Reduced Intensity Transplantation for Severe Sickle Cell Disease

NCT04362293 | Suspended Phase 2 FDA Drug

• 1 other identifier: SCDHCT
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to test a transplant method that may have fewer side effects (or less toxic, less harmful) than conventional high dose chemotherapy conditioning-based transplants for children and young adults with Sickle Cell Disease (SCD). Patients less than or equal to 25 years old with SCD who would likely benefit from allogeneic hematopoietic cell transplantation (HCT) will be included in this study. Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm while patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study. Primary Objective To assess the donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial. Secondary Objectives

• Assess the overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.
• Estimate the primary and secondary graft rejection rate at 1-year, 2-year and 3-year post- transplant.
• Estimate the incidence and severity of acute and chronic (GVHD).
• Estimate the incidence of SCD recurrence after transplant
• Assess the neutrophil and platelet recovery kinetics post-transplant. Exploratory Objectives
• Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta spectratyping, and lymphocyte phenotype and function.
• Conduct longitudinal examination of impact of HCT on patient health-related quality of life (HRQL) and adjustment, and parental adjustment.
• Examine impact of HCT on patient cognitive and academic function.
• Determine factors that influenced the decision to undergo HCT, explore perceptions of the HCT experience, and assess decisional satisfaction/regret.
• Develop and evaluate an objective/quantitative imaging biomarker to assess organ (liver and heart) function/disease status and changes following HCT.
• Develop and evaluate an objective/quantitative imaging biomarker to determine cerebral blood flow and oxygen extraction fraction following HCT.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• Donor T-cell chimerism at 1-year post transplant in each respective arm (MSD, HAPLO) of the trial.

  Number of participants who have achieved donor T-cell chimerism greater than 60% by 1-year post transplant will be reported. The rate of success will be checked for in each arm after the first 10 evaluable patients have been enrolled and followed for up to 1 year.

  1 year after HCT

Secondary Outcomes (5)

• Overall survival and 1-year, 2-year and 3-year post-transplant graft versus host disease (GVHD)-free SCD-free survival.

  Up to 3 years after HCT

• Graft rejection rate.

  Up to 3 years after HCT

• Incidence and severity of acute and chronic (GVHD).

  Up to 3 years after HCT

• Incidence of SCD recurrence after transplant.

  Up to 3 years after HCT

• Neutrophil and platelet recovery.

  Up to 6 months after HCT

Study Arms (2)

Matched Sibling Donor (MSD)

EXPERIMENTAL

Patients with a suitable HLA matched sibling donor (MSD) will be enrolled on the MSD arm.

Drug: hydroxyurea, azathioprine, alemtuzumab, thioptepa, low dose total body irradiation and sirolimus

Haploidentical (HAPLO)

EXPERIMENTAL

Patients without an eligible MSD who have a suitable haploidentical (HAPLO) donor available will be enrolled on the HAPLO arm of the study.

Drug: hydroxyurea, azathioprine, alemtuzumab, thiotepa, plerixafor, low dose total body irradiation, cyclophosphamide and sirolimus

Interventions

hydroxyurea, azathioprine, alemtuzumab, thioptepa, low dose total body irradiation and sirolimus DRUG

The conditioning regimen will consist of hydroxyurea (30mg/Kg) and azathioprine (3mg/Kg) by mouth daily from day -60 to day -8, alemtuzumab subcutaneously daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on days -5 to -3), thiotepa intravenously (10mg/Kg) on day -3 and low dose total body irradiation (TBI) 200 cGY on day -2 with gonadal shielding (if possible). The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x10\^6/kg recipient weight. GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus dose will be adjusted to maintain a target trough level 5-15 ng/mL. Low dose donor lymphocyte infusions will begin on day +28 and continue till donor lymphocyte chimerism reaches at least 90% donor.

Matched Sibling Donor (MSD)

hydroxyurea, azathioprine, alemtuzumab, thiotepa, plerixafor, low dose total body irradiation, cyclophosphamide and sirolimus DRUG

The conditioning regimen will consist of hydroxyurea (30mg/Kg) and azathioprine (3mg/Kg) by mouth daily from day -60 to day -8, alemtuzumab subcutaneously daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on days -5 to -3), thiotepa intravenously (10mg/Kg) on day -3, plerixafor (0.24mg/Kg) subcutaneously every 12 hours on days -3 and -2 and low dose total body irradiation (TBI) 200 cGY on days -2 and -1 with gonadal shielding (if possible). The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x10\^6/kg recipient weight. GVHD prophylaxis will be cyclophosphamide (50mg/Kg) intravenously on days +3 and +4 and sirolimus with a loading dose 3 mg/m2 starting on day +5. Sirolimus dose will be adjusted to maintain a target trough level 5-15 ng/mL. Low dose donor lymphocyte infusions will begin on day +28 and continue till donor lymphocyte chimerism reaches at least 90% donor.

Haploidentical (HAPLO)

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age less than or equal to 25 years.
• Patients with a suitable HLA-matched sibling donor (MSD) can be enrolled on MSD arm of the trial. Patients with single haplotype matched (≥ 3 of 6) family member donor can be enrolled on HAPLO arm of the trial, if they do not have a suitable HLA-matched sibling donor (MSD) available for progenitor cell donation.
• Patients with SCD (any genotype) who meet any ONE of the following criteria:
• History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥ 200 cm/sec by the non-imaging technique (or ≥ 185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
• History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2- weighted images).
• History of two or more episodes of acute chest syndrome (ACS) in the 2-years period preceding enrollment.
• History of two or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the last 12 months.
• History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment in the last 12 months.
• History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
• Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
• At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.

You may not qualify if:

• Karnofsky or Lansky performance score \<60.
• Pregnant or breastfeeding patients.
• Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity or positive NAAT for HIV are excluded.
• Serum conjugated (direct) bilirubin \>3x upper limit of normal for age as per local laboratory. Participants with hyperbilirubinemia or elevated AST as the result of hyperhemolysis, or a severe drop in hemoglobin post blood transfusion, are not excluded as long as it downtrends and return to acceptable limits subsequently.
• Left ventricular shortening fraction \<25% or ejection fraction \<40% by echocardiogram.
• Estimated creatinine clearance less than 50 mL/min/1.73m2.
• Diffusion capacity of carbon monoxide (DLCO) \<35% (adjusted for hemoglobin). Baseline oxygen saturation \<85% or PaO2 \<70.
• Presence of anti-donor specific HLA antibodies unresponsive to desensitization as defined below.
• HLA antibody presence and specificity will be determined by solid phase immunoassays. An anti-donor specific HLA antibody test will be considered positive when the mean fluorescence intensity (MFI) is:
• \>1,000 for donor specific antibodies to HLA-A, -B, and DRB1. or
• \>2,000 for donor specific antibodies to HLA-C, DQB1 and DPB1.
• A participant with presence of anti-donor specific HLA antibodies may be provisionally enrolled on the study if desensitization (see Appendix H) is begun concurrently with pre-conditioning. Response to desensitization will be defined as:
• decreasing anti-donor specific HLA antibody titer with an MFI of less than 5,000 and
• negative C1q-binding anti-HLA antibody assay.
• An HLA-matched sibling donor for MSD arm and at least single haplotype matched (≥ 3 of 6) family member for HAPLO arm.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Publications (1)

• Sharma A, Selukar S, Bi Y, Merlocco A, Morin CE, Goode C, Rai P, Towbin JA, Hankins JS, Gottschalk S, Triplett B, Johnson JN. Impact of hematopoietic cell transplantation on myocardial fibrosis in young patients with sickle cell disease. Blood. 2024 Aug 8;144(6):672-675. doi: 10.1182/blood.2023023028.

  PMID: 38691679 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Hydroxyurea; Azathioprine; Alemtuzumab; Whole-Body Irradiation; Sirolimus; Thiotepa; plerixafor; Cyclophosphamide

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Radiotherapy; Therapeutics; Investigative Techniques; Macrolides; Lactones; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons

Study Officials

• Akshay Sharma, MBBS

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 13, 2020
• First Posted: April 24, 2020
• Study Start: April 30, 2020
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2029
• Last Updated: August 14, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Locations

US (1)