HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies
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| ClinicalTrials.gov Identifier: NCT00145626 |
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Recruitment Status :
Completed
First Posted : September 5, 2005
Results First Posted : December 14, 2015
Last Update Posted : June 19, 2017
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia Acute Lymphocytic Leukemia Myelodysplasia Chronic Myeloid Leukemia Histiocytosis | Drug: Chemotherapy and antibodies Device: Miltenyi Biotec CliniMACS Procedure: Allogeneic stem cell transplantation | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 40 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies |
| Study Start Date : | May 2004 |
| Actual Primary Completion Date : | March 2015 |
| Actual Study Completion Date : | July 2016 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Study Participants
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
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:
Device: Miltenyi Biotec CliniMACS Stem cell selection device Procedure: Allogeneic stem cell transplantation Allogeneic natural killer (NK)cell infusion
Other Names:
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- 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.
- 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.
- 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.
- 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.
- 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
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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
- 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.
- 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.
- 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.
- 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.
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| Ages Eligible for Study: | up to 24 Months (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00145626
| United States, Tennessee | |
| St. Jude Children's Research Hospital | |
| Memphis, Tennessee, United States, 38105 | |
| Principal Investigator: | Brandon Triplett, MD | St. Jude Children's Research Hospital |
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT00145626 |
| Other Study ID Numbers: |
INFT2 NCI-2011-03671 ( Registry Identifier: NCI Clinical Trial Registration Program ) |
| First Posted: | September 5, 2005 Key Record Dates |
| Results First Posted: | December 14, 2015 |
| Last Update Posted: | June 19, 2017 |
| Last Verified: | May 2017 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | Yes |
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Stem cell transplantation Stem cell transplant Haploidentical transplant |
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Leukemia Leukemia, Myeloid Hematologic Neoplasms Leukemia, Myelogenous, Chronic, BCR-ABL Positive Precursor Cell Lymphoblastic Leukemia-Lymphoma Histiocytosis Neoplasms by Histologic Type Neoplasms Leukemia, Lymphoid Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Neoplasms by Site Hematologic Diseases |
Myeloproliferative Disorders Bone Marrow Diseases Cyclophosphamide Melphalan Thiotepa Fludarabine Antibodies Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |