Reduced Intensity Transplantation for Severe Sickle Cell Disease

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

Interventions

DRUG

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

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.

DRUG

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

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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital

  lead OTHER

Principal Investigators

• Akshay Sharma, MBBS · St. Jude Children's Research Hospital

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

2 Years

Max Age

25 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-04-30

Primary Completion

2026-08-01

Completion

2029-08-01

FDA Drug

Yes

Countries

• United States

Study Locations