HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

• To find out the effects (good and bad) of treatment with stem cell and NK cell transplant
• To study the outcome of very young subjects treated with stem cell and NK cell transplant one year after treatment
• To find out what factors affect the outcome of very young subjects treated with stem cell and NK cell transplant
• To study the blood cells in the bone marrow before and after treatment with stem cell and NK cell transplant

• To estimate the incidence of 3 transplant-related adverse outcomes, i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD in the first 100 days after hematopoietic stem cell (HSC) transplantation. [ Time Frame: 5 Years ] [ Designated as safety issue: No ]
• To estimate the incidence of chronic GVHD. [ Time Frame: 5 Years ] [ Designated as safety issue: Yes ]
• To evaluate the factors that affect the one-year survival. [ Time Frame: 5 Years ] [ Designated as safety issue: No ]
• To assess the kinetics of lymphohematopoietic reconstitution. [ Time Frame: 5 Years ] [ Designated as safety issue: No ]
• To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation [ Time Frame: 5 Years ] [ Designated as safety issue: No ]
• To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction. [ Time Frame: 5 Years ] [ Designated as safety issue: No ]

Recent studies of conventional chemotherapy for infants with high-risk hematologic malignancies show that the long-term disease-free survival is low. Although blood and marrow stem cell transplantation using an HLA identical sibling has improved the outcome for these children, less than 25% have this donor source available. Another option is haploidentical transplantation using a partially matched family member donor (i.e. parental donor).

Although haploidentical transplantation has proven curative for some patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including infection and graft versus host disease (GVHD). Building on prior institutional trials, this study will provide patients a haploidentical graft depleted of T lymphocytes using the investigational device, CliniMACS selection system. One week after the transplant procedure, patients will also receive an infusion of additional donor derived white blood cells called Natural Killer (NK) cells in an effort to decrease risks for rejection of the graft, disease relapse, and regimen related toxicity. The primary objective of the study is to evaluate 1 year survival in infants with high risk hematologic malignancies who receive this study treatment.

Secondary objectives for this study include the following:

• To estimate the incidence of three transplant-related adverse outcomes (i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD) in the first 100 days after transplantation.
• To estimate the incidence of chronic graft-versus-host disease.
• To evaluate those factors that affect one-year survival.
• To assess the kinetics of lymphohematopoietic reconstitution.
• To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation.
• To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction.

• Acute Myeloid Leukemia
• Acute Lymphocytic Leukemia
• Myelodysplasia
• Chronic Myeloid Leukemia
• Histiocytosis

• Drug: Chemotherapy and antibodies
  Study participants will receive a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants will receive an infusion of additional donor derived cells called NK cells.
  Other Names:

  • Cyclophosphamide
  • Fludarabine
  • Thiotepa
  • Melphalan
  • OKT3
• Device: Miltenyi Biotec CliniMACS
  Stem cell selection device
• Procedure: Allogeneic stem cell transplantation
  Allogeneic natural killer (NK)cell infusion
  Other Names:

  • Haploidentical stem cell transplantation
  • Allogeneic stem cell transplant
  • Immunotherapy
  • Mismatched family member donor transplant
  • NK cell infusions

Inclusion Criteria:

Must have one of the following diagnosis:

• AML in remission or relapse (e.g., FAB M7 or biphenotypic leukemia)
• High-risk ALL in first remission (e.g., poor responder to prednisone, Ph+ ALL)
• ALL beyond first remission
• Secondary leukemia
• Primary myelodysplasia (including RAEB, RAEB-T, CMML, JCML, and JMML)
• Chronic myeloid leukemia
• Histiocytoses (including multi-system Langerhans' cell histiocytosis and hemophagocytic lymphohistiocytosis

Inclusion criteria Donor research participants

• HIV negative (date).
• Hepatitis B surface antigen negative (date).
• Hepatitis C antibody negative (date).
• Syphilis negative (date).
• Donor is equal to or greater than 3 on 6 HLA match (date).
• Not pregnant (negative pregnancy test).
• Not lactating.
• At least 18 years of age.

Exclusion Criteria

• Patients greater than 24 months of age at the time of transplant.
• HLA-identical sibling donor is available.
• Cardiac function: shortening fraction <25%.
• Pulse oximetry oxygen saturation <92% on room air.
• Glomerular filtration rate less than 40 ml/min/1.73 m2 (may use Technetium-99 result for GFR).
• Direct bilirubin > 3 mg/dl.
• SGPT > 500 U/L.
• Patients with previous allergy to mouse proteins.
• Patients with previous allergy to rabbit serum products.
• Patients with Down's syndrome