Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503)

NCT ID: NCT02766465

Last Updated: 2025-04-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 138 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-16
• Study Completion Date: 2023-08-02

Brief Summary

This is a clinical trial that will compare survival and sickle related outcomes in adolescents and young adults with severe sickle cell disease after bone marrow transplantation and standard of care. The primary outcome is 2-year overall survival.

Detailed Description

This is a prospective phase II multi-center trial of hematopoietic stem cell transplantation or standard of care based on availability of HLA-matched related or unrelated donor after confirmation of clinical eligibility. In order to minimize bias assignment to either treatment arm, clinical eligibility to both treatment arms are similar and donor availability is not known at referral. HLA typing and donor search is initiated upon confirmation of clinical eligibility for the study. Additionally, all analyses of primary and secondary endpoints will follow the Intent-to-Treat principle to address potential bias introduced by participants with donors not proceeding to transplantation or those without a matched donor receiving transplantation with less well-matched donors.

The primary outcome is 2-year overall survival. Our hypothesis is that patients who receive bone marrow transplantation will experience early deaths but that this will plateau by 2 years after transplantation. Patients who receive standard of care will not experience early death but will succumb to their disease at a rate much higher than the general population. Therefore, the goal of the study is to establish that the difference in the proportion of patients surviving is not significantly more than 15% lower in the donor arm at 2-years after assignment to treatment arm.

Secondary endpoints will compare changes in sickle cell disease related events (pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and functional outcomes [6-minute walk distance (6MWD), health-related quality of life, cardiac function, pulmonary function, and mean pain intensity as assessed by a multidimensional electronic pain diary] from baseline to 2-years after assignment to treatment arms.

Additionally for patients assigned to the donor arm and expected to undergo transplantation, hematopoietic recovery, graft rejection, acute and chronic graft-versus-host disease, other significant transplant-related complications and disease-free survival will be reported.

Conditions

Sickle Cell Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Donor Arm

Donor Arm patients will undergo hematopoietic cell transplant. Patients with a matched unrelated donor will receive a bone marrow transplant (unless PBSC graft is pre-approved per section 2.5.1 using a preparative regimen with Busulfan, Fludarabine and rabbit ATG. Patients with an HLA-identical sibling donor can receive a transplant using one of three regimens:

A. Busulfan, Fludarabine, and rabbit ATG using a bone marrow graft (preferred regimen) B. Alemtuzumab/TBI 300 cGy using a peripheral blood graft C. Alemtuzumab, fludarabine, melphalan using a bone marrow graft

Group Type: EXPERIMENTAL

Busulfan

Intervention Type: DRUG

A:

Busulfan dose will be 3.2 mg/kg administered as a single daily dose IV on days -8 through -5 with dosing adjusted using targeted pharmacokinetics.

Fludarabine

Intervention Type: DRUG

A:

Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2).

C:

Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4

r-ATG

Intervention Type: DRUG

A:

r-ATG will be administered IV on day -6 at 0.5mg/kg, on day -5 at 1 mg/kg and on days -4, -3 and -2 at 1.5mg/kg (total r-ATG dose is 6 mg/kg).

Hematopoietic Cell Transplant

Intervention Type: PROCEDURE

A,B,C:

Day 0 is the day of transplantation.

Tacrolimus

Intervention Type: DRUG

A:

Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.

C:

Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines

Methotrexate

Intervention Type: DRUG

A:

Methotrexate will be administered intravenously on day+1 at 15mg/m^2, day+3 at 10mg/m^2, day+6 at 10mg/m^2, and day+11 at 10mg/m^2.

C:

Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant

Alemtuzumab

Intervention Type: DRUG

B:

Alemtuzumab 0.03 mg/kg IV dose will be given on Day -7, Alemtuzumab 0.1 mg/kg IV dose will be given on Day -6, Alemtuzumab 0.3 mg/kg IV dose will be given on Day -5,-4,-3

C:

Alemtuzumab test dose 3 mg IV once 24 hours prior to 1st dose of Alemtuzumab Alemtuzumab 10 mg IV, 15 mg IV, 20 mg IV given on Days -22 through Day -18. Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on three consecutive days.

Total Body Irradiation (TBI)

Intervention Type: DRUG

Total Body Irradiation 300 cGY on Day -2

Sirolimus

Intervention Type: DRUG

Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ \>50%

Melphalan

Intervention Type: DRUG

C:

Melphalan 140 mg/m2 IV dose will be given on Day -3

G-CSF

Intervention Type: DRUG

G-CSF 5 μg/kg/day continue until neutrophil engraftment.

No-Donor Arm

No-donor arm patients will continue with standard of care per their SCD physician.

Group Type: ACTIVE_COMPARATOR

Standard of Care

Intervention Type: PROCEDURE

Continue to receive standard of care treatment per patient's SCD physician.

Interventions

Busulfan

A:

Busulfan dose will be 3.2 mg/kg administered as a single daily dose IV on days -8 through -5 with dosing adjusted using targeted pharmacokinetics.

Intervention Type: DRUG

Fludarabine

A:

Fludarabine dose will be 35 mg/m^2/day administered IV on days -7 through -3 (total fludarabine dose is 175 mg/m^2).

C:

Fludarabine 30mg/m2 IV dose will be given on Days -8, -7, -6, -5, -4

Intervention Type: DRUG

r-ATG

A:

r-ATG will be administered IV on day -6 at 0.5mg/kg, on day -5 at 1 mg/kg and on days -4, -3 and -2 at 1.5mg/kg (total r-ATG dose is 6 mg/kg).

Intervention Type: DRUG

Hematopoietic Cell Transplant

A,B,C:

Day 0 is the day of transplantation.

Intervention Type: PROCEDURE

Tacrolimus

A:

Tacrolimus commences on day -3 and extends through day +180 after transplantation with doses adjusted to maintain appropriate levels according to institutional guidelines.

C:

Tacrolimus at therapeutic doses through Day 180, then taper per institutional guidelines

Intervention Type: DRUG

Methotrexate

A:

Methotrexate will be administered intravenously on day+1 at 15mg/m^2, day+3 at 10mg/m^2, day+6 at 10mg/m^2, and day+11 at 10mg/m^2.

C:

Methotrexate IV 7.5 mg/m2 dose will be given on Days +1, 3, +6 following transplant

Intervention Type: DRUG

Standard of Care

Continue to receive standard of care treatment per patient's SCD physician.

Intervention Type: PROCEDURE

Alemtuzumab

B:

Alemtuzumab 0.03 mg/kg IV dose will be given on Day -7, Alemtuzumab 0.1 mg/kg IV dose will be given on Day -6, Alemtuzumab 0.3 mg/kg IV dose will be given on Day -5,-4,-3

C:

Alemtuzumab test dose 3 mg IV once 24 hours prior to 1st dose of Alemtuzumab Alemtuzumab 10 mg IV, 15 mg IV, 20 mg IV given on Days -22 through Day -18. Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on three consecutive days.

Intervention Type: DRUG

Total Body Irradiation (TBI)

Total Body Irradiation 300 cGY on Day -2

Intervention Type: DRUG

Sirolimus

Sirolimus at therapeutic doses through day 180, then taper per institutional guidelines if donor CD3+ \>50%

Intervention Type: DRUG

Melphalan

C:

Melphalan 140 mg/m2 IV dose will be given on Day -3

Intervention Type: DRUG

G-CSF

G-CSF 5 μg/kg/day continue until neutrophil engraftment.

Intervention Type: DRUG

Other Intervention Names

Busulfex; Fludara; Rabbit antithymocyte globulin; Bone Marrow Transplant; BMT; HCT; Prograf®; MTX; Lemtrada; Rapamune; Alkeran; Granulocyte colony-stimulating factor

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 15 and < 41 years

2. Severe sickle cell disease [Hemoglobin SS (Hb SS), Hemoglobin SC (Hb SC) or Hemoglobin SBeta thalassemia (Hb Sβ) genotype] with at least 1 of the following manifestations (a-e):

1. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours;

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);

3. An average of three or more pain crises per year in the 2-year period preceding enrollment (required intravenous pain management in the outpatient or inpatient hospital setting). Clinical documentation of pain management in the inpatient or outpatient setting is required.

4. Administration of regular RBC transfusion therapy, defined as receiving 8 or more transfusion events per 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 (TRJ) velocity ≥ 2.7 m/sec.

6. Ongoing high impact chronic pain on a majority of days per month for ≥ 6 months as defined as ONE or more of the following: Chronic pain without contributory SCD complications, OR Mixed pain type in which chronic pain is occurring at site(s) (arms, back, chest, or abdominal pain) unrelated to any sites associated with Contributory SCD complications (e.g. leg ulcers and/or avascular necrosis).

i. High impact chronic pain is identified as those reporting "severe interference" with life activities OR "usually or always" experiencing a limitation of their life or work activities including household chores. (See guidelines for identifying HICP in the BMT CTN 1503 Manual of Procedures) ii. Contributory SCD complications are defined as clinical signs (e.g. presence of leg ulcers) or clinical assessments (e.g. imaging confirmation of splenic infarct or avascular necrosis). Chronic pain attributed solely to contributory SCD complications is excluded.

3. Adequate physical function as measured by all of the following:

1. Karnofsky/Lansky performance score ≥ 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).

3. Pulmonary function:

a. Pulse oximetry with a baseline O2 saturation of ≥ 85% b. Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% (corrected for hemoglobin) d. Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance >70 mL/min; or GFR > 70 mL/min/1.73 m2 by radionuclide Glomerular Filtration Rate (GFR).

e. Hepatic function:

1. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory. Participants are not excluded if the serum conjugated (direct) bilirubin is >2x the upper limit of normal for age as per local laboratory and: There is evidence of a hyperhemolytic reaction after a recent RBC transfusion, OR there is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times ULN and not caused by underlying hepatic diseasePatients

2. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 times upper limit of normal as per local laboratory.

Additional inclusion required for donor arm participants to proceed with transplant

1. Liver MRI (≤ 90 days prior to initiation of transplant conditioning) to document hepatic iron content is required for participants who are currently receiving ≥8 packed red blood cell transfusions for ≥1 year or have received ≥20 packed red blood cell transfusions (cumulative). Participants who have hepatic iron content ≥7 mg Fe/ g liver dry weight by liver MRI must have a liver biopsy and histological examination/documentation of the absence of cirrhosis, bridging fibrosis and active hepatitis (≤ 90 days prior to initiation of transplant conditioning).

2. Lack of clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack) by Cerebral MRI/MRA within 30 days prior to initiating transplant conditioning. Subjects with clinical or radiologic evidence of a recent neurologic event will be deferred for ≥ 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation

3. Documentation of participant's willingness to use approved contraception method until discontinuation of all immunosuppressive medications is to be documented in the medical record corresponding with the consent conference.

Exclusion Criteria

1. HLA typing with a donor search prior to referral (consultation with HCT physician).

1. If a subject has had HLA typing and a related donor search that did not identify a suitably matched relative (i.e., sibling) at any time, and also did not have an unrelated donor search, the patient will be considered eligible.

2. If a subject has had HLA typing and a related donor search that did not identify a suitably matched relative (i.e., sibling) at any time and had an unrelated donor search that did not identify a suitably matched unrelated donor ≥ 1 year prior to enrollment, the patient will be considered eligible.

3. If a subject has had HLA typing with no related donor search and had an unrelated donor search that did not identify a suitably matched unrelated donor ≥ 1 year prior to enrollment, the patient will be considered eligible.

4. Subjects with a known HLA-identical sibling or HLA-matched unrelated donor are excluded

2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.

3. Seropositivity for HIV.

4. Previous HCT or solid organ transplant.

5. Participation in a clinical trial in which the patient received an investigational drug or device must be discontinued at enrollment.

6. A history of substance abuse as defined by version IV of the Diagnostic & Statistical Manual of Mental Disorders (DSM IV).

7. Demonstrated lack of compliance with prior medical care as determined by referring physician.

8. Pregnant or breast feeding females.

9. Inability to receive HCT due to alloimmunization, defined as the inability to receive packed red blood cell (pRBC) transfusion therapy.

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Eapen, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

Benioff Children's Hospital at Oakland

Oakland, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Florida Gainsville

Gainesville, Florida, United States

Foundation for Sickle Cell Research/Florida Sickle Inc.

Hollywood, Florida, United States

University of Miami

Miami, Florida, United States

Grady Memorial Hospital

Atlanta, Georgia, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Emory University

Atlanta, Georgia, United States

Augusta University Medical Center

Augusta, Georgia, United States

University of Iowa

Iowa City, Iowa, United States

Children's Hospital of New Orleans

New Orleans, Louisiana, United States

Dana Farber Cancer Institute/Brigham & Women's Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute/Massachusetts General Hospital

Boston, Massachusetts, United States

Boston University

Boston, Massachusetts, United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Washington University/St. Louis Children's Hospital

St Louis, Missouri, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Newark Beth Israel Medical Center

Newark, New Jersey, United States

New York Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, United States

Cohen Children's Medical Center

New Hyde Park, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Weill Cornell Medical College

New York, New York, United States

Montefiore Medical Center/Albert Einstein School of Medicine

The Bronx, New York, United States

University of North Carolina Hospital at Chapel Hill

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Ohio State University

Columbus, Ohio, United States

University of Oklahoma

Oklahoma City, Oklahoma, United States

Oregon Health Sciences University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Texas Health Sciences Center

Houston, Texas, United States

Baylor College of Medicine/The Methodist Hospital

Houston, Texas, United States

University of Texas/MD Anderson CRC

Houston, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Countries

United States

References

Walters MC, Eapen M, Liu Y, El Rassi F, Waller EK, Levine JE, Strouse JJ, Antin JH, Parikh SH, Bakshi N, Dampier C, Jaroscak JJ, Bergmann S, Wong T, Kota V, Pace B, Lekakis LJ, Lulla P, Nickel RS, Kasow KA, Popat U, Smith W, Yu L, DiFronzo N, Geller N, Kamani N, Klings ES, Hassell K, Mendizabal A, Sullivan K, Neuberg D, Krishnamurti L. Hematopoietic cell transplant compared with standard care in adolescents and young adults with sickle cell disease. Blood Adv. 2025 Mar 11;9(5):955-965. doi: 10.1182/bloodadvances.2024013926.

Reference Type: RESULT

PMID: 39471440 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36240296 (View on PubMed)

Krishnamurti L, Neuberg DS, Sullivan KM, Kamani NR, Abraham A, Campigotto F, Zhang W, Dahdoul T, De Castro L, Parikh S, Bakshi N, Haight A, Hassell KL, Loving R, Rosenthal J, Smith SL, Smith W, Spearman M, Stevenson K, Wu CJ, Wiedl C, Waller EK, Walters MC. Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study. Am J Hematol. 2019 Apr;94(4):446-454. doi: 10.1002/ajh.25401. Epub 2019 Feb 11.

Reference Type: DERIVED

PMID: 30637784 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

https://bmtctn.net/

Blood and Marrow Transplant Clinical Trials Network Website

Other Identifiers

1U01HL128568-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 1503

Identifier Type: -

Identifier Source: org_study_id