Back to resultsA Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202) (TransIT)
Primary Purpose
Severe Aplastic Anemia
Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
cyclosporine
Matched Unrelated Donor Hematopoetic Stem Cell Transplant
horse anti-thymocyte globulin (ATG)
rabbit anti-thymocyte globulin (ATG)
Methotrexate
Fludarabine
Cyclophosphamide
low-dose total body irradiation (TBI)
Immunosuppressive Therapy (IST)
Sponsored by
About this trial
This is an interventional treatment trial for Severe Aplastic Anemia
Eligibility Criteria
Inclusion Criteria: To be eligible to participate in the randomized trial, an individual must meet all the following criteria: Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian. Age ≤25 years old at time of randomized trial consent. Confirmed diagnosis of idiopathic SAA, defined as: Bone marrow cellularity <25%, or <30% hematopoietic cells. Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L, platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing). At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution). In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST. Exclusion Criteria: Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children <3). Other testing per center may be performed to exclude IBMFS. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination. Known severe allergy to ATG. Prior allogeneic or autologous stem cell transplant. Prior solid organ transplant. Infection with human immunodeficiency virus (HIV). Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs). Female patients who are pregnant or breast-feeding. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable
Sites / Locations
- University of Alabama at BirminghamRecruiting
- Phoenix Children's HospitalRecruiting
- Children's Hospital Los AngelesRecruiting
- UCLARecruiting
- Children's Hospital & Research Center OaklandRecruiting
- Rady Children's Hospital San DiegoRecruiting
- University of California San FranciscoRecruiting
- Children's Hospital ColoradoRecruiting
- Nemours Children's Hospital, DelawareRecruiting
- University of FloridaRecruiting
- Nicklaus Children's HospitalRecruiting
- Ann & Robert H. Lurie Children's Hospital of ChicagoRecruiting
- University of ChicagoRecruiting
- Indiana University Hospital/Riley Hospital for ChildrenRecruiting
- Children's Hospital NOLARecruiting
- Boston Children's HospitalRecruiting
- Helen DeVos Children's HospitalRecruiting
- University of Mississippi Medical CenterRecruiting
- Washington University in St. LouisRecruiting
- Hackensack University Medical CenterRecruiting
- Roswell Park Comprehensive Cancer CenterRecruiting
- Cohen Children's Medical Center of New YorkRecruiting
- Columbia University Medical CenterRecruiting
- Nationwide Children's HospitalRecruiting
- Oregon Health & Science UniversityRecruiting
- Children's Hospital of PhiladelphiaRecruiting
- St. Jude Children's Research HospitalRecruiting
- Vanderbilt University Medical CenterRecruiting
- Children's Medical Center DallasRecruiting
- University of Utah/Primary Children's HospitalRecruiting
- Fred Hutchinson Cancer CenterRecruiting
- University of Wisconsin Hospital and ClinicsRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
Immunosuppressive Therapy
Matched Unrelated Stem Cell Transplant
Arm Description
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.
Outcomes
Primary Outcome Measures
The primary endpoint of this trial is time from randomization to treatment failure or death from any cause.
The median time to failure or death will be compared on the two arms using the log-rank test. Failure of IST is defined as the date that a second definitive therapy was recommended (BMT, second course of ATG) and failure of BMT defined as the date that a second definitive therapy was recommended (second BMT, course of ATG).
Secondary Outcome Measures
Comparison of subjects with failure of IST or BMT before or at 2 years
The proportion of subjects with failure of IST or BMT before or at 2 years. Failure of IST is defined as initiation of a second definitive therapy (BMT, second course of ATG) and failure of BMT defined as initiation of a second definitive therapy (second BMT, course of ATG).
Comparison of subjects with inadequate counts at 2 years among those who have not died or failed treatment.
The proportion of subjects with inadequate counts at 2 years among those who have not failed therapy or died. Adequate counts are defined as: Absolute Neutrophil Count (ANC) >1 x 10^9/L, Hemoglobin >10g/dL, and Platelets >50 x10^9/L.
Comparison of subjects on immune suppression therapy at 2 years among those who have not died or failed treatment.
The proportion of subjects on immune suppression therapy at 2 years among those who have not failed therapy or died. Immune suppression is defined as systemic therapies necessary to treat SAA or GVHD (cyclosporine, tacrolimus, etc.). Isolated treatment with topical agents will not be considered as immune suppression therapy.
Estimate the time from randomization to initiation of IST or BMT.
The median time in days from randomization to initiation of IST or BMT will be estimated. Initiation of therapy is first day of ATG for IST subjects, or day 0 (infusion day) for bone marrow transplant subjects.
Comparison of the frequency of failure to receive primary assigned therapy (IST or BMT) and reasons for the failure.
The proportion of subjects who fail to receive randomized therapy and the frequency of reasons for failure.
Comparison of the incidence of bacteremia, viremia, and invasive fungal infection in the first two years after randomization in the IST and BMT arms.
Proportion of subjects from the time of randomization in the first 2 years with each of the following:
Documented bacteremia
Documented viremia
Documented invasive fungal infection (defined as confirmed or suspected fungal infection based upon imaging)
Estimate the median time to T- and B-cell immune reconstitution the first year for the URD BMT Arm
Absolute CD3, CD4, CD8, CD19, and CD56 (NK cell) numbers will be tracked at 100 days, 180 days, 1 year and 2 years post initiation of therapy in URT BMT arm. IgG levels free of IVIG replacement will be collected at the same timepoints. The median time to T- and B-cell reconstitution will be estimated.
Comparison of overall survival at 1 and 2 years from randomization in both arms.
Proportion of subjects who have died at 1 year and 2 years after randomization for any reason.
Comparison of treatment-related mortality (TRM) at 1 and 2 years from randomization in both arms.
Proportion of subjects who have died at 1 year and 2 years after randomization due to treatment-related reasons. TRM is defined as death in recipients without relapse or progression of their disease. Non-medical, accidental causes of death, e.g., natural disasters, are not considered TRM.
Comparison of the median time from randomization to and rates of neutrophil recovery on both arms
The time from randomization to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date).
Comparison of the median time from randomization to and rate of platelet recovery on both arms
The time from randomization to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week.
Comparison of the median time from randomization to and rates of red blood cell recovery on both arms
The time from randomization to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks.
Comparison of the median time from initiation of therapy to and rates of neutrophil recovery on both arms
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date).
Comparison of the median time from initiation of therapy to and rate of platelet recovery on both arms
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week.
Comparison of the median time from initiation of therapy to and rates of red blood cell recovery on both arms.
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks.
Estimate the rates of engraftment in patients who are randomized to URD BMT.
Proportion of subjects with engraftment in patients who receive URD BMT.
Estimate the rates of primary graft failure in patients who are randomized to URD BMT .
Proportion of subjects with primary graft failure in patients who receive URD BMT. Primary graft failure is defined as failure to achieve neutrophil recovery by Day +28 following a conditioning regimen induced neutrophil nadir < 0.5 x10^9/L.
Estimate the rates of secondary graft failure in patients who are randomized to URD BMT .
Proportion of subjects with secondary graft failure in patients who receive URD BMT. Secondary graft failure will be defined as a fall in the neutrophil count after documented primary engraftment to < 0.5 x10^9/L sustained for more than three days that cannot be attributed to other causes such as drugs, infection, GVHD, etc., and is not responsive to G-CSF or GM-CSF.
Estimate the rates of grade II-IV acute GVHD in patients who are randomized to URD BMT .
Proportion of subjects with grade II-IV in patients who receive URD BMT.
Estimate the rates of grade III-IV acute GVHD in patients who are randomized to URD BMT.
Proportion of subjects with grade III-IV acute GVHD in patients who receive URD BMT.
Estimate the rates of severe chronic GVHD in patients who are randomized to URD BMT.
Proportion of subjects with severe chronic GVHD in patients who receive URD BMT.
Estimate the rates of response of patients randomized to IST
Proportion of subjects with IST response. IST response criteria is:
Complete Response: Hemoglobin ≥10 g/dL and ANC ≥1x10^9/L and Platelets ≥100x10^9/L Very Good Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥50x10^9/L Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥20x10^9/L and transfusion independent No Response (failure): Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L Lost Response: A lost response is captured by not meeting hematologic response criteria at a particular time point after having an initial response (complete, very good partial, or partial), or the need for additional treatment.
Estimate the rates of failure of patients randomized to IST
Proportion of subjects with IST failure at 6 months (defined as Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L).
Describe the secondary therapies given and outcomes achieved for patients failing initial therapy
Collect secondary therapies given for failure of primary randomized therapy (BMT after IST, second course of IST, second BMT). For the outcome after subsequent therapy, the median survival time will be estimated.
Comparison of rates of secondary MDS, AML, other subsequent neoplasms, and development of Paroxysmal Nocturnal Hemoglobinuria in both treatment arms for the duration of the trial.
Proportion of subjects in each treatment arm with i) subsequent neoplasms, ii) presence of a PNH clone at time of randomization who go on to develop symptomatic PNH through the duration of the protocol.
Comparison of HR-QoL score between patients randomized to both arms
Change in score between baseline and two years and the trajectory of change over all timepoints.
Comparison of gonadal function values between patients randomized to both arms
Proportion of subjects with gonadal function values outside the expected percentile for that age.
Full Information
NCT ID
NCT05600426
First Posted
October 20, 2022
Last Updated
October 10, 2023
Sponsor
Boston Children's Hospital
Collaborators
Center for International Blood and Marrow Transplant Research, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), North American Pediatric Aplastic Anemia Consortium, Pediatric Transplantation and Cellular Therapy Consortium, Blood and Marrow Transplant Clinical Trials Network
1. Study Identification
Unique Protocol Identification Number
NCT05600426
Brief Title
A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
Acronym
TransIT
Official Title
A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation With Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 25, 2023 (Actual)
Primary Completion Date
December 2029 (Anticipated)
Study Completion Date
December 2029 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston Children's Hospital
Collaborators
Center for International Blood and Marrow Transplant Research, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), North American Pediatric Aplastic Anemia Consortium, Pediatric Transplantation and Cellular Therapy Consortium, Blood and Marrow Transplant Clinical Trials Network
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Severe Aplastic Anemia (SAA) is a rare condition in which the body stops producing enough new blood cells. SAA can be cured with immune suppressive therapy or a bone marrow transplant. Regular treatment for patients with aplastic anemia who have a matched sibling (brother or sister), or family donor is a bone marrow transplant. Patients without a matched family donor normally are treated with immune suppressive therapy (IST). Match unrelated donor (URD) bone marrow transplant (BMT) is used as a secondary treatment in patients who did not get better with IST, had their disease come back, or a new worse disease replaced it (like leukemia).
This trial will compare time from randomization to failure of treatment or death from any cause of IST versus URD BMT when used as initial therapy to treat SAA.
The trial will also assess whether health-related quality of life and early markers of fertility differ between those randomized to URD BMT or IST, as well as assess the presence of marrow failure-related genes and presence of gene mutations associated with MDS or leukemia and the change in gene signatures after treatment in both study arms.
This study treatment does not include any investigational drugs. The medicines and procedures in this study are standard for treatment of SAA.
Detailed Description
This study is a multi-center randomized phase III trial to compare the failure free survival between those randomized to IST vs 9-10/10 HLA matched URD BMT. The study will also address patient-reported outcomes and gonadal function in each arm and explore critical biological correlates including assessing germline genetic mutations associated with pediatric SAA that may lead to a predisposition to the disease and the risk of development of clonal hematopoiesis following IST vs BMT in pediatric and young adult SAA.
This clinical trial will randomize 234 children/AYA over 3.3-4.7 years at a 1:1 ratio between initial treatment with immune suppression therapy (IST) with horse ATG (hATG)/cyclosporine (CsA) versus well- matched (9-10/10 allele) unrelated donor (URD) bone marrow transplantation (BMT) using a regimen of rabbit ATG (rATG)/fludarabine/cyclophosphamide and 200 cGy TBI. Duration of subject participation for all study procedures in this study will be up to 2 years after treatment; a single later timepoint between 3 and 5 years will be collected to follow patients for specific protocol defined late effects and survival.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Unblinded, stratified, multi-center, phase 3, randomized controlled trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
234 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Immunosuppressive Therapy
Arm Type
Active Comparator
Arm Description
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
Arm Title
Matched Unrelated Stem Cell Transplant
Arm Type
Active Comparator
Arm Description
Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Intervention Description
cyclosporine
Intervention Type
Procedure
Intervention Name(s)
Matched Unrelated Donor Hematopoetic Stem Cell Transplant
Intervention Description
Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation (HSCT)
Intervention Type
Drug
Intervention Name(s)
horse anti-thymocyte globulin (ATG)
Other Intervention Name(s)
ATGAM
Intervention Description
horse anti-thymocyte globulin (ATG)
Intervention Type
Drug
Intervention Name(s)
rabbit anti-thymocyte globulin (ATG)
Other Intervention Name(s)
thymoglobulin
Intervention Description
rabbit anti-thymocyte globulin (ATG)
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
methotrexate
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
fludarabine
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
cyclophosphamide
Intervention Type
Radiation
Intervention Name(s)
low-dose total body irradiation (TBI)
Intervention Description
low-dose total body irradiation (TBI)
Intervention Type
Procedure
Intervention Name(s)
Immunosuppressive Therapy (IST)
Intervention Description
Immunosuppressive Therapy (IST)
Primary Outcome Measure Information:
Title
The primary endpoint of this trial is time from randomization to treatment failure or death from any cause.
Description
The median time to failure or death will be compared on the two arms using the log-rank test. Failure of IST is defined as the date that a second definitive therapy was recommended (BMT, second course of ATG) and failure of BMT defined as the date that a second definitive therapy was recommended (second BMT, course of ATG).
Time Frame
Randomization to 2 years post-randomization
Secondary Outcome Measure Information:
Title
Comparison of subjects with failure of IST or BMT before or at 2 years
Description
The proportion of subjects with failure of IST or BMT before or at 2 years. Failure of IST is defined as initiation of a second definitive therapy (BMT, second course of ATG) and failure of BMT defined as initiation of a second definitive therapy (second BMT, course of ATG).
Time Frame
Randomization to 2 years post-randomization
Title
Comparison of subjects with inadequate counts at 2 years among those who have not died or failed treatment.
Description
The proportion of subjects with inadequate counts at 2 years among those who have not failed therapy or died. Adequate counts are defined as: Absolute Neutrophil Count (ANC) >1 x 10^9/L, Hemoglobin >10g/dL, and Platelets >50 x10^9/L.
Time Frame
Randomization to 2 years post-randomization
Title
Comparison of subjects on immune suppression therapy at 2 years among those who have not died or failed treatment.
Description
The proportion of subjects on immune suppression therapy at 2 years among those who have not failed therapy or died. Immune suppression is defined as systemic therapies necessary to treat SAA or GVHD (cyclosporine, tacrolimus, etc.). Isolated treatment with topical agents will not be considered as immune suppression therapy.
Time Frame
Randomization to 2 years post-randomization
Title
Estimate the time from randomization to initiation of IST or BMT.
Description
The median time in days from randomization to initiation of IST or BMT will be estimated. Initiation of therapy is first day of ATG for IST subjects, or day 0 (infusion day) for bone marrow transplant subjects.
Time Frame
Randomization through Day 100
Title
Comparison of the frequency of failure to receive primary assigned therapy (IST or BMT) and reasons for the failure.
Description
The proportion of subjects who fail to receive randomized therapy and the frequency of reasons for failure.
Time Frame
Randomization through Day 100
Title
Comparison of the incidence of bacteremia, viremia, and invasive fungal infection in the first two years after randomization in the IST and BMT arms.
Description
Proportion of subjects from the time of randomization in the first 2 years with each of the following:
Documented bacteremia
Documented viremia
Documented invasive fungal infection (defined as confirmed or suspected fungal infection based upon imaging)
Time Frame
Randomization through two years post randomization
Title
Estimate the median time to T- and B-cell immune reconstitution the first year for the URD BMT Arm
Description
Absolute CD3, CD4, CD8, CD19, and CD56 (NK cell) numbers will be tracked at 100 days, 180 days, 1 year and 2 years post initiation of therapy in URT BMT arm. IgG levels free of IVIG replacement will be collected at the same timepoints. The median time to T- and B-cell reconstitution will be estimated.
Time Frame
Initiation of therapy (Day 0) to 100 days, 180 days, 1 year and 2 years
Title
Comparison of overall survival at 1 and 2 years from randomization in both arms.
Description
Proportion of subjects who have died at 1 year and 2 years after randomization for any reason.
Time Frame
Randomization to one year, randomization to two years
Title
Comparison of treatment-related mortality (TRM) at 1 and 2 years from randomization in both arms.
Description
Proportion of subjects who have died at 1 year and 2 years after randomization due to treatment-related reasons. TRM is defined as death in recipients without relapse or progression of their disease. Non-medical, accidental causes of death, e.g., natural disasters, are not considered TRM.
Time Frame
Randomization to 1 year, randomization to 2 years
Title
Comparison of the median time from randomization to and rates of neutrophil recovery on both arms
Description
The time from randomization to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date).
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Comparison of the median time from randomization to and rate of platelet recovery on both arms
Description
The time from randomization to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week.
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Comparison of the median time from randomization to and rates of red blood cell recovery on both arms
Description
The time from randomization to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks.
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Comparison of the median time from initiation of therapy to and rates of neutrophil recovery on both arms
Description
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to neutrophil recovery. Neutrophil recovery is defined as ANC 0.5 x109/L for 3 consecutive measures for neutrophils (recovery date is the first date).
Time Frame
Initiation of therapy to 100 days, 180 days, 1 year and 2 years
Title
Comparison of the median time from initiation of therapy to and rate of platelet recovery on both arms
Description
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to platelet recovery. Platelet recovery is defined as platelet levels >= 20 x10^9/L for 3 consecutive measures (recovery is the first date) with no platelet transfusions for 1 full week.
Time Frame
Initiation of therapy to 100 days, 180 days, 1 year and 2 years
Title
Comparison of the median time from initiation of therapy to and rates of red blood cell recovery on both arms.
Description
The time from initiation of therapy (defined as Day 1 for patients randomized to IST and Day 0 for patients randomized to URD BMT) to red blood cell recovery. Red blood cell recovery is defined as RBC hemoglobin level >= 8g/dL and 10g/dL with no RBC transfusions for 4 weeks.
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Estimate the rates of engraftment in patients who are randomized to URD BMT.
Description
Proportion of subjects with engraftment in patients who receive URD BMT.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of primary graft failure in patients who are randomized to URD BMT .
Description
Proportion of subjects with primary graft failure in patients who receive URD BMT. Primary graft failure is defined as failure to achieve neutrophil recovery by Day +28 following a conditioning regimen induced neutrophil nadir < 0.5 x10^9/L.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of secondary graft failure in patients who are randomized to URD BMT .
Description
Proportion of subjects with secondary graft failure in patients who receive URD BMT. Secondary graft failure will be defined as a fall in the neutrophil count after documented primary engraftment to < 0.5 x10^9/L sustained for more than three days that cannot be attributed to other causes such as drugs, infection, GVHD, etc., and is not responsive to G-CSF or GM-CSF.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of grade II-IV acute GVHD in patients who are randomized to URD BMT .
Description
Proportion of subjects with grade II-IV in patients who receive URD BMT.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of grade III-IV acute GVHD in patients who are randomized to URD BMT.
Description
Proportion of subjects with grade III-IV acute GVHD in patients who receive URD BMT.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of severe chronic GVHD in patients who are randomized to URD BMT.
Description
Proportion of subjects with severe chronic GVHD in patients who receive URD BMT.
Time Frame
Randomization to 3-5 years
Title
Estimate the rates of response of patients randomized to IST
Description
Proportion of subjects with IST response. IST response criteria is:
Complete Response: Hemoglobin ≥10 g/dL and ANC ≥1x10^9/L and Platelets ≥100x10^9/L Very Good Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥50x10^9/L Partial Response: Hemoglobin ≥8 g/dL and ANC ≥0.5x10^9/L and Platelets ≥20x10^9/L and transfusion independent No Response (failure): Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L Lost Response: A lost response is captured by not meeting hematologic response criteria at a particular time point after having an initial response (complete, very good partial, or partial), or the need for additional treatment.
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Estimate the rates of failure of patients randomized to IST
Description
Proportion of subjects with IST failure at 6 months (defined as Hemoglobin <8 g/dL or ANC <0.5x10^9/L or Platelets <20x10^9/L).
Time Frame
Randomization to 100 days, 180 days, 1 year and 2 years
Title
Describe the secondary therapies given and outcomes achieved for patients failing initial therapy
Description
Collect secondary therapies given for failure of primary randomized therapy (BMT after IST, second course of IST, second BMT). For the outcome after subsequent therapy, the median survival time will be estimated.
Time Frame
Randomization to 3-5 years
Title
Comparison of rates of secondary MDS, AML, other subsequent neoplasms, and development of Paroxysmal Nocturnal Hemoglobinuria in both treatment arms for the duration of the trial.
Description
Proportion of subjects in each treatment arm with i) subsequent neoplasms, ii) presence of a PNH clone at time of randomization who go on to develop symptomatic PNH through the duration of the protocol.
Time Frame
Randomization to 3-5 years
Title
Comparison of HR-QoL score between patients randomized to both arms
Description
Change in score between baseline and two years and the trajectory of change over all timepoints.
Time Frame
Randomization to 2 years post-randomization, randomization to up to 5 years post-randomization
Title
Comparison of gonadal function values between patients randomized to both arms
Description
Proportion of subjects with gonadal function values outside the expected percentile for that age.
Time Frame
Randomization to 1 year post-randomization, randomization to 2 years post-randomization, and randomization to up to 5 years post-randomization
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
To be eligible to participate in the randomized trial, an individual must meet all the following criteria:
Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian.
Age ≤25 years old at time of randomized trial consent.
Confirmed diagnosis of idiopathic SAA, defined as:
Bone marrow cellularity <25%, or <30% hematopoietic cells.
Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L, platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL.
No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing).
At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution).
In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST.
Exclusion Criteria:
Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children <3). Other testing per center may be performed to exclude IBMFS.
Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination.
Known severe allergy to ATG.
Prior allogeneic or autologous stem cell transplant.
Prior solid organ transplant.
Infection with human immunodeficiency virus (HIV).
Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs).
Female patients who are pregnant or breast-feeding.
Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.
Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Leah Cheng, MA
Phone
857-218-4731
Email
leah.cheng@childrens.harvard.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kristi Wilmes, MS
Phone
(763) 406-3416
Email
kwilmes@NMDP.ORG
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Williams, MD
Organizational Affiliation
Boston Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Michael Pulsipher, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bronwen Shaw, MD
Organizational Affiliation
CIBMTR/Medical College of Wisconsin (MCW)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35249
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chibuzo Ilonze, MD
Email
cilonze@uabmc.edu
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Holly Miller, DO
Email
hmiller2@phoenixchildrens.com
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paibel Aguayo-Hiraldo, MD
Email
paguayohiraldo@chla.usc.edu
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Theodore B Moore, MD
Email
TBMoore@mednet.ucla.edu
Facility Name
Children's Hospital & Research Center Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nahal Lalefar, MD
Email
Nahal.Lalefar@ucsf.edu
Facility Name
Rady Children's Hospital San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicholas Gloude, MD
Email
ngloude@rchsd.org
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristin Shimano, MD
Email
Kristin.Shimano@ucsf.edu
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Taizo Nakano, MD
Email
Taizo.Nakano@childrenscolorado.org
Facility Name
Nemours Children's Hospital, Delaware
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emi Caywood, MD
Email
Emi.Caywood@nemours.org
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jordan Milner, MD
Email
jordan.milner@peds.ufl.edu
Facility Name
Nicklaus Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jorge Galvez Silva, MD
Email
JorgeRicardo.GalvezSilva@Nicklaushealth.org
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sonali Chaudhury, MD
Email
SChaudhury@luriechildrens.org
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James LaBelle, MD
Email
jlabelle@bsd.uchicago.edu
Facility Name
Indiana University Hospital/Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kathleen Overholt, MD
Email
koverho@iu.edu
Facility Name
Children's Hospital NOLA
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70118
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lolie Yu, MD
Email
lyu@lsuhsc.edu
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Akiko Shimamura, MD, PhD
Phone
617-355-8246
Email
akiko.shimamura@childrens.harvard.edu
First Name & Middle Initial & Last Name & Degree
Leah Cheng
Phone
857-218-4731
Email
leah.cheng@childrens.harvard.edu
Facility Name
Helen DeVos Children's Hospital
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Troy Quigg, DO
Email
troy.quigg@corewellhealth.org
Facility Name
University of Mississippi Medical Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dereck B Davis, MD
Email
ddavis7@umc.edu
Facility Name
Washington University in St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shalini Shenoy, MD
Email
shalinishenoy@wustl.edu
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alfred Gillio, MD
Email
alfred.gillio@hmhn.org
Facility Name
Roswell Park Comprehensive Cancer Center
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nataliya Buxbaum, MD
Email
nataliya.buxbaum@roswellpark.org
Facility Name
Cohen Children's Medical Center of New York
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jonathan Fish, MD
Email
jfish1@northwell.edu
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Monica Bhatia, MD
Email
mb2476@cumc.columbia.edu
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rajinder Bajwa, MD
Email
Rajinder.Bajwa@nationwidechildrens.org
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Evan Shereck, MD, MEd
Email
shereck@ohsu.edu
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Timothy Olson, MD, PhD
Email
olsont@email.chop.edu
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marcin Wlodarski, MD, PhD
Email
Marcin.Wlodarski@stjude.org
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James Connelly, MD
Email
james.a.connelly@vumc.org
Facility Name
Children's Medical Center Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tiffany Simms-Waldrip, MD
Email
tiffany.simms-waldrip@utsouthwestern.edu
Facility Name
University of Utah/Primary Children's Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ahmad Rayes, MD
Phone
801-662-4700
Email
ahmad.rayes@hsc.utah.edu
Facility Name
Fred Hutchinson Cancer Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Madhavi Lakkaraja, MD
Email
mlakkara@fredhutch.org
Facility Name
University of Wisconsin Hospital and Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kenneth DeSantes, MD
Email
kbdesantes@pediatrics.wisc.edu
12. IPD Sharing Statement
Learn more about this trial
A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)
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