Minimizing Toxicity in HLA-identical Related Donor Transplantation for Children With Sickle Cell Disease (SUN)

This multisite prospective study seeks to determine if HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Alemtuzumab, low dose total body irradiation, Sirolimus

Detailed Description

This is a prospective, multicenter phase II study of HLA-identical sibling donor HSCT in 30 pediatric patients with SCD using nonmyeloablative conditioning with alemtuzumab, total-body irradiation, and sirolimus. The primary Objective of this study is to determine if the SUN regimen can decrease the incidence of grade II-IV acute graft-versus host disease (GVHD) by day +100 while maintaining similar disease-free survival compared to establish HLA-identical donor hematopoietic stem cell transplant (HSCT) regimens in children with SCD. The secondary Objective is to determine if health-related quality of life (HRQoL) for children undergoing SUN HSCT is preserved during the early post-transplant time period. To determine if the SUN regimen can decrease the number of platelet transfusions compared to established HLA-identical HSCT regimens in children with SCD. The tertiary/Exploratory Objectives: To describe other markers of toxicity (duration of neutropenia, mucositis, length of hospitalization) and indicators of a successful HSCT (HRQoL at 1 year, proportion needing additional immunosuppression during the first year, proportion able to wean sirolimus at 1 year).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Robert Nickel, MD; Phone Number: 202-476-5000; Email: RNickel@childrensnational.org
• Study Contact Backup: Name: Fahmida Hoq, MBBS; Phone Number: 202-476-5000; Email: FHoq@childrensnational.org

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital
      • Contact: Gregory Guilcher
      • Contact: Phone Number: 1-403-955-7272; Email: Greg.Guilcher@AHS.ca
      • Principal Investigator: Gregory Guilcher, MD
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital for Sick Children
      • Contact: Brandon Rothberg
      • Contact: Phone Number: 202042 416-813-7654; Email: brandon.rothberg@sickkids.ca
      • Principal Investigator: KY Chiang, MD
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Health System
      • Contact: Fahmida Hoq, MBBS, MS; Phone Number: 202-476-3634; Email: fhoq@childrensnational.org
      • Contact: Mariam Odinakachukwu; Phone Number: 202-476-2957; Email: mailto:modinakach@childrensnational.org
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
      • Contact: Olga Jonas; Phone Number: 312-227-4871; Email: ojonas@luriechildrens.org
      • Contact: Ella Ramsey; Email: dramsey@luriechildrens.org
      • Principal Investigator: Sonali Chaudhury, MD
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Recruiting
      • Levine Children's Hospital
      • Contact: Janice Hollifield; Phone Number: 980-442-2342; Email: Janice.hollifield@atriumhealth.org
      • Principal Investigator: Michael Kent, MD
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Hemalatha Rangarajan; Phone Number: 614-355-1689; Email: Hemalatha.Rangarajan@nationwidechildrens.org
      • Principal Investigator: Hemalatha Rangarajan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:

• 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 lifetime.
• History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
• History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
• 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.

Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:

• Clinically significant neurologic event (overt stroke).
• History of two or more episodes of ACS in the 2-years period preceding enrollment.
• History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
• History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
• 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.

Exclusion Criteria:

• • General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.
• Infection Disease: 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 for HIV and patients with active Hepatitis B or C determined by serology and/or NAAT are excluded.
• Liver: Direct (conjugated) bilirubin > 1.5 mg/dL, transaminases >5x upper limit of normal for age.
• Cardiac: Left ventricular shortening fraction <25% or ejection fraction <50% by ECHO.
• Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.
• Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.
• Heme: History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative). Major ABO incompatibility with donor.

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: SUN regimen; Alemtuzumab, low dose total body irradiation, Sirolimus HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

Drug: Alemtuzumab, low dose total body irradiation, Sirolimus; The conditioning regimen (SUN regimen) will consist of alemtuzumab daily for 5 days (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on Days -5 to -3) and low dose total body irradiation (TBI) 300 cGY on Day -2 with gonadal shielding if possible. The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x106/kg recipient weight, goal of 10 x 106/kg (no upper limit). A peripheral blood stem cell (PBSC) graft was selected as it engrafts faster than bone marrow and would lead to shorter period of neutropenia and infection and less thrombocytopenia and need for platelet transfusion. GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus will be continued at 1 mg/m2/day starting on day 0 and dose adjusted to maintain a target trough level 5-15 ng/mL for the first 3 months and 5-10 ng/mL for the remainder of the first year.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute GVHD	Acute grade II-IV GVHD	100 days post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PedsQL 4.0 Measurement model for the Pediatric Quality of Life Inventory	PedsQL 4.0 assessments of health related quality of life before/after transplant	Day +30, and day +100 post transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-Reported Outcomes Measurement Information System (PROMIS)	PROMIS assessments of health related quality of life before/after transplant	Day +30, and day +100 post transplant
Platelet transfusion	Number of platelet transfusions	100 days post transplant

Collaborators and Investigators

• Sponsor: Robert Nickel
• Collaborators: The Hospital for Sick Children; Ann & Robert H Lurie Children's Hospital of Chicago; Nationwide Children's Hospital; Morgan Stanley Children's Hospital; Alberta Children's Hospital; Levine Children's Hospital; The Children's Hospital at Montefiore
• Investigators: Principal Investigator: Rober Nickel, MD, Children's National Health System

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2018
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: June 6, 2018
• First Submitted That Met QC Criteria: July 13, 2018
• First Posted (Actual): July 16, 2018

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Alemtuzumab
• Other Study ID Numbers: IRB 10322

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No