Stem Cell Transplantation for Sickle Cell Anemia

Reduced Intensity Matched Sibling Bone Marrow Transplantation for Sickle Cell Anemia in Patients 2-30 Years Old

This protocol will be investigating the use of stem cell transplantation, in related donors, to cure sickle cell disease. Sickle cell disease is a recessive disorder caused by a point mutation that results in the substitution of valine for glutamic acid at the sixth position in the B-chain of hemoglobin. This leads to sickling of the red blood cells under many conditions, such as hypoxia, dehydration, and hyperthermia. The sickling leads to vaso-occlusion, which causes irreversible damage in almost all systems in the body, including the central nervous system (CNS), lungs, heart, bones, eyes, liver, and kidneys.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Alemtuzumab; Drug: Fludarabine; Drug: Melphalan; Procedure: Stem Cells

Detailed Description

Primary objective:

1) To determine disease free survival (DFS) at two years after matched sibling transplant using bone marrow (BM) after a conditioning regimen consisting of distal timed Alemtuzumab, Fludarabine, and Melphalan for patients 2-30 y/o

Secondary objectives:

1. Overall survival
2. Rate of neutrophil and platelet engraftment for BM
3. Incidence of graft failure
4. Incidence of grade II-IV and grade III-IV acute graft vs host disease (GVHD)
5. Incidence of chronic GVHD
6. Incidence of other transplant complications, such as veno-occlusive disease, central nervous system (CNS) toxicity, and idiopathic pneumonia syndrome (IPS)
7. Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus
8. Incidence of invasive fungal disease
9. Time to immune reconstitution via monitoring of lymphocyte subpopulations and immunoglobulin levels

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient Eligibility

  1) Matched sibling donors (9-10/10 marrow/PBSC or 5-6/6 UCB (single or double) with a total TNC dose of greater than 5 x 107/kg recipient weight)

  1. Age 2-30
  2. Hb SS, S-thal0, S-thal+, SC
  3. Evidence of ongoing hemolysis: Hb<10, retic >5%, LDH > 500, TB>2
  4. Karnofsky/Lansky score >50
  5. LVSF>26% or LVEF>40%
  6. DLCO >40% or O2 sat >85% for those patients that can't perform PFTs
  7. GFR >70 and serum creatinine < 1.5 * ULN for age
  8. ALT and AST < 5 x ULN, direct bilirubin <2 x ULN
  9. If the patient has been on chronic transfusion or has a ferritin >1000, liver biopsy should be done and show no evidence of bridging fibrosis or cirrhosis

• Exclusion criteria

  1. Evidence of uncontrolled bacterial, viral, or fungal infection within one month prior to initiation of the conditioning regimen
  2. Pregnant or breastfeeding
  3. HIV positive
  4. Written informed consent not obtained

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: Related donor; Matched sibling donors (9-10/10 marrow/PBSC or 5-6/6 UCB (single) with a total TNC dose of greater than 5 x 107/kg recipient weight), age 2-30 years after conditioning regimen Alemtuzumab , Fludarabine, and Melphalan. 1) Patients will receive a conditioning regimen composed of Alemtuzumab, Fludarabine, and Melphalan as detailed in the table below. Day Treatment; -22 Alemtuzumab 3mg IV (test dose); -21 Alemtuzumab 10mg IV; -20 Alemtuzumab 15mg IV; -19 Alemtuzumab 20mg IV; -8 Fludarabine 30mg/m2 IV; -7 Fludarabine 30mg/m2 IV; -6 Fludarabine 30mg/m2 IV; -5 Fludarabine 30mg/m2 IV; -4 Fludarabine 30mg/m2 IV; -3 Melphalan 140mg/m2 IV; -2 Rest Day; -1 Rest Day; 0 Stem Cell Infusion

Drug: Alemtuzumab; Adjusted Ideal Body Weight Formula: AIBW = IBW + [(0.4) x (ABW - IBW)] b) Medications i.) Alemtuzumab I. Hb S% must be < or = 45% within 7 days prior to initiation of Alemtuzumab II. Iron chelation and hydroxyurea must be discontinued >48 hours before initiating therapy III. Alemtuzumab will be diluted in 100mL of 0.9% NS and infused at a rate as below; Other Names: Alemtuzumab (Campath); Drug: Fludarabine; I. Fludarabine should be diluted in 100 ml 0.9%NS and given over 30 minutes. II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Fludarabine; Other Names: Fludarabine (Fludara); Drug: Melphalan; I. Melphalan should be diluted in 0.9%NS to a concentration of 0.1 -0.45 mg/mL and given over 45 minutes. *Entire dose must be infused within 60 minutes of reconstitution in Pharmacy. II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Melphalan III. Patients should be encouraged to suck on a popsicle or something similar during the Melphalan infusion.; Other Names: Melphalan (Alkeran); Procedure: Stem Cells; Infusion of Hematopoietic Stem Cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Graft Failure	Primary endpoint: In each group, the Number of participants with Graft Failure at the 2 years endpoint will be estimated using the Kaplan Meier product limit estimator.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Secondary endpoints: Overall survival: The distribution of time to death from any cause will be estimated by Kaplan- Meier product limit function and plotted. The overall survival will be measured from the time of transplant to any death and patients will be followed for 2 years.	2 years

Collaborators and Investigators

• Sponsor: Hackensack Meridian Health
• Investigators: Principal Investigator: Jennifer Krajewski, MD, Hackensack Meridian Health

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): September 1, 2021
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: June 12, 2013
• First Submitted That Met QC Criteria: June 13, 2013
• First Posted (Estimate): June 14, 2013

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Stem cell transplant; Stem cell transplantation; Sickle cell; Unrelated; Related
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Melphalan; Fludarabine; Fludarabine phosphate; Alemtuzumab
• Other Study ID Numbers: Pro00001894