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

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00145626
• Collaborator: Assisi Foundation (Other)
• Enrollment: 40
• Location: 1
• Arm: 1
• Duration (Months): 146
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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

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 Design

• Study Type: Interventional
• 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 1, 2004
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

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 Thiotepa Melphalan OKT3 ; Device: Miltenyi Biotec CliniMACS; Stem cell selection device; Procedure: Allogeneic stem cell transplantation; 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

Outcome Measures

Primary Outcome Measures

1. One-year Survival [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 Outcome Measures

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 24 Months
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• St. Jude Children's Research Hospital
• Assisi Foundation

Investigators

• Principal Investigator: Brandon Triplett, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT00145626
• Other Study ID Numbers: INFT2; NCI-2011-03671
• First Posted: Sep 5, 2005
• Last Update Posted: Jun 19, 2017
• Last Verified: May 1, 2017

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by St. Jude Children's Research Hospital: Stem cell transplantation; Stem cell transplant; Haploidentical transplant
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Hematologic Neoplasms; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Histiocytosis; Cyclophosphamide; Melphalan; Thiotepa; Fludarabine; Antibodies

Study Results

Participant Flow

Recruitment Details	19 participants and 21 stem cell donors were enrolled between October 2006 and June 2011. The study was temporarily closed to accrual in June 2011 due to unavailability of study drug. The study was formally closed March 2015 because of continued unavailability of study drug. The 21 donors are excluded from this report.
Pre-assignment Detail	19 stem cell recipients were enrolled, and 5 were excluded. Two participants did not have natural killer cell infusions due to donor was unable to donate enough CD34+ cells or CD56+ cells for infusion, 1 participant became ineligible because they turned 2 years old prior to start of therapy, 1 withdrew and 1 expired.

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Period Title: Overall Study
STARTED	19
COMPLETED	14
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Alive	Expired	Total
Arm/Group Description	Group of participants who survived to at least one year post HSCT. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.	Those participants who did not survive to at least one year post HSCT. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.	Total of all reporting groups
Overall Participants	7	7	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.0 (0.34)	1.0 (0.52)	1.0 (0.42)
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	1.0	0.8	0.9
Sex: Female, Male (Count of Participants)
Female	3 42.9%	3 42.9%	6 42.9%
Male	4 57.1%	4 57.1%	8 57.1%
Race/Ethnicity, Customized (Number) [Number]
Black	2 28.6%	2 28.6%	4 28.6%
Other	1 14.3%	1 14.3%	2 14.3%
White	4 57.1%	4 57.1%	8 57.1%

Outcome Measures

1. Primary Outcome

Title	One-year Survival
Description	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.
Time Frame	One year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	14
Number [percentage of participants]	50 714.3%

2. Secondary Outcome

Title	Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality
Description	The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.
Time Frame	100 days post-transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	14
Number [participants]	3 42.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Participants
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative Incidence
	Estimated Value	0.214
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.114
	Estimation Comments	The cumulative incidence estimate and its standard error for occurrence of regimen-related mortality by the end of the first 100 days post-transplant was calculated.

3. Secondary Outcome

Title	Number of Transplant-Related Adverse Outcomes: Engraftment Failure
Description	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.
Time Frame	100 days post-transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	14
Number (95% Confidence Interval) [proportion of engraftment failures]	0.286

4. Secondary Outcome

Title	Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)
Description	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.
Time Frame	100 days post-transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	14
Number [Number of Deaths]	0

5. Secondary Outcome

Title	Number of Incidences of Chronic GVHD.
Description	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
Time Frame	Up to 5 years after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	14
Extensive chronic GVHD	0 0%
Limited chronic GVHD	1 14.3%
No chronic GHVHD	13 185.7%

6. Secondary Outcome

Title	Factors Affecting One-year Survival: Median Age of Donor at HSCT
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
Median (Full Range) [Years]	21.5	27.2	25.73

7. Secondary Outcome

Title	Factors Affecting One-year Survival: Median Dose of CD34
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
Median (Full Range) [CD34 X 10^6/kg]	35.2	38.3	37.8

8. Secondary Outcome

Title	Factors Affecting One-year Survival: Median Dose of NK Cells
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
Median (Full Range) [NKcells X 10^6/kg]	40.2	37.6	38.9

9. Secondary Outcome

Title	Factors Affecting One-year Survival: Disease Status at HSCT
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
Active Disease	0 0%	1 14.3%	1 7.1%
Complete Remission-1	6 85.7%	2 28.6%	8 57.1%
Complete Remission-2	0 0%	1 14.3%	1 7.1%
Progressive Disease	1 14.3%	0 0%	1 7.1%
Relapse	0 0%	3 42.9%	3 21.4%

10. Secondary Outcome

Title	Factors Affecting One-year Survival: Donor Type
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
Father	2 28.6%	4 57.1%	6 42.9%
Mother	5 71.4%	2 28.6%	7 50%
Uncle	0 0%	1 14.3%	1 7.1%

11. Secondary Outcome

Title	Factors Affecting One-year Survival: Match N/6 HLA Loci
Description	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).
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	Fourteen study participants were evaluable for the outcome measures. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	7	7	14
3/6 HLA Loci	6 85.7%	3 42.9%	9 64.3%
4/6 HLA Loci	1 14.3%	4 57.1%	5 35.7%

12. Secondary Outcome

Title	Factors Affecting One-year Survival: Minimal Residual Disease (MRD)
Description	Detection of leukemia blasts in bone marrow by flow cytometry
Time Frame	Up to one year after transplant

Outcome Measure Data

Analysis Population Description

Only four of the 14 participants had MRD measured at the one-year time point.

Arm/Group Title	Alive	Expired	Study Participants
Arm/Group Description	Group of participants who survived to at least one year post HSCT.	Those participants who did not survive to at least one year post HSCT.	MRD data were collected on four study participants. Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	3	1	4
Negative for MRD	2 28.6%	1 14.3%	3 21.4%
Positive for MRD	1 14.3%	0 0%	1 7.1%

13. Secondary Outcome

Title	Incidence of and Risk Factors for Organ Dysfunction.
Description	The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
Time Frame	Up to 5 Years after transplant

Outcome Measure Data

Analysis Population Description

There was not enough data available after 1 year post-transplant to evaluate long term outcomes on this study.

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	0

14. Secondary Outcome

Title	Incidence of and Risk Factors for Long-term Neurocognitive Deficit.
Description	The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
Time Frame	Up to 5 Years after transplant

Outcome Measure Data

Analysis Population Description

There was not enough data available after 1 year post-transplant to evaluate long term outcomes on this study.

Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
Measure Participants	0

15. Secondary Outcome

Title	Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation
Description	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.
Time Frame	Baseline before HSCT, 1 year post HSCT, and up to 5 years post HSCT

Outcome Measure Data

Analysis Population Description

MRD data was collected on only four participants during at least one time point.

Arm/Group Title	Study Participants: Before HSCT	Study Participants: 1 Year Post HSCT	Study Participants: 5 Years Post HSCT
Arm/Group Description	All study participants as previously described.	All study participants as previously described.	All study participants as previously described.
Measure Participants	4	4	4
Negative MRD	1 14.3%	1 14.3%	1 7.1%
Positive MRD	0 0%	0 0%	0 0%
Data Not Collected	0 0%	0 0%	0 0%
Negative MRD	0 0%	0 0%	1 7.1%
Positive MRD	0 0%	0 0%	0 0%
Data Not Collected	1 14.3%	1 14.3%	0 0%
Negative MRD	1 14.3%	0 0%	0 0%
Positive MRD	0 0%	0 0%	0 0%
Data Not Collected	0 0%	1 14.3%	1 7.1%
Negative MRD	0 0%	0 0%	0 0%
Positive MRD	1 14.3%	0 0%	0 0%
Data Not Collected	0 0%	1 14.3%	1 7.1%

16. Secondary Outcome

Title	Kinetics of Lymphohematopoietic Reconstitution
Description	The lymphohematopoietic reconstitution will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
Time Frame	From 0-3 months after HSCT through 4-5 years after HSCT

Outcome Measure Data

Analysis Population Description

Data was not available for analysis for all patients at all time points.

Arm/Group Title	0-3 Months After HSCT	3-6 Months After HSCT	6-9 Months After HSCT	9-12 Months After HSCT	1-2 Years After HSCT	2-3 Years After HSCT	3-4 Years After HSCT	4-5 Years After HSCT
Arm/Group Description	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.	Study participants as previously described.
Measure Participants	14	14	14	14	14	14	14	14
CD3 Lymphocyte	0.22	0.57	1.15	2.24	1.65	2.88	2.65	1.87
CD3 Gamma Delta	0.00	0.04	0.08	0.09	0.70	0.24	0.21	0.38
CD4 Lymphocyte	0.13	0.42	0.92	1.37	0.96	1.56	1.33	1.94
CD8 Lymphocyte	0.01	0.09	0.29	0.36	0.61	1.05	1.10	0.70
CD19 Lymphocyte	0.26	0.48	0.61	0.52	0.45	0.56	0.56	0.43
CD56 Lymphocyte	0.36	0.33	0.20	0.19	0.22	0.32	0.34	0.19
CD4/CD8 Ratio	2.60	5.53	3.36	1.90	1.88	1.38	1.30	1.30
Absolute Lymphocyte Value	0.88	1.29	1.95	2.90	2.59	3.76	3.65	2.40

Adverse Events

Time Frame	Adverse events are reported from the on-study date through April 2015 (up to one year post-transplant). All 16 patients who were enrolled and proceeded to transplant are included.
Arm/Group Title	Study Participants
Arm/Group Description	Study participants received 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 post-transplant, participants received an infusion of additional donor derived cells called natural killer (NK) cells. Stem cells were obtained from donors using the Miltenyi Biotec CliniMACS stem cell selection device.
All Cause Mortality
	Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Study Participants
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Blood and lymphatic system disorders
Graft Failure	1/16 (6.3%)	1
Graft Rejection	3/16 (18.8%)	3
Leukocytosis	1/16 (6.3%)	1
Post-Transplant Lymphoproliferative Disease	1/16 (6.3%)	1
Cardiac disorders
Cardiac Tamponade	1/16 (6.3%)	1
Gastrointestinal disorders
Colitis	1/16 (6.3%)	1
Gastrointestinal Perforation	1/16 (6.3%)	1
General disorders
Fever without Neutropenia	9/16 (56.3%)	21
Hepatobiliary disorders
Hyperbilirubinemia	1/16 (6.3%)	1
Veno-Occlusive Disease, Hepatic	1/16 (6.3%)	1
Infections and infestations
Febrile Neutropenia	1/16 (6.3%)	1
Fever Without Neutropenia	1/16 (6.3%)	1
Infection, Aspergillus, Central Nervous System	1/16 (6.3%)	1
Infection, Methicillin Resistant Staphylococcus Aureus	1/16 (6.3%)	1
Infection, RSV, Pneumonitis	1/16 (6.3%)	1
Infection, Staphylococcus Aureus, Blood	2/16 (12.5%)	2
Infection, Staphylococcus Epidermidis, Blood	1/16 (6.3%)	2
Infection, Stenotrophomonas, Blood	1/16 (6.3%)	1
Metabolism and nutrition disorders
Hypernatremia	1/16 (6.3%)	1
Nervous system disorders
Seizure	2/16 (12.5%)	3
Renal and urinary disorders
Failure, Renal	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	3/16 (18.8%)	4
Respiratory Distress	1/16 (6.3%)	1
Vascular disorders
Hemorrhage, Brain	1/16 (6.3%)	1
Engraftment Syndrome	2/16 (12.5%)	2
Other (Not Including Serious) Adverse Events
	Study Participants
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Eosinophilia	1/16 (6.3%)	1
Coagulopathy	1/16 (6.3%)	1
Coagulopathy, Elevated Bleeding Times	1/16 (6.3%)	1
Splenic Infarction	1/16 (6.3%)	1
Cardiac disorders
Prolonged QTc	1/16 (6.3%)	1
Heart block (incomplete right bundle branch block)	1/16 (6.3%)	1
Tachycardia	2/16 (12.5%)	2
Edema of hand	1/16 (6.3%)	1
Edema, Anasarca	3/16 (18.8%)	3
Edema, Facial	1/16 (6.3%)	1
Edema, Feet	1/16 (6.3%)	1
Edema, Generalized	1/16 (6.3%)	1
Edema, Lower Extremity	1/16 (6.3%)	1
Hypertension	3/16 (18.8%)	3
Hypotension	3/16 (18.8%)	3
Murmur	1/16 (6.3%)	1
Pulmonary Edema	1/16 (6.3%)	1
Eye disorders
Exposure Keratitis	1/16 (6.3%)	1
Glaucoma, Right Eye	1/16 (6.3%)	1
Hyphema, Right Eye	1/16 (6.3%)	1
Gastrointestinal disorders
Colitis	1/16 (6.3%)	1
Diarrhea	3/16 (18.8%)	4
Hemorrhage, Gastrointestinal, Oral	1/16 (6.3%)	1
Loss of Appetite	3/16 (18.8%)	3
Mucositis	2/16 (12.5%)	2
Nausea	2/16 (12.5%)	2
Stomatitis	1/16 (6.3%)	1
Vomiting	2/16 (12.5%)	2
General disorders
Fever Without Neutrophenia	6/16 (37.5%)	8
Weight Loss	1/16 (6.3%)	1
Pain, Abdominal	1/16 (6.3%)	1
Pain, Generalized, Multiple Sites	1/16 (6.3%)	1
Pain, Gums	1/16 (6.3%)	1
Pain, Throat	1/16 (6.3%)	1
Cytokine Release Syndrome, Rituximab	1/16 (6.3%)	1
Hepatobiliary disorders
Failure, Hepatic	1/16 (6.3%)	1
Hepatomegaly	3/16 (18.8%)	3
Hypoalbuminemia	1/16 (6.3%)	1
Splenomegaly	1/16 (6.3%)	1
Veno-Occlusive Disease, Hepatic	2/16 (12.5%)	2
Immune system disorders
Allergic Drug Reaction, Defibrotide	2/16 (12.5%)	2
Allergic Drug Reaction, OKT3	3/16 (18.8%)	3
Allergic Drug Reaction, Thiotepa	1/16 (6.3%)	1
Allergic Reaction, Pure Red Blood Cells	1/16 (6.3%)	1
Allergic Reaction, Platelet Transfusion	1/16 (6.3%)	1
Rash, Generalized	1/16 (6.3%)	1
Infections and infestations
Febrile Neutropenia	10/16 (62.5%)	12
Fever Without Neutropenia	1/16 (6.3%)	1
Infection With Neutropenia, Klebsiella and Escherichia Coli, Blood	1/16 (6.3%)	1
Infection Without Neutropenia, Enterococcus Faecalis, Blood	2/16 (12.5%)	2
Infection With Neutropenia, Gamma Hemolytic Streptococcus, Skin	1/16 (6.3%)	1
Infection, Adenovirus, Stool	1/16 (6.3%)	1
Infection, Aspergillus Terreus, Lungs	1/16 (6.3%)	1
Infection, Aspergillus, Retina	1/16 (6.3%)	1
Infection, Candida, Diaper Area with Rash	1/16 (6.3%)	1
Infection, Candidiasis, Mouth	1/16 (6.3%)	1
Infection, Coagulase Negative Staph, Blood	2/16 (12.5%)	2
Infection, Coagulase Negative Staphylococcus, Wrist	1/16 (6.3%)	1
Infection, Influenza Virus A	1/16 (6.3%)	1
Infection, Klebsiella Pneumoniae, Hickman Line	1/16 (6.3%)	1
Infection, Legionella, Mucous	1/16 (6.3%)	1
Infection, Pantoea Species, Blood	1/16 (6.3%)	1
Infection, Parainfluenza Virus 3	1/16 (6.3%)	1
Infection, Pseudomonas Aeruginosa, Blood	1/16 (6.3%)	1
Infection, Staphylococcus Aureus, Skin	1/16 (6.3%)	1
Infection, Stomatococcus Mucilaginosus, Blood	1/16 (6.3%)	1
Infection, Stool, Vancomycin Resistant Enterococci	1/16 (6.3%)	1
Infection, Streptococcus Mitis, Hickman Line	1/16 (6.3%)	1
Metabolism and nutrition disorders
Hypernatremia	1/16 (6.3%)	1
Hyperuricemia	1/16 (6.3%)	1
Hypophosphatemia	1/16 (6.3%)	1
Nervous system disorders
Meningoencephalitis	1/16 (6.3%)	1
Mood Alteration - Anxiety/Agitation	1/16 (6.3%)	1
Renal and urinary disorders
Renal Disease	1/16 (6.3%)	1
Renal Failure	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/16 (6.3%)	1
Cough	2/16 (12.5%)	2
Hemorrhage, Pulmonary	1/16 (6.3%)	1
Interstitial Lung Disease	1/16 (6.3%)	1
Nodule, Pulmonary	1/16 (6.3%)	1
Pulmonary Airspace Disease, Diffuse, Bilateral	1/16 (6.3%)	1
Respiratory Distress	1/16 (6.3%)	1
Respiratory Failure	1/16 (6.3%)	1
Tachypnea	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Abscess, Longissimus Colli, left	1/16 (6.3%)	1
Erythema, Face	1/16 (6.3%)	1
Erythema, Genitourinary	1/16 (6.3%)	1
Erythema, Labia, Perianal Region	1/16 (6.3%)	1
Erythema, Neck	1/16 (6.3%)	1
Erythema, Perianal	2/16 (12.5%)	2
Hyperpigmentation, Peri-Rectal	1/16 (6.3%)	1
Petechiae, Eyes	1/16 (6.3%)	1
Rash	2/16 (12.5%)	2
Rash, Diaper	1/16 (6.3%)	1
Rash, Face	1/16 (6.3%)	1
Rash, Generalized	1/16 (6.3%)	1
Rash, Labia	1/16 (6.3%)	1
Rash, Lower Left Leg	1/16 (6.3%)	1
Rash, Palms and Feet	1/16 (6.3%)	1
Rash, Perineum	1/16 (6.3%)	1
Rash, Scaly, Non-Erythematous	1/16 (6.3%)	1
Rash, Thorax	1/16 (6.3%)	1
Skin Lesion	1/16 (6.3%)	1
Toxic Epidermal Necrolysis	1/16 (6.3%)	1
Vascular disorders
Bilateral Subdural hematomas	1/16 (6.3%)	1
Epistaxis	2/16 (12.5%)	2
Gastrointestinal Hemorrhage	1/16 (6.3%)	1
Hematemesis	2/16 (12.5%)	2
Hematoma, Scalp	1/16 (6.3%)	1
Hematuria	1/16 (6.3%)	1
Hemorrhage, Biopsy Site	1/16 (6.3%)	1
Hemorrhage, Secretions from Endotracheal Tube, Respiratory Tract	1/16 (6.3%)	1
Hemorrhage, Vasocath Site	1/16 (6.3%)	1
Petechiae, Lower Extremity	1/16 (6.3%)	1
Capillary Leak Syndrome	1/16 (6.3%)	1
Engraftment Syndrome	2/16 (12.5%)	2
Abdominal Compartment Syndrome	1/16 (6.3%)	1
Systemic Inflammatory Response Syndrome	1/16 (6.3%)	1

Limitations/Caveats

The study was limited due to the unavailability of the study drug OKT3 beginning in June 2011. The study was temporarily closed to accrual. Because OKT3 is still unavailable, the study was formally closed to accrual in March 2015.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.