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

May 25, 2017 updated by: St. Jude Children's Research Hospital

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Actual)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children's Research Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 2 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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:
  • Cyclophosphamide
  • Fludarabine
  • Melphalan
  • Thiotepa
  • OKT3
Device: Miltenyi Biotec CliniMACS
Stem cell selection device
Procedure: Allogeneic stem cell transplantation
Allogeneic natural killer (NK)cell infusion
Other Names:
  • Allogeneic stem cell transplant
  • Immunotherapy
  • Haploidentical stem cell transplantation
  • Mismatched family member donor transplant
  • NK cell infusions

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
One year after transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
100 days post-transplantation
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.
100 days post-transplantation
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.
100 days post-transplantation
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
Up to 5 years after transplant
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).
Up to one year after transplant
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).
Up to one year after transplant
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).
Up to one year after transplant
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).
Up to one year after transplant
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).
Up to one year after transplant
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).
Up to one year after transplant
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
Up to one year after transplant
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.
Up to 5 Years after transplant
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.
Up to 5 Years after transplant
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.
Baseline before HSCT, 1 year post HSCT, and up to 5 years post HSCT
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.
From 0-3 months after HSCT through 4-5 years after HSCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Collaborators

Assisi Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2004

Primary Completion (Actual)

March 1, 2015

Study Completion (Actual)

July 1, 2016

Study Registration Dates

First Submitted

September 1, 2005

First Submitted That Met QC Criteria

September 1, 2005

First Posted (Estimate)

September 5, 2005

Study Record Updates

Last Update Posted (Actual)

June 19, 2017

Last Update Submitted That Met QC Criteria

May 25, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INFT2
  • NCI-2011-03671 (Registry Identifier: NCI Clinical Trial Registration Program)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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