T-cell Depleted Alternative Donor Transplantation

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00968864
• Collaborator: (none)
• Enrollment: 53
• Location: 1
• Arm: 1
• Duration (Months): 87
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary purpose is to determine the ability of CD34+ selection and T cell depletion using the CliniMACS® device to prevent severe acute graft-versus-host disease (GVHD) in patients receiving a stem cell transplant from an alternative (unrelated and mismatched related) donor. The secondary objectives include evaluation of engraftment, immune recovery, and post-transplant infections.

Patients requiring stem cell transplants for either malignant (cancerous) or non-malignant disease will be included in the study. The recipients will be grouped into one of two groups based on whether the donor is mismatched related (Cohort A) or unrelated (Cohort B). The patient will receive a conditioning regimen including chemotherapy drugs and/or total body irradiation based on the disease for which the transplant is performed.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Myeloid Leukemia; Myelodysplastic Syndrome; Lymphomas; Bone Marrow Failure; Hemoglobinopathy; Immune Deficiency; Osteopetrosis	Device: CliniMACS® (T cell depletion)	Phase 2

Detailed Description

A major issue in alternative donor (mismatched related and unrelated donor transplantation is the development of graft-versus-host disease (GVHD). Several clinical trials have shown that the use of T-cell depleted peripheral blood stem cells (PBSC) reduces GVHD in alternative donor transplants. The purpose of this study is to determine the ability of CD34 positive selection and T cell depletion using the CliniMACS® Device as the only GVHD prophylaxis to prevent severe acute GVHD in recipients of an alternative donor PBSC transplant. Mismatched related donors will match at least 3 of 6 Human leukocyte antigens(HLA)(haplocompatible) and unrelated donors will match at least 6 out of 8 HLA antigens with the transplant recipient. The conditioning therapy including chemotherapy, anti-thymocyte globulin (ATG), +/- total body irradiation (TBI) will be based on the patient's diagnosis. The transplant recipient will be followed for 5 years after transplant for GVHD, engraftment, post-transplant infections, disease relapse, and overall survival. In addition, this study will serve as a platform for a companion study of therapy to accelerate immune recovery after transplant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Using the CliniMACS® Device for CD34+ Cell Selection and T Cell Depletion for Graft-versus-Host Disease Prophylaxis in Alternative Donor Stem Cell Transplant Recipients
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: CliniMACS® (T cell depletion) Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device.

Device: CliniMACS® (T cell depletion); Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.; Other Names: CliniMACS device T-cell depletion

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Severe Graft vs. Host Disease (GVHD). [Within 30 days after stem cell transplant]

   Severe GVHD defined as grade III/IV GVHD.

Secondary Outcome Measures

1. Number of Participants With Engraftment and Time to Engraftment [Within 28 days after stem cell transplant]

   Engraftment was measured as time to absolute neutrophil count >500

2. Number of Participants With Post-transplant Infections [1 year]

3. Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD) [5 years]

4. Number of Participants With Post-transplant Leukemia Relapse [5 years]

5. Number of Participants With Transplant-related Mortality [2 year]

   Transplant-related mortality includes death due to regimen-related toxicity or GVHD (all causes other than disease relapse). Those who died due to disease relapse are not included in the analyzed population for that time point.

6. Number of Participants With Transplant-related Toxicities [1 year]

7. Overall Survival [2 years]

8. Device Performance: Dose of CD34+ Cells and CD3+ Cells Given [Length of the trial (5 years)]

   For mismatched related donors, the target cell dose after processing is >/= 20 x 10^6 CD34+ cells/kg patient body weight, but >/= 8 x 10^6 is acceptable. For unrelated donors the target cell dose after processing is >/= 10 x 10^6 CD34+ cells/kg patient body weight, but >/= 4 x 10^6 is acceptable. The target T cell dose is </= 3 x 10^4 CD3+ cells/ kg.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age < 30 years

• Patient must have a malignant or non-malignant disease that can benefit from alternative stem cell transplantation. Examples include acute and chronic leukemias, myelodysplastic syndrome, lymphoma, severe acquired and congenital cytopenias, white and red blood cell abnormalities, and immunodeficiencies.

• Patients with acute lymphoblastic leukemia must be in morphological remission (< 5% blasts) at the time of transplant. Patients with acute non-lymphocytic leukemia will preferably be in morphologic remission but may be enrolled when aplastic after chemotherapy or with < 20% blasts. Patients with lymphoma must be in complete or close to complete remission (if residual adenopathy, PET scan must be negative or only have slight uptake, eg. SUV < 2).

• Patients must lack a healthy HLA-identical related donor of at least one year of age.

• Patient must have a mismatched related or an unrelated donor who is:

1. Able to receive G-CSF and undergo apheresis either through placement of catheters in antecubital veins or a temporary central venous catheter,

2. Healthy,

3. Willing,

4. For recipients of an unrelated donor transplant, recipient eligibility will be restricted as follows if in the judgment of the recipients' transplant physician, the recipient cannot receive a transplant with combined positive and negative fractions as described in Section 6.1.3.2 or an unmanipulated PBSC product.

5. Meets eligibility criteria for donors.

• If only one mismatched related relative is available, an acceptable unrelated donor must be identified as a backup.

• Patient or authorized guardian must sign informed consent for this study.

Exclusion Criteria:

• Patient with an anticipated life expectancy of < 1 month

• Active infectious hepatitis or CMV infection

• HIV or HTLV-I/II infection

• Serious infection (bacterial, fungal, viral) within the last 4 weeks

• Cardiac ejection fraction < 45%; can be lower if patient is not in clinical cardiac failure and a reduced intensity conditioning regimen is used.

• Creatinine clearance <60 ml/min/1.72 m2; can be lower if a reduced intensity conditioning regimen is used.

• Pulmonary diffusion capacity (adjusted for Hgb), FEV1, or FVC <60% of predicted or O2 sat < 94% if unable to perform PFTs; can be lower if a reduced intensity conditioning regimen is used.

• Serum ALT > 3 x upper limit of normal (can be up to 5 x upper limit of normal if a reduced intensity conditioning regimen is used) or bilirubin > 2. The bilirubin criteria for sickle cell disease patients is direct bilirubin >2x upper limit of normal.

• Performance score (Lansky/Karnofsky) < 50

• Any condition that compromises compliance with the procedures of this protocol, as judged by the principal investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Levine Children's Hospital, Carolinas Medical Center	Charlotte	North Carolina	United States	28204

Sponsors and Collaborators

• Wake Forest University Health Sciences

Investigators

• Principal Investigator: Andrew Gilman, MD, Department of Pediatrics, Levine Children's Hospital, Carolinas Healthcare System

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 30, 2015
• Informed Consent Form: Recipient Consent - Jan 30, 2015
• Informed Consent Form: Donor Consent - Mar 11, 2014

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT00968864
• Other Study ID Numbers: LCH BMT 09-01
• First Posted: Aug 31, 2009
• Last Update Posted: Apr 22, 2022
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Wake Forest University Health Sciences: T cell depleted; Matched unrelated donors; Haplocompatible donors
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Osteopetrosis; Myelodysplastic Syndromes; Hemoglobinopathies; Bone Marrow Failure Disorders; Pancytopenia; Immunologic Deficiency Syndromes

Study Results

Participant Flow

Recruitment Details	Candidates for bone marrow transplant who did not have a healthy HLA-identical related donor, at Levine Children's Hospital between December 2009 and June 2016.
Pre-assignment Detail	Subjects were enrolled to two cohorts based on donor type, Mismatched Related Donor (MMRD) and Matched Unrelated Donor (MUD).

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Period Title: Overall Study
STARTED	53
COMPLETED	52
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Overall Participants	52
Age, Customized (Count of Participants)
Less than 1 year	4 7.7%
1-2 years	3 5.8%
2-4 years	5 9.6%
4-6 years	6 11.5%
6-8 years	3 5.8%
8-10 years	4 7.7%
10-12 years	6 11.5%
12-14 years	5 9.6%
14-16 years	5 9.6%
16-18 years	8 15.4%
Greater than 18 years	3 5.8%
Sex: Female, Male (Count of Participants)
Female	25 48.1%
Male	27 51.9%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	10 19.2%
African American	26 50%
Hispanic or Latino	13 25%
Other	3 5.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Severe Graft vs. Host Disease (GVHD).
Description	Severe GVHD defined as grade III/IV GVHD.
Time Frame	Within 30 days after stem cell transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	52
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With Engraftment and Time to Engraftment
Description	Engraftment was measured as time to absolute neutrophil count >500
Time Frame	Within 28 days after stem cell transplant

Outcome Measure Data

Analysis Population Description

There were 2 cases of primary graft failure in the mismatched related donor cohort; both achieved engraftment following a second transplant.

Arm/Group Title	Mismatched Related Donor Cohort	Matched Unrelated Donor Cohort
Arm/Group Description
Measure Participants	41	9
Mean (Full Range) [days]	15	13

3. Secondary Outcome

Title	Number of Participants With Post-transplant Infections
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	52
HHV-6 reactivation, no disease	39 75%
Viral URI (adeno, paraflu, rhino, rsv)	25 48.1%
Clostridium difficile colitis	24 46.2%
Adenovirus reactivation, no disease	15 28.8%
Bacteremia, gram positive	12 23.1%
Candidiasis (not invasive)	11 21.2%
Sinusitis	11 21.2%
Bacteremia, gram negative	9 17.3%
CMV reactivation, no disease	9 17.3%
BK virus, no disease	7 13.5%
EBV-related lymphoproliferative disease	6 11.5%
BK virus, hemorrhagic cystitis	5 9.6%
Adenovirus disease	5 9.6%
Infection with normal ANC - grade 3	5 9.6%
Norovirus	5 9.6%
Positive Galactomannan	5 9.6%
Acute otitis media	4 7.7%
HSV - mouth sores	4 7.7%
EBV reactivation, no disease	4 7.7%
Pneumonia	3 5.8%
Varicella zoster	3 5.8%
Candidiasis (invasive)	2 3.8%
CMV, GI disease/ encephalitis	2 3.8%
Disseminated aspergillus	2 3.8%
Methicillin-Resistant Staph Aureus	2 3.8%
Rotavirus	2 3.8%
Nocardia	2 3.8%
Pneumonia - fungal (non-aspergillus)	1 1.9%
Influenza	1 1.9%
Parvovirus B19 (low level)	1 1.9%
Sapovirus	1 1.9%
Septic arthritis (prosthetic joint)	1 1.9%
Possible respiratory infection (rhizomucor)	1 1.9%

4. Secondary Outcome

Title	Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD)
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	52
Count of Participants [Participants]	6 11.5%

5. Secondary Outcome

Title	Number of Participants With Post-transplant Leukemia Relapse
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Of the 43 recipients in the mismatched related donor cohort, 24 of those had leukemia. No recipients in the matched unrelated donor cohort had leukemia.

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	24
Count of Participants [Participants]	5 9.6%

6. Secondary Outcome

Title	Number of Participants With Transplant-related Mortality
Description	Transplant-related mortality includes death due to regimen-related toxicity or GVHD (all causes other than disease relapse). Those who died due to disease relapse are not included in the analyzed population for that time point.
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

Those who died due to disease relapse are not included in the analyzed population for that time point.

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	52
Day 100	1 1.9%
1 year	9 17.3%
2 years	11 21.2%

7. Secondary Outcome

Title	Number of Participants With Transplant-related Toxicities
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
Measure Participants	52
Thrombotic Microangiopathy	8 15.4%
Idiopathic Pneumonia Syndrome	3 5.8%
Veno-occlusive Disease	1 1.9%

8. Secondary Outcome

Title	Overall Survival
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Subjects at least 2 years after transplant are evaluable for 2 year overall survival.

Arm/Group Title	Mismatched Related Donor Cohort: Malignant Disease	Mismatched Related Donor: Non-malignant Disease	Matched Unrelated Donor Cohort
Arm/Group Description	Number of recipients alive following bone marrow transplant for malignant disease.	Number of recipients alive following bone marrow transplant for non-malignant disease.	Number of recipients alive following bone marrow transplant for non-malignant disease.
Measure Participants	17	13	7
Count of Participants [Participants]	9 17.3%	9 NaN	6 NaN

9. Secondary Outcome

Title	Device Performance: Dose of CD34+ Cells and CD3+ Cells Given
Description	For mismatched related donors, the target cell dose after processing is >/= 20 x 10^6 CD34+ cells/kg patient body weight, but >/= 8 x 10^6 is acceptable. For unrelated donors the target cell dose after processing is >/= 10 x 10^6 CD34+ cells/kg patient body weight, but >/= 4 x 10^6 is acceptable. The target T cell dose is </= 3 x 10^4 CD3+ cells/ kg.
Time Frame	Length of the trial (5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mismatched Related Donor Cohort	Matched Unrelated Donor Cohort
Arm/Group Description
Measure Participants	43	9
x 10^6 CD34+ cells/ kg	20.26	15.16
x 10^4 CD3+ cells/ kg	0.02	0.3

Adverse Events

Time Frame	From the start of the conditioning regimen for transplant until 1 year after transplant
Arm/Group Title	T Cell Depletion Using CliniMACS®
Arm/Group Description	Recipients will receive T cell-depleted PBSC from eligible donors after receiving conditioning therapy using CliniMACS® device. CliniMACS® (T cell depletion): Stem cells will be collected from donors after they receive Granulocyte colony-stimulating factor (G-CSF). The cells will be processed using the CliniMACS device to select for CD34+ stem cells and to deplete T cells. Recipients will receive conditioning therapy that is based on their disease type and then receive the CD34+ stem cells.
All Cause Mortality
	T Cell Depletion Using CliniMACS®
	Affected / at Risk (%)	# Events
Total	15/52 (28.8%)
Serious Adverse Events
	T Cell Depletion Using CliniMACS®
	Affected / at Risk (%)	# Events
Total	45/52 (86.5%)
Blood and lymphatic system disorders
Thrombotic microangiopathy	6/52 (11.5%)
Decreasing donor chimerism	2/52 (3.8%)
Leukopenia/ Neutropenia - grade 3	1/52 (1.9%)
Graft failure	1/52 (1.9%)
Cardiac disorders
Pericardial effusion	1/52 (1.9%)
Gastrointestinal disorders
Acute gastroenteritis/ diarrhea	5/52 (9.6%)
Pneumoatosis Intestinalis	1/52 (1.9%)
Mucositis/ dehydration	1/52 (1.9%)
General disorders
Fever	32/52 (61.5%)
Infusion reaction	1/52 (1.9%)
Hypothermia	1/52 (1.9%)
Immune system disorders
Graft vs. Host disease	9/52 (17.3%)
Infections and infestations
HHV-6 Reactivation	9/52 (17.3%)
CMV reactivation	4/52 (7.7%)
EBV-related lymphoproliferative disease	4/52 (7.7%)
Pneumonia	4/52 (7.7%)
Infection w/ unknown absolute neutrophil count (ANC)	3/52 (5.8%)
Infection - grade 4	2/52 (3.8%)
Infection - eye	1/52 (1.9%)
Metabolism and nutrition disorders
Dehydration with hypernatremia	1/52 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Relapse	2/26 (7.7%)
Nervous system disorders
Seizures	2/52 (3.8%)
Renal and urinary disorders
Hemorrhagic cystitis	3/52 (5.8%)
Renal failure	1/52 (1.9%)
Renal & Urinary disorder - grade 3	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	3/52 (5.8%)
Viral upper respiratory infection	2/52 (3.8%)
Pleural effusion	1/52 (1.9%)
Pulmonary/ Upper Respiratory- other	1/52 (1.9%)
Bronchopulmonary hemorrhage	1/52 (1.9%)
Aspiration	1/52 (1.9%)
Vascular disorders
Hypertension	1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	T Cell Depletion Using CliniMACS®
	Affected / at Risk (%)	# Events
Total	33/52 (63.5%)
Blood and lymphatic system disorders
Thrombotic microangiopathy - grade 4	4/52 (7.7%)
Thrombotic microangiopathy - grade 3	4/52 (7.7%)
Investigations
Elevated ALT - grade 4	3/52 (5.8%)
Metabolism and nutrition disorders
Hypokalemia - grade 4	4/52 (7.7%)
Nervous system disorders
Seizures - grade 3	5/52 (9.6%)
Posterior Reversible Encephalopathy Syndrome	3/52 (5.8%)
Renal and urinary disorders
Renal and Urinary disorder - grade 3	4/52 (7.7%)
Renal disorder - grade 4	3/52 (5.8%)
Respiratory, thoracic and mediastinal disorders
Hypoxia - grade 3	14/52 (26.9%)
Hypoxia - grade 4	4/52 (7.7%)
Idiopathic pneumonia syndrome	3/52 (5.8%)
Skin and subcutaneous tissue disorders
Rash - grade 3	5/52 (9.6%)
Vascular disorders
Hypertension - grade 4	3/52 (5.8%)
Thrombosis - grade 3 (catheter-related)	3/52 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.