Pilot Study of Non-Myeloablative, HLA-Matched Allogeneic Stem Cell Transplantation for Pediatric Hematopoietic Malignancies
Condition: Hodgkin Lymphoma; Lymphocytic Leukemia; Mixed Cell Leukemia; Myelodysplastic Syndrome; Non Hodgkin's Lymphoma; CML; ALL; AML; Lymphoma
MeSH terms: Lymphoma; Leukemia; Preleukemia; Hematologic Neoplasms; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Stem cell transplantation
Intervention type(s): Procedure
Intervention description(s): >3 x 106/kg CD34+ stem cells by IV infusion
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia; Myelodysplastic Syndrome; Bone Marrow Transplant; Pediatric Oncology; Lymphoma; Efficacy; Safety; Childhood Cancer