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Optimizing Haploidentical Aplastic Anemia Transplantation (BMT CTN 1502) (CHAMP)

Primary Purpose

Severe Aplastic Anemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Antithymocyte Globulin (ATG)
Fludarabine
Cyclophosphamide
Total Body Irradiation (TBI)
Haplo HSCT
Tacrolimus
Mycophenolate mofetil (MMF)
G-CSF
Sponsored by
Medical College of Wisconsin
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Haploidentical Bone Marrow, Hematopoietic Stem Cell Transplant (HSCT), Severe Aplastic Anemia (SAA), Antithymocyte Globulin (ATG)

Eligibility Criteria

undefined - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patient is < 75 years of age at time of enrollment.
  2. Confirmed diagnosis of SAA, either from initial diagnosis or follow-up assessments, defined as:

    1. Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% residual hematopoietic cells.
    2. Two out of three of the following (in peripheral blood): Neutrophils < 0.5 x10^9/L, Platelets < 20 x10^9/L, or Reticulocyte count < 20 x10^9/L (<60 x 10^9/L using an automated analysis)
  3. No suitable fully matched related sibling donor (6/6 match for human leukocyte antigen (HLA)-A and B at intermediate or high resolution and DRB1 at high resolution using DNA-based typing) available.
  4. Failed at least one trial of immunosuppressive therapy (IST) by being refractory or having relapsed. IST could have included ATG based regimens, calcineurin inhibitors and/or other higher dose therapy directed at the treatment of primary SAA.
  5. Available relative of the patient who is a haploidentical match, including biological parents, siblings or half siblings, children, uncles/aunts, first cousins, etc. Eligible haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1 typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must demonstrate that they are a full haplotype match by being identical at a minimum of one allele (at high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, -C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local center. See Section 2.4 for additional information.
  6. Patient and/or legal guardian must sign informed consent for HSCT.
  7. The haplo donor and/or legal guardian must be able to sign informed consent documents.
  8. The potential haplo donor must be willing and able to donate bone marrow.
  9. The weight of the haplo donor must be ≥ 20 kg.
  10. Adequate organ function defined as:

    1. Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 40%. For patients aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or Multi Gated Acquisition Scan (MUGA) may be substituted for LVEF.
    2. Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 x ULN for age.
    3. Renal: For patients > 13.0 years of age at the time of enrollment: estimated creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual body weight). For patients < 13.0 years of age at enrollment: Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90 mL/min/1.73 m2. If the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m^2.
    4. Pulmonary: For patients > 13.0 years of age: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced expiratory volume in one second (FEV1) > 50% predicted (without administration of bronchodilator) and forced vital capacity (FVC) > 50% predicted. For patients < 13.0 years of age unable to perform pulmonary function tests (PFT) due to age or developmental ability: (1) no evidence of dyspnea at rest and (2) no need for supplemental oxygen and (3) O2 saturation > 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care (e.g., Utah, 4,200 feet above sea level, does not give supplemental oxygen unless below 90%)).
  11. Karnofsky or Lansky performance status ≥ 60%.
  12. Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence.

Exclusion Criteria:

  1. Inherited bone marrow failure syndromes such as Fanconi anemia must be ruled out according to center standard.
  2. Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7).
  3. Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity (MFI) > 1000 by solid phase immunoassay).
  4. Prior allogeneic stem cell transplant.
  5. Prior solid organ transplant.
  6. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® that would prohibit use for the patient as this study requires use of the Thymoglobulin® preparation of ATG.
  7. Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
  8. Seropositive for the human immunodeficiency virus (HIV).
  9. Active Hepatitis B or C determined by a detectable viral load of HBV or HCV.
  10. Female patients who are pregnant (per institutional practice) or breast-feeding.
  11. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated with curative intent ≤ 5 years previously will not be allowed unless approved by the Protocol Chairs and/or Protocol Officer.
  12. Alemtuzumab or ATG within 2 weeks of enrollment.

Sites / Locations

  • City of Hope National Medical Center
  • Children's Hospital of Los Angeles
  • Children's Hospital and Research Center Oakland
  • Stanford Hospital and Clinics
  • Children's National Medical Center
  • University of Florida College of Medicine
  • Miami Children's Hospital
  • All Children's Hospital
  • H. Lee Moffitt Cancer Center
  • Northside Hospital
  • Indiana University Medical Center/ Riley Hospital for Children
  • University of Louisville/Kosair Children's Hospital
  • Johns Hopkins Unversity
  • University of Michigan Medical Center
  • Karmanos Cancer Institute/Children's Hospital of Michigan
  • Children's Mercy Hospital and Clinics
  • Washington University/Barnes Jewish Hospital
  • Hackensack University Medical Center
  • Roswell Park Cancer Institute
  • Duke University Medical Center
  • Oregon Health and Science University
  • Penn State College of Medicine/The Milton S. Hershey Medical Center
  • University of Pennsylvania Cancer Center
  • Baylor College of Medicine
  • University of Texas/MD Anderson Cancer Center
  • Texas Transplant Institute
  • Fred Hutchinson Cancer Research Center
  • Children's Hospital of Wisconsin/Midwest Children's Cancer

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Haplo Bone Marrow HSCT

Arm Description

Patients will be treated with a preparative regimen of Antithymocyte Globulin (ATG) (4.5 mg/kg), fludarabine (150 mg/m^2), cyclophosphamide (29 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the haplo HSCT. GVHD prophylaxis will be with post-HSCT cyclophosphamide (100 mg/kg), tacrolimus, and mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.

Outcomes

Primary Outcome Measures

Percentage of Participants With Overall Survival (OS)
Overall survival (OS) is the primary endpoint of this study. The time to this event is the time from transplant to death from any cause or last follow-up or 1 year from transplant, whichever occurs first. The one-year OS probability and its 95% confidence interval were estimated using the Kaplan-Meier estimator and Greenwood's formula.

Secondary Outcome Measures

Percentage of Participants With Neutrophil Recovery
Neutrophil recovery is achieving an absolute neutrophil count (ANC) > 0.5 x10^9/L for three consecutive measurements on different days, with the first of the three days being defined as the day of neutrophil engraftment. The cumulative percentage of neutrophil engraftment was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to neutrophil engraftment treated as a competing risk.
Percentage of Participants With Platelet Recovery
Platelet recovery is defined by achieving a platelet count > 20 x 10^9/L with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be defined as the day of platelet engraftment. The cumulative percentage of platelet engraftment was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to platelet engraftment treated as a competing risk.
Participants Alive With Sustained Engraftment
Being alive and engrafted is defined as not having experienced death, primary graft failure, or secondary graft failure. Donor cell engraftment is defined as donor chimerism greater than or equal to 5% on or after Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including CD3 and CD33 or CD15 fractions. For this protocol, lineage-specific, myeloid, and T cell chimerisms are required. This endpoint was adjudicated by the Endpoint Review Committee (ERC) and ERC data was used for the analysis.
Percentage of Participants With Graft-Failure-Free Survival
Events for Graft-Failure-Free Survival (GFFS) including death, primary graft failure, secondary graft failure. The time to this event is the time from transplant to death from any cause, or graft failure, or last follow-up, or 1 year from transplant, whichever occurs first. For patients experiencing primary graft failure, Day 0.1 was used for primary graft failure event date to count the event in. The one-year GFFS probability and its 95% confidence interval were estimated using the Kaplan-Meier estimator and Greenwood's formula.
Percentage of Participants With Primary Graft Failure
Primary graft failure is defined by the lack of neutrophil engraftment by Day 56 post-HSCT or failure to achieve at least 5% donor chimerism (whole blood or marrow) on any measurements up to and including Day +56. For this protocol, lineage-specific, myeloid, and T cell chimerisms are required. Myeloid engraftment might not proceed at the same rate as T cell engraftment. If myeloid has greater than or equal to 5% donor, even if T cell compartment does not, this is not considered primary graft failure. Secondary graft failure is defined by initial neutrophil engraftment (ANC greater than or equal to 0.5 x 10^8/L measured for 3 consecutive measurements on different days) followed by sustained subsequent decline in ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days or initial whole blood or marrow donor chimerism greater than or equal to 5%, but then declining to less than 5% on subsequent measurements or second infusion/transplant given for graft failure.
Percentage of Participants With Secondary Graft Failure
Secondary graft failure is defined as any one of the following: Initial neutrophil engraftment (ANC greater than or equal to 0.5 x10^9/L measured for three consecutive measurements on different days) followed by sustained subsequent decline in ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days; Initial whole blood or marrow donor chimerism greater than or equal to 5%, but then declining to less than 5% on subsequent measurements; Second infusion/transplant given after Day 56 for graft failure.
Participants Alive With Autologous Recovery
Autologous recovery is defined as ANC > 0.5 x 10^9/L and transfusion independence but with < 5% donor chimerism (whole blood or m. arrow). This endpoint was reviewed and adjudicated by ERC. The analysis is based on ERC data.
Percentage of Participants With Acute Graft-vs-host-disease (GVHD)
Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The time of onset of grades II-IV and grades III-IV acute GVHD were recorded. This endpoint is evaluated through 100 days post-transplant. Cumulative percentage of acute GVHD post-transplant are estimated using the cumulative incidence function, treating death prior to acute GVHD as the competing risk.
Participants With Maximum Acute GVHD
Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). Acute GVHD grading is performed by the consensus conference criteria (Przepiorka et al. 1995) with higher grade indicating worse outcomes. Grade I acute GVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Maximum grade of acute GVHD through 100 days post transplant is reported.
Percentage of Participants With Chronic GVHD
The event for this secondary endpoint is any chronic GVHD based on 2014 NIH Consensus Criteria. This includes mild, moderate and severe chronic GVHD. The analyses of Chronic GVHD use the site-reported data. The cumulative percentage of chronic GVHD is computed using the cumulative incidence function, treating death prior to chronic GVHD as a competing risk. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.
Number of Participants Experiencing Chronic GVHD With Maximum Severity
The event for this secondary endpoint is any chronic GVHD based on 2014 NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. The overall chronic GVHD severity is based on the eight organs score. The maximin severity level of chronic GVHD include mild, moderate and severe.
Immune Reconstitution of Flow Cytometry
Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done through flow cytometric analysis.
Immune Reconstitution of Quantitative Immunoglobulins
Quantitative immunoglobulins of IgA, IgG, IgM were done at baseline and 1-year post-transplant.
Participants With Infections of Maximum Grade 2 and Grade 3
Number of participants who reported the Maximum Infection Severity of Grade 2 and Grade 3. Only grade 2 and grade 3 infections occurring post transplantation were reported on the study. Grade 2 and grade 3 infections are defined by the BMT CTN Technical MOP. Higher infection grade indicates worse infection severity. The infection grading criteria are published online (https://bmtctn.net/administrative-manual-procedures-moppolicy-guidelines). Severity of grade 1, 2 and 3 are described for bacterial, fungal, viral, parasitic, and nonmicrobiological infections. For example, grade 2 fungal infections are defined as candida esophagitis, or proven or probably fungal sinusistis confirmed radiologically without orbital, brain or bone involvement. Grade 3 fungal infections are defined as Fungemia including candidemia, Proven or probably invasive fungal infections, Disseminated infections with histoplasmosis, blastomycosis, coccidiomycosis, or Cryptococcus, or Pneumocystis jiroveci pneumonia.
Frequencies of Infections Categorized by Infection Type
The number of systemic infections is reported. Infections are categorized by infection type. A participant can report multiple types of infections, so the categories are not mutually exclusive for participants. All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation were reported on the study.
Percentage of Participants With Cytomegalovirus (CMV), Epstein Barr Virus (EBV) or Post-Transplant Lymphoproliferative Disease (PTLD)
CMV viremia and disease, EBV viremia, and PTLD are monitored and reported per protocol. The cumulative percentage of each outcome was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to event treated as a competing risk.
Participants With Grade 3-5 Toxicities by SOC
Toxicities are evaluated for the study participants at Day 28, Day 56, Day 100, Day 180 and Day 365 post-transplant and graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3-5 toxicities are reported with higher grade indicating worse outcomes. Toxicities are summarized here by system organ class (SOC). A participant can report multiple toxicities, so the categories are not mutually exclusive for participants.
Health Related Quality of Life (HR-QoL) - Medical Outcomes Study Short Form (MOS SF-36)
HR-QoL will be measured using patient reported surveys at baseline and then at Day 100, Day 180, and Day 365 post-transplant. The MOS SF-36 is used for adult participants (> 18 years). MOS SF-36 is a 36-item general assessment of HR-QoL with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. Each domain is positively scored with higher scores associated with positive outcome. The scale is 0 to 100 where 0 is maximum disability and 100 is no disability. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as the outcome measures in summarizing the SF-36 data for this study. These two summaries have the same score scale and Interpretation.
Health Related Quality of Life (HR-QoL) - PedsQL Stem Cell Transplant Module
HR-QoL will be measured using patient reported surveys at baseline and then at Day 100, Day 180, and Day 365 post-transplant. The PedsQL Stem Cell Transplant Module for pediatric participants (8 years through 18 years). The PedsQL Stem Cell Transplant Module is a 46-item instrument that measures HR-QoL in children and adolescents undergoing hematopoietic stem cell transplant, and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.

Full Information

First Posted
September 27, 2016
Last Updated
November 28, 2022
Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI), Blood and Marrow Transplant Clinical Trials Network, National Marrow Donor Program
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1. Study Identification

Unique Protocol Identification Number
NCT02918292
Brief Title
Optimizing Haploidentical Aplastic Anemia Transplantation (BMT CTN 1502)
Acronym
CHAMP
Official Title
Optimizing Haploidentical Aplastic Anemia Transplantation (CHAMP) (BMT CTN 1502)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
July 3, 2017 (Actual)
Primary Completion Date
August 17, 2021 (Actual)
Study Completion Date
August 17, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medical College of Wisconsin
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI), Blood and Marrow Transplant Clinical Trials Network, National Marrow Donor Program

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
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
This study is a prospective, multicenter phase II study with patients receiving haploidentical transplantation for Severe Aplastic Anemia (SAA). The primary objective is to assess overall survival (OS) at 1 year post-hematopoietic stem cell transplantation (HSCT).
Detailed Description
Acquired SAA is a rare bone marrow failure disorder with an estimated annual incidence of 2 cases per million and with over 600 new cases in the United States each year. A major challenge in treating acquired SAA is the management of patients who are refractory to immunosuppressant therapy (IST) or have relapsed after IST. HSCT is the only curative option for these patients but many are ineligible because they lack a suitable donor. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) seeks to increase options for these patients by using novel therapeutic strategies of GVHD prophylaxis with PTCy to expand the donor pool to include haploidentical donors. The goal of this protocol is to test whether optimized approaches using haploidentical donors will achieve acceptable outcomes in SAA patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia
Keywords
Haploidentical Bone Marrow, Hematopoietic Stem Cell Transplant (HSCT), Severe Aplastic Anemia (SAA), Antithymocyte Globulin (ATG)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Haplo Bone Marrow HSCT
Arm Type
Experimental
Arm Description
Patients will be treated with a preparative regimen of Antithymocyte Globulin (ATG) (4.5 mg/kg), fludarabine (150 mg/m^2), cyclophosphamide (29 mg/kg), and low dose total body irradiation (TBI) (200 cGy) before undergoing the haplo HSCT. GVHD prophylaxis will be with post-HSCT cyclophosphamide (100 mg/kg), tacrolimus, and mycophenolate mofetil (MMF). G-CSF will be administered post-transplant.
Intervention Type
Drug
Intervention Name(s)
Antithymocyte Globulin (ATG)
Other Intervention Name(s)
Thymoglobulin®, rATG
Intervention Description
Administration of ATG will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara®
Intervention Description
Fludarabine dose will be 30 mg/m^2 IV daily for 5 days from Day -6 to Day -2.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan®
Intervention Description
Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation.
Intervention Type
Radiation
Intervention Name(s)
Total Body Irradiation (TBI)
Intervention Description
TBI is to be delivered in a single dose of 200 cGy on Day -1.
Intervention Type
Procedure
Intervention Name(s)
Haplo HSCT
Intervention Description
Eligible patients without a fully matched related or unrelated donor available will undergo haploidentical bone marrow transplant.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Prograf®
Intervention Description
Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Other Intervention Name(s)
Cellcept®
Intervention Description
MMF dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5.
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Filgrastim, Neupogen®
Intervention Description
G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is > 1500 for 3 days.
Primary Outcome Measure Information:
Title
Percentage of Participants With Overall Survival (OS)
Description
Overall survival (OS) is the primary endpoint of this study. The time to this event is the time from transplant to death from any cause or last follow-up or 1 year from transplant, whichever occurs first. The one-year OS probability and its 95% confidence interval were estimated using the Kaplan-Meier estimator and Greenwood's formula.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Percentage of Participants With Neutrophil Recovery
Description
Neutrophil recovery is achieving an absolute neutrophil count (ANC) > 0.5 x10^9/L for three consecutive measurements on different days, with the first of the three days being defined as the day of neutrophil engraftment. The cumulative percentage of neutrophil engraftment was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to neutrophil engraftment treated as a competing risk.
Time Frame
Day 28 and 56
Title
Percentage of Participants With Platelet Recovery
Description
Platelet recovery is defined by achieving a platelet count > 20 x 10^9/L with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be defined as the day of platelet engraftment. The cumulative percentage of platelet engraftment was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to platelet engraftment treated as a competing risk.
Time Frame
Day 100
Title
Participants Alive With Sustained Engraftment
Description
Being alive and engrafted is defined as not having experienced death, primary graft failure, or secondary graft failure. Donor cell engraftment is defined as donor chimerism greater than or equal to 5% on or after Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, including CD3 and CD33 or CD15 fractions. For this protocol, lineage-specific, myeloid, and T cell chimerisms are required. This endpoint was adjudicated by the Endpoint Review Committee (ERC) and ERC data was used for the analysis.
Time Frame
1 year
Title
Percentage of Participants With Graft-Failure-Free Survival
Description
Events for Graft-Failure-Free Survival (GFFS) including death, primary graft failure, secondary graft failure. The time to this event is the time from transplant to death from any cause, or graft failure, or last follow-up, or 1 year from transplant, whichever occurs first. For patients experiencing primary graft failure, Day 0.1 was used for primary graft failure event date to count the event in. The one-year GFFS probability and its 95% confidence interval were estimated using the Kaplan-Meier estimator and Greenwood's formula.
Time Frame
1 year
Title
Percentage of Participants With Primary Graft Failure
Description
Primary graft failure is defined by the lack of neutrophil engraftment by Day 56 post-HSCT or failure to achieve at least 5% donor chimerism (whole blood or marrow) on any measurements up to and including Day +56. For this protocol, lineage-specific, myeloid, and T cell chimerisms are required. Myeloid engraftment might not proceed at the same rate as T cell engraftment. If myeloid has greater than or equal to 5% donor, even if T cell compartment does not, this is not considered primary graft failure. Secondary graft failure is defined by initial neutrophil engraftment (ANC greater than or equal to 0.5 x 10^8/L measured for 3 consecutive measurements on different days) followed by sustained subsequent decline in ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days or initial whole blood or marrow donor chimerism greater than or equal to 5%, but then declining to less than 5% on subsequent measurements or second infusion/transplant given for graft failure.
Time Frame
Day 56
Title
Percentage of Participants With Secondary Graft Failure
Description
Secondary graft failure is defined as any one of the following: Initial neutrophil engraftment (ANC greater than or equal to 0.5 x10^9/L measured for three consecutive measurements on different days) followed by sustained subsequent decline in ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days; Initial whole blood or marrow donor chimerism greater than or equal to 5%, but then declining to less than 5% on subsequent measurements; Second infusion/transplant given after Day 56 for graft failure.
Time Frame
1 year
Title
Participants Alive With Autologous Recovery
Description
Autologous recovery is defined as ANC > 0.5 x 10^9/L and transfusion independence but with < 5% donor chimerism (whole blood or m. arrow). This endpoint was reviewed and adjudicated by ERC. The analysis is based on ERC data.
Time Frame
1 year
Title
Percentage of Participants With Acute Graft-vs-host-disease (GVHD)
Description
Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The time of onset of grades II-IV and grades III-IV acute GVHD were recorded. This endpoint is evaluated through 100 days post-transplant. Cumulative percentage of acute GVHD post-transplant are estimated using the cumulative incidence function, treating death prior to acute GVHD as the competing risk.
Time Frame
Day 100
Title
Participants With Maximum Acute GVHD
Description
Acute GVHD is graded by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). Acute GVHD grading is performed by the consensus conference criteria (Przepiorka et al. 1995) with higher grade indicating worse outcomes. Grade I acute GVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Maximum grade of acute GVHD through 100 days post transplant is reported.
Time Frame
Day 100
Title
Percentage of Participants With Chronic GVHD
Description
The event for this secondary endpoint is any chronic GVHD based on 2014 NIH Consensus Criteria. This includes mild, moderate and severe chronic GVHD. The analyses of Chronic GVHD use the site-reported data. The cumulative percentage of chronic GVHD is computed using the cumulative incidence function, treating death prior to chronic GVHD as a competing risk. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.
Time Frame
1 year
Title
Number of Participants Experiencing Chronic GVHD With Maximum Severity
Description
The event for this secondary endpoint is any chronic GVHD based on 2014 NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. The overall chronic GVHD severity is based on the eight organs score. The maximin severity level of chronic GVHD include mild, moderate and severe.
Time Frame
1 year
Title
Immune Reconstitution of Flow Cytometry
Description
Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done through flow cytometric analysis.
Time Frame
Baseline, Days 100, 180, and 365
Title
Immune Reconstitution of Quantitative Immunoglobulins
Description
Quantitative immunoglobulins of IgA, IgG, IgM were done at baseline and 1-year post-transplant.
Time Frame
baseline and 1-year
Title
Participants With Infections of Maximum Grade 2 and Grade 3
Description
Number of participants who reported the Maximum Infection Severity of Grade 2 and Grade 3. Only grade 2 and grade 3 infections occurring post transplantation were reported on the study. Grade 2 and grade 3 infections are defined by the BMT CTN Technical MOP. Higher infection grade indicates worse infection severity. The infection grading criteria are published online (https://bmtctn.net/administrative-manual-procedures-moppolicy-guidelines). Severity of grade 1, 2 and 3 are described for bacterial, fungal, viral, parasitic, and nonmicrobiological infections. For example, grade 2 fungal infections are defined as candida esophagitis, or proven or probably fungal sinusistis confirmed radiologically without orbital, brain or bone involvement. Grade 3 fungal infections are defined as Fungemia including candidemia, Proven or probably invasive fungal infections, Disseminated infections with histoplasmosis, blastomycosis, coccidiomycosis, or Cryptococcus, or Pneumocystis jiroveci pneumonia.
Time Frame
1 Year
Title
Frequencies of Infections Categorized by Infection Type
Description
The number of systemic infections is reported. Infections are categorized by infection type. A participant can report multiple types of infections, so the categories are not mutually exclusive for participants. All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation were reported on the study.
Time Frame
1 Year
Title
Percentage of Participants With Cytomegalovirus (CMV), Epstein Barr Virus (EBV) or Post-Transplant Lymphoproliferative Disease (PTLD)
Description
CMV viremia and disease, EBV viremia, and PTLD are monitored and reported per protocol. The cumulative percentage of each outcome was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to event treated as a competing risk.
Time Frame
1 Year
Title
Participants With Grade 3-5 Toxicities by SOC
Description
Toxicities are evaluated for the study participants at Day 28, Day 56, Day 100, Day 180 and Day 365 post-transplant and graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3-5 toxicities are reported with higher grade indicating worse outcomes. Toxicities are summarized here by system organ class (SOC). A participant can report multiple toxicities, so the categories are not mutually exclusive for participants.
Time Frame
1 Year
Title
Health Related Quality of Life (HR-QoL) - Medical Outcomes Study Short Form (MOS SF-36)
Description
HR-QoL will be measured using patient reported surveys at baseline and then at Day 100, Day 180, and Day 365 post-transplant. The MOS SF-36 is used for adult participants (> 18 years). MOS SF-36 is a 36-item general assessment of HR-QoL with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. Each domain is positively scored with higher scores associated with positive outcome. The scale is 0 to 100 where 0 is maximum disability and 100 is no disability. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as the outcome measures in summarizing the SF-36 data for this study. These two summaries have the same score scale and Interpretation.
Time Frame
Baseline, Day 100, 6 Months, and 1 Year
Title
Health Related Quality of Life (HR-QoL) - PedsQL Stem Cell Transplant Module
Description
HR-QoL will be measured using patient reported surveys at baseline and then at Day 100, Day 180, and Day 365 post-transplant. The PedsQL Stem Cell Transplant Module for pediatric participants (8 years through 18 years). The PedsQL Stem Cell Transplant Module is a 46-item instrument that measures HR-QoL in children and adolescents undergoing hematopoietic stem cell transplant, and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.
Time Frame
Baseline, Day 100, 6 Months, and 1 Year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient is < 75 years of age at time of enrollment. Confirmed diagnosis of SAA, either from initial diagnosis or follow-up assessments, defined as: Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% residual hematopoietic cells. Two out of three of the following (in peripheral blood): Neutrophils < 0.5 x10^9/L, Platelets < 20 x10^9/L, or Reticulocyte count < 20 x10^9/L (<60 x 10^9/L using an automated analysis) No suitable fully matched related sibling donor (6/6 match for human leukocyte antigen (HLA)-A and B at intermediate or high resolution and DRB1 at high resolution using DNA-based typing) available. Failed at least one trial of immunosuppressive therapy (IST) by being refractory or having relapsed. IST could have included ATG based regimens, calcineurin inhibitors and/or other higher dose therapy directed at the treatment of primary SAA. Available relative of the patient who is a haploidentical match, including biological parents, siblings or half siblings, children, uncles/aunts, first cousins, etc. Eligible haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1 typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must demonstrate that they are a full haplotype match by being identical at a minimum of one allele (at high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, -C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local center. See Section 2.4 for additional information. Patient and/or legal guardian must sign informed consent for HSCT. The haplo donor and/or legal guardian must be able to sign informed consent documents. The potential haplo donor must be willing and able to donate bone marrow. The weight of the haplo donor must be ≥ 20 kg. Adequate organ function defined as: Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 40%. For patients aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or Multi Gated Acquisition Scan (MUGA) may be substituted for LVEF. Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 x ULN for age. Renal: For patients > 13.0 years of age at the time of enrollment: estimated creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula and actual body weight). For patients < 13.0 years of age at enrollment: Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90 mL/min/1.73 m2. If the estimated GFR is < 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m^2. Pulmonary: For patients > 13.0 years of age: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) > 40% and forced expiratory volume in one second (FEV1) > 50% predicted (without administration of bronchodilator) and forced vital capacity (FVC) > 50% predicted. For patients < 13.0 years of age unable to perform pulmonary function tests (PFT) due to age or developmental ability: (1) no evidence of dyspnea at rest and (2) no need for supplemental oxygen and (3) O2 saturation > 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care (e.g., Utah, 4,200 feet above sea level, does not give supplemental oxygen unless below 90%)). Karnofsky or Lansky performance status ≥ 60%. Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence. Exclusion Criteria: Inherited bone marrow failure syndromes such as Fanconi anemia must be ruled out according to center standard. Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7). Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity (MFI) > 1000 by solid phase immunoassay). Prior allogeneic stem cell transplant. Prior solid organ transplant. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® that would prohibit use for the patient as this study requires use of the Thymoglobulin® preparation of ATG. Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment. Seropositive for the human immunodeficiency virus (HIV). Active Hepatitis B or C determined by a detectable viral load of HBV or HCV. Female patients who are pregnant (per institutional practice) or breast-feeding. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated with curative intent ≤ 5 years previously will not be allowed unless approved by the Protocol Chairs and/or Protocol Officer. Alemtuzumab or ATG within 2 weeks of enrollment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary Horowitz, MD, MS
Organizational Affiliation
Center for International Blood and Marrow Transplant Research
Official's Role
Study Director
Facility Information:
Facility Name
City of Hope National Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Children's Hospital of Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's Hospital and Research Center Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94618
Country
United States
Facility Name
Stanford Hospital and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
University of Florida College of Medicine
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Miami Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
H. Lee Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33624
Country
United States
Facility Name
Northside Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Indiana University Medical Center/ Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Louisville/Kosair Children's Hospital
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Johns Hopkins Unversity
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48105
Country
United States
Facility Name
Karmanos Cancer Institute/Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Children's Mercy Hospital and Clinics
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Washington University/Barnes Jewish Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3098
Country
United States
Facility Name
Penn State College of Medicine/The Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
University of Pennsylvania Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas/MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Texas Transplant Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Children's Hospital of Wisconsin/Midwest Children's Cancer
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53211
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
IPD Sharing Time Frame
Within 6 months of official study closure at participating sites.
IPD Sharing Access Criteria
Available to the public
IPD Sharing URL
https://biolincc.nhlbi.nih.gov/home/
Citations:
PubMed Identifier
35907408
Citation
DeZern AE, Eapen M, Wu J, Talano JA, Solh M, Davila Saldana BJ, Karanes C, Horwitz ME, Mallhi K, Arai S, Farhadfar N, Hexner E, Westervelt P, Antin JH, Deeg HJ, Leifer E, Brodsky RA, Logan BR, Horowitz MM, Jones RJ, Pulsipher MA. Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2022 Sep;9(9):e660-e669. doi: 10.1016/S2352-3026(22)00206-X. Epub 2022 Jul 27. Erratum In: Lancet Haematol. 2022 Sep;9(9):e641.
Results Reference
result
Links:
URL
https://bethematch.org/
Description
National Marrow Donor Program

Learn more about this trial

Optimizing Haploidentical Aplastic Anemia Transplantation (BMT CTN 1502)

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