Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Bone Marrow Failure, Chronic Myeloid Leukemia, Hemoglobinopathy, Immune Deficiency, Lymphomas, Myelodysplastic Syndrome, Osteopetrosis
Conditions
Keywords
T cell depleted, Matched unrelated donors, Haplocompatible donors
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.
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.
Interventions
DEVICECliniMACS® (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.
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Number of Participants With Post-transplant Infections | 1 year | — |
| Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD) | 5 years | — |
| Number of Participants With Post-transplant Leukemia Relapse | 5 years | — |
| 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. |
| Number of Participants With Transplant-related Toxicities | 1 year | — |
| Overall Survival | 2 years | — |
| 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. |
Countries
United States
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 details
Subjects were enrolled to two cohorts based on donor type, Mismatched Related Donor (MMRD) and Matched Unrelated Donor (MUD).
Participants by arm
| Arm | Count |
|---|---|
| T Cell Depletion Using CliniMACS® 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. | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol exception/ not evaluable | 1 |
Baseline characteristics
| Characteristic | T Cell Depletion Using CliniMACS® |
|---|---|
| Age, Customized 10-12 years | 6 Participants |
| Age, Customized 12-14 years | 5 Participants |
| Age, Customized 1-2 years | 3 Participants |
| Age, Customized 14-16 years | 5 Participants |
| Age, Customized 16-18 years | 8 Participants |
| Age, Customized 2-4 years | 5 Participants |
| Age, Customized 4-6 years | 6 Participants |
| Age, Customized 6-8 years | 3 Participants |
| Age, Customized 8-10 years | 4 Participants |
| Age, Customized Greater than 18 years | 3 Participants |
| Age, Customized Less than 1 year | 4 Participants |
| Race/Ethnicity, Customized African American | 26 Participants |
| Race/Ethnicity, Customized Caucasian | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 52 |
| other Total, other adverse events | 33 / 52 |
| serious Total, serious adverse events | 45 / 52 |
Outcome results
Primary
Number of Participants With Severe Graft vs. Host Disease (GVHD).
Severe GVHD defined as grade III/IV GVHD.
Time frame: Within 30 days after stem cell transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Severe Graft vs. Host Disease (GVHD). | 0 Participants |
Secondary
Device Performance: Dose of CD34+ Cells and CD3+ Cells Given
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)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| T Cell Depletion Using CliniMACS® | Device Performance: Dose of CD34+ Cells and CD3+ Cells Given | x 10^6 CD34+ cells/ kg | 20.26 cells/ kg |
| T Cell Depletion Using CliniMACS® | Device Performance: Dose of CD34+ Cells and CD3+ Cells Given | x 10^4 CD3+ cells/ kg | 0.02 cells/ kg |
| Matched Unrelated Donor Cohort | Device Performance: Dose of CD34+ Cells and CD3+ Cells Given | x 10^6 CD34+ cells/ kg | 15.16 cells/ kg |
| Matched Unrelated Donor Cohort | Device Performance: Dose of CD34+ Cells and CD3+ Cells Given | x 10^4 CD3+ cells/ kg | 0.3 cells/ kg |
Secondary
Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD)
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With EBV-related Post Transplant Lymphoproliferative Disorder (PTLD) | 6 Participants |
Secondary
Number of Participants With Engraftment and Time to Engraftment
Engraftment was measured as time to absolute neutrophil count \>500
Time frame: Within 28 days after stem cell transplant
Population: There were 2 cases of primary graft failure in the mismatched related donor cohort; both achieved engraftment following a second transplant.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Engraftment and Time to Engraftment | 15 days |
| Matched Unrelated Donor Cohort | Number of Participants With Engraftment and Time to Engraftment | 13 days |
Secondary
Number of Participants With Post-transplant Infections
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | HHV-6 reactivation, no disease | 39 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Viral URI (adeno, paraflu, rhino, rsv) | 25 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Clostridium difficile colitis | 24 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Adenovirus reactivation, no disease | 15 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Bacteremia, gram positive | 12 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Candidiasis (not invasive) | 11 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Sinusitis | 11 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Bacteremia, gram negative | 9 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | CMV reactivation, no disease | 9 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | BK virus, no disease | 7 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | EBV-related lymphoproliferative disease | 6 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | BK virus, hemorrhagic cystitis | 5 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Adenovirus disease | 5 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Infection with normal ANC - grade 3 | 5 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Norovirus | 5 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Positive Galactomannan | 5 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Acute otitis media | 4 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | HSV - mouth sores | 4 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | EBV reactivation, no disease | 4 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Pneumonia | 3 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Varicella zoster | 3 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Candidiasis (invasive) | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | CMV, GI disease/ encephalitis | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Disseminated aspergillus | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Methicillin-Resistant Staph Aureus | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Rotavirus | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Nocardia | 2 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Pneumonia - fungal (non-aspergillus) | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Influenza | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Parvovirus B19 (low level) | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Sapovirus | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Septic arthritis (prosthetic joint) | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Infections | Possible respiratory infection (rhizomucor) | 1 Participants |
Secondary
Number of Participants With Post-transplant Leukemia Relapse
Time frame: 5 years
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Post-transplant Leukemia Relapse | 5 Participants |
Secondary
Number of Participants With Transplant-related Mortality
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
Population: Those who died due to disease relapse are not included in the analyzed population for that time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Mortality | Day 100 | 1 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Mortality | 1 year | 9 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Mortality | 2 years | 11 Participants |
Secondary
Number of Participants With Transplant-related Toxicities
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Toxicities | Thrombotic Microangiopathy | 8 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Toxicities | Idiopathic Pneumonia Syndrome | 3 Participants |
| T Cell Depletion Using CliniMACS® | Number of Participants With Transplant-related Toxicities | Veno-occlusive Disease | 1 Participants |
Secondary
Overall Survival
Time frame: 2 years
Population: Subjects at least 2 years after transplant are evaluable for 2 year overall survival.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T Cell Depletion Using CliniMACS® | Overall Survival | 9 Participants |
| Matched Unrelated Donor Cohort | Overall Survival | 9 Participants |
| Matched Unrelated Donor Cohort | Overall Survival | 6 Participants |