Clinical trial NCT02766465: Bone Marrow Transplantation vs Standard of Care in Patients With Severe Sickle Cell Disease (BMT CTN 1503)
Official title: A Study to Compare Bone Marrow Transplantation to Standard Care in Adolescents and Young Adults With Severe Sickle Cell Disease (BMT CTN 1503)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease
Young Adults
Phase II Trial
Hematopoietic Cell Transplantation (HCT)
Human Leukocyte Antigen (HLA)
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: Dana-Farber Cancer Institute
name: National Marrow Donor Program
name: Emory University
First posted: 2016-05-09
Enrollment: 138
Sex: ALL
Minimum age (years): 15
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients are enrolled without a known donor. All patients have 180 days from confirmation of eligibility to confirm a donor. Patients with a donor will be assigned to the Donor Arm and receive HCT; patients without a donor will be assigned to the no donor arm and continue receiving standard of care for their SCD.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Overall Survival (OS) at 2 Years After Biologic Assignment
timeFrame: 2 Years
Secondary outcomes:
measure: Frequencies of Sickle Cell Disease (SCD) Events of Special Interest
timeFrame: 2 Years
measure: Change in 6-minute Walk Distance (6MWD) Assessment From Baseline
timeFrame: Baseline, 2 years
measure: Change in Transcuspid Regurgitant Jet Velocity (TRJV) Assessment From Baseline
timeFrame: Baseline, 2 years
measure: Change in Albuminuria Assessment From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Physical Function Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Anxiety Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Depression Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Fatigue Score Changes in From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Sleep Disturbance Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Participation in Social Roles Score Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Pain Interference Score Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component Pain Intensity Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component 28-Day Pain Diary Average Pain Intensity Changes From Baseline
timeFrame: Baseline, 2 years
measure: Health-Related Quality of Life (HRQoL) Component ASCQ-Me Stiffness Changes From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Forced Expiratory Volume 1 Second (FEV1) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Forced Vital Capacity (FVC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Ratio of FEV1 to FVC (FEV1/FVC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Vital Capacity (VC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Total Lung Capacity (TLC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Residual Volume (RV) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Expiratory Reserve Volume (ERV) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Inspiratory Capacity (IC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Functional Residual Capacity (FRC) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Diffusing Capacity for Carbon Monoxide (DLCO) From Baseline
timeFrame: Baseline, 2 years
measure: Change in Pulmonary Function of Oxygen Saturation From Baseline
timeFrame: Baseline, 2 years
measure: Frequencies of Infections
timeFrame: 2 years
measure: Percentage of Participants With Grades II-IV Acute GVHD at Day 180 After Biological Assignment
timeFrame: 180 days after biological assignment
measure: Percentage of Participants With Chronic GVHD at Day 600 After Biological Assignment
timeFrame: Day 600 after biological assignment
measure: Number of Participants With Primary and Secondary Graft Failure
timeFrame: 2 years
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Benioff Children's Hospital at Oakland
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Gainsville
state: Florida
city: Hollywood
country: United States
facility: Foundation for Sickle Cell Research/Florida Sickle Inc.
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Children's Hospital of New Orleans
state: Louisiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute/Brigham & Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute/Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University/St. Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center/Albert Einstein School of Medicine
state: New York
city: Brooklyn
country: United States
facility: New York Presbyterian Brooklyn Methodist Hospital
state: New York
city: New Hyde Park
country: United States
facility: Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Health Sciences Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/The Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas/MD Anderson CRC
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Eapen, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.