Stem Cell Transplantation for Sickle Cell Anemia

Sponsor

Hackensack Meridian Health (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01877837

Collaborator

(none)

Enrollment

Location

Arm

149

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease	Drug: Alemtuzumab Drug: Fludarabine Drug: Melphalan Procedure: Stem Cells	Phase 3

Detailed Description

Primary objective:

To determine disease free survival (DFS) at one year after matched sibling transplant using either bone marrow (BM), peripheral blood stem cells (PBSC), or umbilical cord blood (UCB) after a conditioning regimen consisting of Alemtuzumab, Fludarabine, and Melphalan in patients 2-30 y/o

Secondary objectives:

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

Study Design

Study Type:

Interventional

Actual Enrollment :

26 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Reduced Intensity Stem Cell Transplantation for Sickle Cell Anemia in Patients 2-30 Years Old

Study Start Date :

Jun 1, 2011

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Graft Failure [1 year]
Primary endpoint: In each group, the DFS at the 1 year endpoint will be estimated using the Kaplan Meier product limit estimator. The frequencies of the events, ie graft failure, will be enumerated and presented.

Secondary Outcome Measures

Overall survival [2 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient Eligibility

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)

Age 2-30
Hb SS, S-thal0, S-thal+, SC
Evidence of ongoing hemolysis: Hb<10, retic >5%, LDH > 500, TB>2
Karnofsky/Lansky score >50
LVSF>26% or LVEF>40%
DLCO >40% or O2 sat >85% for those patients that can't perform PFTs
GFR >70 and serum creatinine < 1.5 * ULN for age
ALT and AST < 5 x ULN, direct bilirubin <2 x ULN
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

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