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NCT Number: NCT00145626

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

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.

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Key information

Conditions

Acute Myeloid Leukemia Acute Lymphocytic Leukemia Anemia Anemia, Refractory Anemia, Refractory, with Excess of Blasts Bone Marrow Diseases Chronic Disease Chronic Myeloid Leukemia Disease Attributes Hematologic Diseases Hemic and Lymphatic Diseases Histiocytosis Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid Leukemia, Myeloid, Acute Lymphatic Diseases Lymphoproliferative Disorders Myelodysplasia Myelodysplastic Syndromes Myeloproliferative Disorders Neoplasms Neoplasms by Histologic Type Pathologic Processes Pathological Conditions, Signs and Symptoms Precursor Cell Lymphoblastic Leukemia-Lymphoma

Age range

Up to 24 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Chemotherapy and antibodies

Drug

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

Miltenyi Biotec CliniMACS

Device

Stem cell selection device

allogeneic stem cell transplantation

Procedure

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

Primary outcomes

  1. One-year Survival

    Time frame: One year after transplant

    The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system.

    The Kaplan-Meier estimate for one-year survival is reported.

Secondary outcomes

  1. Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality

    Time frame: 100 days post-transplantation

    The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.

  2. Number of Transplant-Related Adverse Outcomes: Engraftment Failure

    Time frame: 100 days post-transplantation

    Engraftment failure is defined as <10% donor cell chimerism at any time point between 28 and 100 days after transplant with no evidence of disease relapse or requiring stem cell boost.

  3. Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)

    Time frame: 100 days post-transplantation

    The cumulative incidence estimate for occurrence of fatal acute GVHD by the end of the first 100 days post-transplant was calculated using method of Kalbfleisch and Prentice.

  4. Number of Incidences of Chronic GVHD.

    Time frame: Up to 5 years after transplant

    Chronic GVHD was graded according to Seattle Criteria: limited or extensive. Limited is defined as localized skin and/or hepatic dysfunction. Extensive is defined as one or more of the following:

    • generalized skin involvement
    • liver histology showing chronic aggressive hepatitis, bridging necrosis or cirrhosis
    • eye dryness with Schirmer's test <5 mm wetting
    • oral: involvement of salivary glands or oral mucosa
    • other: another target organ involvement

  5. Factors Affecting One-year Survival: Median Age of Donor at HSCT

    Time frame: Up to one year after transplant

    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  6. Factors Affecting One-year Survival: Median Dose of CD34

    Time frame: Up to one year after transplant

    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  7. Factors Affecting One-year Survival: Median Dose of NK Cells

    Time frame: Up to one year after transplant

    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  8. Factors Affecting One-year Survival: Disease Status at HSCT

    Time frame: Up to one year after transplant

    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  9. Factors Affecting One-year Survival: Donor Type

    Time frame: Up to one year after transplant

    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  10. Factors Affecting One-year Survival: Match N/6 HLA Loci

    Time frame: Up to one year after transplant

    HLA typing determined the degree of match by looking at 6 different HLA loci. The results indicate the number of the 6 loci that matched for each participant. Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).

  11. Factors Affecting One-year Survival: Minimal Residual Disease (MRD)

    Time frame: Up to one year after transplant

    Detection of leukemia blasts in bone marrow by flow cytometry

  12. Incidence of and Risk Factors for Organ Dysfunction.

    Time frame: Up to 5 Years after transplant

    The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

  13. Incidence of and Risk Factors for Long-term Neurocognitive Deficit.

    Time frame: Up to 5 Years after transplant

    The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

  14. Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation

    Time frame: Baseline before HSCT, 1 year post HSCT, and up to 5 years post HSCT

    The presence or absence of MRD before and after the bone marrow transplant (BMT) and its frequency distribution will be obtained for each time point separately.

  15. Kinetics of Lymphohematopoietic Reconstitution

    Time frame: From 0-3 months after HSCT through 4-5 years after HSCT

    The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.

Sponsors and collaborators

Lead sponsor

St. Jude Children's Research Hospital

Other

Collaborators

  • Assisi Foundation

Registry information

Important dates

Study start
2004
Primary completion
2015
Study completion
2016
First posted
Sep 5, 2005
Registry last updated
Jun 19, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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