Haploidentical Bone Marrow Transplantation in Sickle Cell Patients (BMTCTN1507)

Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients With Symptomatic Sickle Cell Disease. (BMTCTN1507)

This is a Phase II, single arm, multi-center trial, designed to estimate the efficacy and toxicity of haploidentical bone marrow transplantation (BMT) in patients with sickle cell disease (SCD). Based on their age and entry criteria patients are stratified into two groups: (1) children with severe SCD; and (2) adults with severe SCD.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Procedure: Haploidentical Bone Marrow Transplantation; Drug: Hydroxyurea; Drug: Rabbit-ATG; Drug: Thiotepa; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total Body Irradiation; Drug: Mesna

Detailed Description

This study is designed as a Phase II multi-center trial to determine the feasibility of achieving a high rate of event-free survival (EFS) at 2 years post transplant using pre-conditioning hydroxyurea (HU) with a conditioning regimen that consists of a combination of Thymoglobulin/Cyclophosphamide/Fludarabine/Thiotepa with post-grafting high-dose cyclophosphamide in patients with severe SCD who have HLA-haploidentical donors. EFS is defined as survival without a qualifying event. This is a single arm study in which participants will be enrolled into one of two strata. The first stratum will be restricted to children who have stroke and 40 children will be enrolled in this stratum. The second stratum will consist of adult patients with severe sickle cell disease and 40 participants will be enrolled in this stratum.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado - Denver/Children's Hospital of Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida College of Medicine
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital/University of Miami Children's Hospital
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
    • Indianapolis, Indiana, United States, 46020
      • Riley Children's Hospital at IU Health
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Helen Devos Children's at Spectrum Health
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University, St. Louis
    • St Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Cancer Center
    • Lake Success, New York, United States, 11042
      • Northwell Health/Monter Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland/Case Western
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Memphis, Tennessee, United States, 38104
      • Methodist Healthcare/West Cancer Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital (Baylor)
    • Houston, Texas, United States, 77030
      • University of Texas/MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 41 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adequate physical function as measured by all of the following:

1. A Karnofsky/Lansky performance score of ≥ 60.
2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction > 26% by cardiac echocardiogram or by Multi Gated Acquisition Scan (MUGA) scan.
3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin).
4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m²

5. Hepatic function:

   1. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded.
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5x upper limit of normal as per local laboratory.
6. Liver MRI using a validated methodology per institutional preference (T2* or R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative). Participants who have hepatic iron content ≥ 10 mg Fe/g liver dry weight by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy and histological examination including documentation of the absence of cirrhosis, bridging fibrosis, and active hepatitis.

7. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C, DRB1, and have available:

   An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required. Confirmatory donor HLA typing must be completed < 100 days prior to Segment A enrollment

8. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Inclusion Criteria for Stratum 1: Children Ages 5.00 - 14.99 years of age at enrollment

1. Age 5.00 - 14.99 years at Segment A enrollment

2. Participants with sickle cell anemiam disease (Hb SS or Sß° Thalassemia) who have one or more of the following:

   1. A neurological event resulting in focal neurologic deficits that lasted ≥ 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both.
   2. Abnormal transcranial Doppler (TCD) measurement with a timed average maximum mean velocity of at least 200 cm/sec in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used > 185 cm/sec plus evidence of intracranial vasculopathy.
   3. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2-weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s).
   4. Acute severe vaso-occlusive pain episodes requiring hospitalization and recalcitrant to maximum medical therapy. Episodes of pain to be adjudicated by selected committee.
   5. One acute chest syndrome episode resulting in intensive care admission requiring non-mechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), simple nasal cannula, face mask O2(e.g. ventimask, rebreather), CPAP, SiPAP, BiPAP, high flow nasal cannula (HFNC) or invasive mechanical ventilatory support (delivered by ETT or trach).
   6. Right heart catheterization confirmed pulmonary artery pressure >25 mmHG or mean pulmonary vascular resistance 206(57-421) dyn·s·cm-5
   7. Essential hypertension on antihypertensive medications >95% upper limit of normal age (as defined according to the American Academy of Pediatrics)
   8. Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months) recalcitrant to medical treatment or unable to use hydroxyurea due to SCD phenotype with the approval of the adjudication committee

Inclusion Criteria for Stratum 2: Adults Ages 15.00 - 45.99 at enrollment

Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who are 15.00 - 45.99 years of age at enrollment AND who have one or more of the following:

1. Age 15.00 - 45.99 years at Segment A enrollment

2. Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who have one or more of the following:

   1. A neurological event resulting in focal neurologic deficits that lasted ≥ 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both.
   2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
   3. History of three or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea); painful episodes related to priapism, osteonecrosis or any sickle-related complication are acceptable;
   4. Administration of regular RBC transfusion therapy, defined as receiving ≥8 packed red blood cell transfusions per year for ≥1 year in the 12 months before enrollment to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome);
   5. An echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) ≥ 2.7 m/sec.

Exclusion Criteria:

1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donor are not excluded.
2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
3. Evidence of HIV infection or known HIV positive serology.
4. Participants who have received a previous hematopoetic cell transplant (HCT).
5. Participants who have had an Encephaloduroarteriosynangiosis (EDAS) procedure in the 6 months prior to enrollment
6. Participants who have received a prior solid organ transplant
7. Participants who have participated in another clinical trial in which the patient received an investigational or off-label use of a drug or device within 3 months of enrollment.
8. Females who are pregnant or breastfeeding.
9. Participants with clinically significant, uncontrolled autoimmune disease, requiring active medical management (immunosuppressive therapy or chemotherapy), which, in the judgment of the local Principal Investigator, indicates that the patient could not tolerate transplantation.
10. Females of child bearing potential (to include all female participants > 10 years of age, unless postmenopausal for a minimum of 1 year before the time of consent or surgically sterilized), who do not agree to practice two (2) effective methods of contraception at the same time, or do not agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the time of signing of informed consent through 12 months post-transplant.
11. Males (even if surgical sterilized) who do not agree to practice effective barrier contraception, or who do not agree to practice true abstinence from the time of signing informed consent through 12 months post-transplant.
12. Presence of anti-donor specific HLA antibodies. HLA antibody presence and specificity will be determined by solid phase immunoassays. An anti-donor specific HLA antibody will be considered positive when the mean fluorescence intensity (MFI) is higher than the cut-off defined by each institution. Recommended cut-off values are MFI >1000 for donor specific antibody to HLA-A, -B, and DRB1 and MFI >2000 for HLA-C, DQB1 and DPB1. This must be measured before the final donor selection, and < 100 days before enrollment in Segment A (preferably < 30 days before Segment A enrollment). If MFI >1000 for donor specific antibody to HLA-A, -B, DRB1 and/or MFI >2000 for HLA-C, DQB1 and DPB1, documentation must be submitted to the DCC coordinator for review and approval by a Protocol Chair and/or Protocol Officer prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Haploidentical Transplantation; A conditioning regimen with Hydroxyurea, rabbit-ATG, Thiotepa, Fludarabine, Cyclophosphamide, Total Body Irradiation, and Mesna will be administered prior to Haploidentical Bone Marrow Transplantation.

Procedure: Haploidentical Bone Marrow Transplantation; Eligible patients with a first degree Human Leukocyte Antigen (HLA)- haploidentical donor will undergo Haploidentical bone marrow transplantation at Day 0 with non T-cell depleted bone marrow. For Graft-vs-Host Disease (GVHD) prophylaxis, patients will be given sirolimus and mycophenolate mofetil beginning on Day +5.; Drug: Hydroxyurea; HU will be given daily at 30mg/kg from Day -70 through Day -10.; Other Names: Hydrea; Droxia; Drug: Rabbit-ATG; Rabbit-ATG (rATG) will be given at 0.5mg/kg on Day -9, and at 2.0mg/kg on Day -8 and Day -7.; Other Names: Thymoglobulin; Drug: Thiotepa; Thiotepa will be given at 10mg/kg on Day -7; Other Names: Chemo; Drug: Fludarabine; Fludarabine will be given at 30mg/m2 from Day -6 to Day -2; Other Names: Fludara; Drug: Cyclophosphamide; Cyclophosphamide will be given at 14.5mg/kg on Day -6 and Day -5, and at 50 mg/kg on Days +3 and +4.; Other Names: Cytoxan®; Radiation: Total Body Irradiation; Total Body Irradiation will be given at 200cGy on Day -1; Other Names: TBI; Drug: Mesna; Mesna will be given at 40mg/kg on Days +3 and +4; Other Names: Mesnex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Two-Year Post-Transplant Event Free Survival (EFS)	EFS is defined as survival without a qualifying event from transplant. Primary graft failure (PGF), secondary graft failure (SGF), second infusion of hematopoietic cells, or death from any cause will count as events for this endpoint. This endpoint was adjudicated by an Endpoint Review Committee. PGF is lack of engraftment on or before Day 42 post-transplant. Engraftment is defined as having greater than or equal to 5% donor cells post-transplant, from any molecular chimerism assessment (e.g., unsorted, myeloid, or T-cell) on a peripheral blood or bone marrow aspirate sample. SGF is defined as < 5% donor whole blood or myeloid chimerism in peripheral blood or bone marrow beyond day +42 post-transplant in patients with prior documentation of hematopoietic recovery with >5% donor cells by day +42 post-transplant. Infusion of a second stem cell product will be considered graft rejection, and counted toward primary or, depending on timing of the second infusion, secondary graft rejection	2 years post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Two-Year Post-Transplant Overall Survival (OS)	Death from any cause will be the event and patients will be censored at the date of last contact or two years post-transplant, whichever comes first.	2 years post-transplant
Number of Participants With Graft Failure	Primary Graft Failure (PGF) is lack of engraftment on or before Day 42 post-transplant. Engraftment is defined as having greater than or equal to 5% donor cells post-transplant, from any molecular chimerism assessment (e.g., unsorted, myeloid, or T-cell) on a peripheral blood or bone marrow aspirate sample. Secondary Graft Failure (SGF) is defined as < 5% donor whole blood or myeloid chimerism in peripheral blood or bone marrow beyond day +42 post-transplant in patients with prior documentation of hematopoietic recovery with >5% donor cells by day +42 post-transplant. Infusion of a second stem cell product will be considered graft rejection, and counted toward primary or, depending on timing of the second infusion, secondary graft rejection.	2 Years post-transplant
Percentage of Participants With Disease Recurrence Post-Transplant	Disease Recurrence is defined as primary graft failure, secondary graft failure, or sickle hemoglobin (HbS) > 70% within 2 years post-transplant. Cumulative Incidence of Disease Recurrence was estimated with a 95% confidence interval using the Aalen-Johansen estimator with death prior to disease recurrence treated as a competing risk. This endpoint was adjudicated by an Endpoint Review Committee.	1 year and 2 years post-transplant
Percentage of Participants With Neutrophil Recovery Post-Transplant	Neutrophil recovery is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of ≥500/μL after conditioning. The incidence of neutrophil recovery from transplant will be estimated using the cumulative incidence function with a 95% confidence interval using the Aalen-Johansen estimator with death or second transplant without neutrophil recovery as a competing risk.	42 Days post-transplant
Percentage of Participants With Platelet Recovery Post-Transplant	Platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/μL AND did not receive a platelet transfusion in the previous 7 days. The incidence of platelet recovery from transplant will be estimated using the cumulative incidence function with a 95% confidence interval using the Aalen-Johansen estimator with death or second transplant without platelet recovery as a competing risk.	60 Days, 100 Days post-transplant
Mean Percentage of Donor Chimerism Post-Transplant	A point estimate and confidence interval will be provided for the mean percent donor chimerism at the time points specified including Day 28, Day 100, Day 180, 1 year, and 2 years post-transplant. For each participant's visit with multiple chimerism sources recorded, donor percentage is determined by taking the first non-missing chimerism percentage in the following order of sources: marrow, blood, myeloid, and t-cell.	Days 28, 100, and 180 and at 1 and 2 years post-transplant
Percentage of Participants by Donor Chimerism Category Post-Transplant	At Day 28, Day 100, Day 180, 1 year and 2 years post-transplant, the proportions with low chimerism (<5%), mixed chimerism (5-95%), or full chimerism (>95%) will be tabulated and described. For each participant's visit with multiple chimerism sources recorded, donor percentage is determined by taking the first non-missing chimerism percentage in the following order of sources: marrow, blood, myeloid, and t-cell.	Days 28, 100, and 180 and at 1 and 2 years post-transplant
Number of Participants by Maximum Acute GVHD Grade Post-Transplant	Acute GVHD was graded according to Consensus Criteria with higher grade indicating worse outcomes. Grade I aGVHD is defined as stage 1-2 skin rash and no liver or GI involvement. Grade II is stage 3 skin rash, or stage 1 liver involvement, or stage 1 GI involvement. Grade III is stage 0-3 skin rash, with stage 2-3 liver involvement, or stage 2-3 GI involvement. Grade IV is stage 4 skin rash, liver, or GI involvement. Maximum grade is defined as the maximum grade of acute GVHD (0-IV) that a participant experiences by Day 100 post-transplant.	100 Days post-transplant
Percentage of Participants With Acute GVHD Post-Transplant	Acute GVHD was graded according to Consensus Criteria with higher grade indicating worse outcomes. Grade I aGVHD is defined as stage 1-2 skin rash and no liver or GI involvement. Grade II is stage 3 skin rash, or stage 1 liver involvement, or stage 1 GI involvement. Grade III is stage 0-3 skin rash, with stage 2-3 liver involvement, or stage 2-3 GI involvement. Grade IV is stage 4 skin rash, liver, or GI involvement. The cumulative incidence of acute GVHD grade II-IV and III-IV at Day 100 was estimated using the Aalen-Johansen estimator with 95% confidence intervals, treating death prior to aGVHD as a competing event. Time to aGVHD is defined as time from transplant until onset of grades II-IV and III-IV aGVHD, respectively.	100 Days post-transplant
Number of Participants by Maximum Chronic GVHD Severity Post-Transplant	Chronic GVHD is based on NIH Consensus Criteria (2014 NIH Consensus Criteria) and includes mild, moderate and severe chronic GVHD. Skin/hair, ocular, oral, pulmonary, gastrointestinal, hepatic, genitourinary, musculoskeletal, and hematologic systems were scored on a 0-3 scale to reflect degree of cGVHD involvement. Maximum grade is defined as the maximum grade of chronic GVHD (mild, moderate, or severe) that a participant experiences by 2 years post-transplant.	2 Years post-transplant
Percentage of Participants With Chronic GVHD Post-Transplant	Percentage of participants with chronic GVHD (cGVHD) at will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate with the complementary log-log transformation, treating death prior to cGVHD as a competing event. Chronic GVHD is based on NIH Consensus Criteria (2014 NIH Consensus Criteria) and includes mild, moderate and severe chronic GVHD. Skin/hair, ocular, oral, pulmonary, gastrointestinal, hepatic, genitourinary, musculoskeletal, and hematologic systems were scored on a 0-3 scale to reflect degree of cGVHD involvement. This endpoint considers any cGVHD onset.	6 months, 1 year, 2 years post-transplant
Number of Participants With Complications and Events Post-Transplant	The number of participants experiencing the following complications and events will be tabulated at baseline, 1 year and 2 years post-transplant: Idiopathic pneumonia syndrome (IPS), Veno-occlusive disease (VOD), Various Central Nervous System (CNS) toxicities, Stroke, participants on immunosuppression for GVHD, and significant infections reported (any bacterial/fungal sepsis, Cytomegalovirus (CMV) reactivation with/without clinical disease, adenovirus, Epstein-Barr Virus (EBV)).	Baseline, 1 year, and 2 years post-transplant
Number of Participants With Sickle Cell Disease Events of Special Interest Post-Transplant	Participants will be followed for the entire 2 year duration of their time on study for the recurrence of Sickle Cell Disease (SCD) related complications. These SCD related complications are referred to as SCD events of special interest (SCD-EOSI) and will be summarized with frequency. These SCD-EOSI include: pulmonary hypertension, new onset of significant cerebrovascular event, renal function compromise, new onset of avascular necrosis of hip or shoulder, new onset of leg ulceration, new onset of acute chest syndrome, and new onset of painful vaso-occlusive crisis requiring hospitalization or parenteral opioid drug in the outpatient setting.	Baseline, 6 months, 1 year, 18 months, and 2 Years post-transplant
Summary of Hematological Outcomes in Percentages	Hematological Outcomes will be summarized with mean and standard deviation at various timepoints. Depending on the measurement, "baseline" could be pre-hydroxyurea conditioning (day -70 pre-transplant) and/or pre-thymoglobulin (day -7 pre-transplant). Measures include: hemoglobin (Hgb) %, reticulocyte count %, and hemoglobin S level %.	Baseline, Day 28, Day 100, 6 months, 1, and 2 years post-transplant
Summary of Glomerular Filtration Rate (GFR)	Renal Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-thymoglobulin (day -7 pre-transplant). Measures include: GFR (mL/min/1.73m2) and Estimated GFR. Estimated GFR is computed using the CKD-EPI Creatinine Equation 2021 for Adults and the Bedside Schwartz 2009 equation for Pediatrics.	Baseline, 1, and 2 years post-transplant
Summary of Lung Function in Liters	Lung Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Measures include: FEV1 (L), FVC (L), and TLC (L). All values in this table were reported by study site.	Baseline, 1, and 2 years post-transplant
Summary of Cardiac Function	Cardiac Function is measured through tricuspid regurgitant jet velocity (TRJV). It will be summarized with mean and standard deviation at Baseline, 1, and 2 years post-transplant. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant).	Baseline, 1, and 2 years post-transplant
Summary of Six Minute Walk Distance	Six Minute Walk Distance is measured in meters to assess how far a participant can walk in 6 minutes. It will be summarized with mean and standard deviation at Baseline, 1, and 2 years post-transplant. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Change from baseline will also be provided at the 1 and 2 years post-transplant visit.	Baseline, 1, and 2 years post-transplant
Mean Patient Reported Quality of Life (QoL) Score	Health-Related Quality of Life (QoL) assessed using the NIH's PROMIS short forms administered to English- and Spanish-speaking patients in the adult stratum. Questions about fatigue (short form 8a), pain interference (short form 8a), and pain intensity (short form 3a) are asked regarding the degree of difficulty in performing activities of daily living such as housework, social activities, and day to day activities. It is scored from 0 to 10 and converted to a standardized T-score with mean 50 and standard deviation 10. A higher T-score represents worse fatigue, pain interfering with more daily activities, and worse pain intensity.	Baseline, 1, and 2 years post-transplant
Mean Patient Reported Pain Intensity Score From Pain Diary	Subjects who speak English and are 15 years or older will be asked to use a web-based diary to report pain intensity on a scale from 0 (no pain) to 10 (worst pain). Subject pain intensity score is reported as an aggregate of several AM and PM scores at Baseline, one year, and two years post-transplant timepoints.	Baseline, 1, and 2 years post-transplant
Number of Participants by Cause of Death	Cause of Death is tabulated by age strata. Deaths among participants who were not transplanted are included.	From Enrollment to 2 Years post-transplant
Number of Participants by Maximum Grade of Infection	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.	From Transplant to 2 Years post-transplant
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.	From Transplant to 2 Years post-transplant
Frequency of Hospital Readmissions by Cause	Participants could be readmitted to a hospital for many reasons during follow-up. The causes of each readmission are tabulated by age strata. The protocol-specified scheduled transplant hospitalization is not included in this table.	From Transplant to 2 Years post-transplant
Summary of Lactate Dehydrogenase (LDH)	Hematological Outcomes will be summarized with mean and standard deviation at various post-transplant timepoints. Measures in this table include: LDH (U/L)	Day 28, Day 100, 6 months, 1, and 2 years post-transplant
Summary of Bilirubin	Hematological Outcomes will be summarized with mean and standard deviation at various timepoints. Baseline timepoint is pre-thymoglobulin (day -7 pre-transplant). Measures in this table include: Bilirubin (mg/dL)	Baseline, Day 28, Day 100, 6 months, 1, and 2 years post-transplant
Summary of Serum Ferritin	Hematological Outcomes will be summarized with mean and standard deviation at various timepoints. Baseline refers to pre-thymoglobulin (day -7 pre-transplant). Measures in this table include: Serum Ferritin Level (ng/dL)	Baseline pre-thymoglobulin visit (day -7 pre-transplant)
Summary of Creatinine Clearance	Renal Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-thymoglobulin (day -7 pre-transplant). Measures include: Creatinine Clearance (mL/min).	Baseline, 1, and 2 years post-transplant
Summary of Urine Albumin Creatine Ratio	Renal Function Outcomes will be summarized with mean and standard deviation at various timepoints. Measures include: Urine Albumin Creatine Ratio (mg/g).	1 and 2 years post-transplant
Summary of Lung Function Percent Predicted	Lung Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Measures include: FEV1 (percent predicted), FVC (percent predicted), FEV1/FVC (percent predicted), and TLC (percent predicted). All values in this table, including percent predicted, were reported by study site.	Baseline, 1, and 2 years post-transplant
Summary of Lung Function Ratio of Liters	Lung Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Measures include: FEV1/FVC (ratio of Liters). All values in this table were reported by study site.	Baseline, 1, and 2 years post-transplant
Summary of Lung Function Percentages of Lab Measure	Lung Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Measures include: DLCO (%) and Oxygen Saturation (%). All values in this table were reported by study site.	Baseline, 1, and 2 years post-transplant
Summary of Lung Function Ratio of Percent Predicted	Lung Function Outcomes will be summarized with mean and standard deviation at various timepoints. "Baseline" refers to pre-hydroxyurea (day -70 pre-transplant). Measures include: FEV1/FVC (ratio of percent predicted). All values in this table were reported by study site.	Baseline, 1, and 2 years post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Follow-up Days Since Transplant	Average number of post-transplant follow-up days by age strata.	From transplant up to 2 years post-transplant

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program; Blood and Marrow Transplant Clinical Trials Network
• Investigators: Study Director: Mary Horowitz, MD, Center for International Blood and Marrow Transplant Research

Publications and helpful links

General Publications

• Hong S, Horwitz ME. Cures for Sickle Cell Abound - How about Access? NEJM Evid. 2025 Mar;4(3):EVIDe2400428. doi: 10.1056/EVIDe2400428. Epub 2025 Feb 25. No abstract available.
• Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.
• Kassim AA, Walters MC, Eapen M, Smith M, Logan BR, Solh M, McKinney C, Nieder M, Ross M, Kent M, Abusin GA, Mallhi K, Silva JG, Shaughnessy P, Kanter J, Haines H, Farah R, Khaled YA, Ritzau N, Mendizabal A, Abraham A, Bollard C, Cooke K, de la Fuente J, Hanna R, Horowitz MM, Jordan LC, Bakshi N, Krishnamurti L, Leifer E, Mahadeo KM, Shenoy S, Jones RJ, DeBaun MR, Brodsky RA. Haploidentical Bone Marrow Transplantation for Sickle Cell Disease. NEJM Evid. 2025 Mar;4(3):EVIDoa2400192. doi: 10.1056/EVIDoa2400192. Epub 2025 Feb 25.

Helpful Links

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2017
• Primary Completion (Actual): January 29, 2025
• Study Completion (Actual): January 29, 2025

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: August 24, 2017
• First Posted (Actual): August 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Transplant; Haploidentical; Bone Marrow; Reduced Intensity Conditioning
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Therapeutics; Hydrocarbons, Acyclic; Hydrocarbons; Amides; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Alkanes; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Biological Products; Complex Mixtures; Triethylenephosphoramide; Aziridines; Azirines; Sulfhydryl Compounds; Urea; Immune Sera; Cyclophosphamide; Mesna; Thiotepa; Antilymphocyte Serum; Hydroxyurea; fludarabine; fludarabine phosphate; Drug Therapy; Whole-Body Irradiation; thymoglobulin
• Other Study ID Numbers: BMTCTN1507; 5U24CA076518 (U.S. NIH Grant/Contract); 2U10HL069294-11 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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 Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• 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