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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Myelodysplasia, Chronic Myeloid Leukemia, Histiocytosis

Intervention / Treatment
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* Drug: Chemotherapy and antibodies
* Device: Miltenyi Biotec CliniMACS
* Procedure: Allogeneic stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Participants<br>Participants who meet the eligibility criteria for this study. Donor cells will be obtained using the Miltenyi Biotec CliniMACS device. Interventions: Chemotherapy and antibodies, allogeneic stem cell transplantation. | Drug: Chemotherapy and antibodies<br>* 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.<br>* Other names: OKT3;Device: Miltenyi Biotec CliniMACS<br>* Stem cell selection device<br>Procedure: Allogeneic stem cell transplantation<br>* Allogeneic natural killer (NK)cell infusion<br>* Other names: NK cell infusions;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Survival | 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. | One year after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality | The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice. | 100 days post-transplantation | 
| Number of Transplant-Related Adverse Outcomes: Engraftment Failure | 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. | 100 days post-transplantation | 
| Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD) | 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. | 100 days post-transplantation | 
| Number of Incidences of Chronic GVHD. | 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 | Up to 5 years after transplant | 
| Factors Affecting One-year Survival: Median Age of Donor at HSCT | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Median Dose of CD34 | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Median Dose of NK Cells | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Disease Status at HSCT | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Donor Type | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Match N/6 HLA Loci | 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). | Up to one year after transplant | 
| Factors Affecting One-year Survival: Minimal Residual Disease (MRD) | Detection of leukemia blasts in bone marrow by flow cytometry | Up to one year after transplant | 
| Incidence of and Risk Factors for Organ Dysfunction. | The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly. | Up to 5 Years after transplant | 
| Incidence of and Risk Factors for Long-term Neurocognitive Deficit. | The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly. | Up to 5 Years after transplant | 
| Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation | 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. | Baseline before HSCT, 1 year post HSCT, and up to 5 years post HSCT | 
| Kinetics of Lymphohematopoietic Reconstitution | The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly. | From 0-3 months after HSCT through 4-5 years after HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem cell transplantation, Stem cell transplant, Haploidentical transplant