelated donor
• Histologically confirmed non-Hodgkin's lymphoma beyond first complete remission or primary induction failure and tumors that are chemosensitive defined as at least 50% reduction in mass size

• Eligible for related or unrelated donor transplantation
• Histologically confirmed MDS with intermediate or high-risk disease defined by International Prognostic Scoring System and paroxysmal nocturnal hematuria

• Eligible for related or unrelated donor transplantation
• Treatment-related MDS or leukemia allowed if primary malignancy (e.g., neuroblastoma or Ewing's sarcoma) at low risk of recurrence
• No AML, ALL, or LL in relapse or greater than third remission
• No CML in blast crisis defined as more than 30% blasts plus promyelocytes
• No active CNS involvement
• History of leukemia cutis allowed
• HLA compatible donor available

• 5/6 or 6/6 HLA antigen matched related or unrelated

PATIENT CHARACTERISTICS:

Age:

• 18 and under

Performance status:

• Karnofsky 70-100% OR
• Lansky 50-100%

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2.5 times upper limit of normal (ULN)
• AST no greater than 3 times ULN (unless liver involvement is present)

Renal:

• Creatinine normal OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• LVEF at least 50% at rest (if less than 50% at rest, must increase with exercise)

Pulmonary:

• Asymptomatic with no prior risk features OR
• DLCO greater than 40% predicted (corrected for hemoglobin) if symptomatic

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV I/II negative
• No uncontrolled viral, bacterial, or fungal infection
• No known hypersensitivity to bovine proteins

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characterisitics

Chemotherapy:

• See Disease Characteristics

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy that would preclude total body irradiation dose

Surgery:

• Not specified