Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

  • STATUS
    Recruiting
  • End date
    Jul 13, 2023
  • participants needed
    15
  • sponsor
    Emory University
Updated on 13 February 2021
hypertension
iron
stroke
fludarabine
cyclophosphamide
bone marrow transplant
anti-thymocyte globulin
hydroxyurea
hemoglobin s
blood transfusion
preparative regimen
asthma
iron overload
acute chest syndrome
hemoglobinopathy
chest syndrome
sickle cell trait

Summary

The purpose of this study is to learn if it is possible and safe to treat persons with severe sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA) half-matched related donors. Preparation before transplant includes the chemotherapy drugs hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also includes radiation.

Description

The purpose of this study is to learn if it is possible and safe to treat persons with severe sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA) half-matched related donors. Preparation before transplant includes the chemotherapy drugs hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also includes radiation.

Investigators also seek to understand the side effects of BMT in adolescents and young adults with SCD and measure how often serious side effects occur including those that are expected and unexpected. After transplant, investigators will measure the health of the body organs that ordinarily would have been damaged by having SCD in addition to testing the lungs, brain, and kidneys.

Details
Condition SICKLE CELL ANEMIA, Sickle Cell Disease
Treatment cyclophosphamide, hydroxyurea, Fludarabine monophosphate, Total body irradiation, thiotepa, Bone Marrow Transplant (BMT), Bone Marrow Harvest (Donation), Rabbit Anti-thymocyte Globulin
Clinical Study IdentifierNCT02757885
SponsorEmory University
Last Modified on13 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Disease severity: Participants with SCD who have 1 or more of the following (i-v)
Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours
History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea)
History of three or more severe pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea)
Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and ACS). Patients on chronic transfusion who have to discontinue transfusion because of allo-sensitization will be eligible
An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity 2.7 m/sec. Patients under the age of 18 years must have cardiac catheterization proven pulmonary arterial hypertension to qualify on this eligibility criterion
Age: Patients must be 15 - 40 years of age inclusive OR if younger than 15 years must be pubertal
Adequate physical function as measured by
Karnofsky/Lansky performance score 60
Cardiac function: Left ventricular ejection fraction (LVEF) > 40% or LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan
Pulmonary function: Pulse oximetry with a baseline O2 saturation of 85% and DLCO > 40% (corrected for hemoglobin)
Renal function: Serum creatinine 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m2 or GFR > 70 mL/min/1.73 m2 by radionuclide GFR
Hepatic function: Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory and ALT and AST < 5 x upper limit of normal as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion, are not excluded
For participants with a suitable donor who meet eligibility criteria and are willing to proceed to HCT, if they have received chronic transfusion therapy for 1 year and have clinical evidence of iron overload by serum ferritin or MRI, an evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis, and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale
Suitable Donor: To undergo transplantation on this study, participants must have an adult first degree relative who shares at least 1 human leukocyte antigen (HLA) haplotype with the participant, does not have SCD or other hemoglobinopathy, and is in good health; if these criteria are met, they will be allowed to serve as donors. Relatives with sickle cell trait are not excluded as donors. When more than 1 donor is available, the donor with the fewest HLA allele mismatches will be chosen, unless the patient had donor anti-HLA antibodies or there was a medical reason to exclude the donor. If donor anti-HLA antibodies are detected, the next best related match will be chosen. Umbilical cord blood or peripheral blood stem cell donors will not be accepted

Exclusion Criteria

Availability of HLA matched sibling or 8 of 8 HLA-A, B, C and DRB1 matched unrelated donor
Presence of donor specific antibodies in the patient
Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995). The presence of bridging fibrosis will be an exclusion criterion
Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment
Seropositivity for HIV
Previous hematopoietic cell transplantation (HCT)
Participation in a clinical trial in which the patient received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment
Demonstrated lack of compliance with prior medical care
Unwilling to use approved contraception for at least 6 months after transplant
A history of substance abuse in the last 5 years that interferes with care
Pregnant or breast feeding females at the time of consideration for HCT
Donor Selection Criteria
Preference will be given to related marrow donors who are 2-4 (out of 8) HLA
antigen mismatched and towards whom the recipient does not have donor specific
antibodies. Donors will sign an informed consent disclosing that the marrow
donation will be used by a patient participating in this study. The donor must
be matched with the recipient for at least 4 of 8 HLA alleles (HLA -A, -B, -C
and -DRB1 by allele-level DNA methodology). The target total nucleated cell
count (TNC) is 3.5-8.0 x 108/kg of recipient weight. Marrow will be collected
without mobilization. Mobilized peripheral blood stem cell (HPC-A) collections
will not be permitted. Donors must undergo hemoglobinopathy screening by
electrophoresis; donors who have a hemoglobinopathy will be excluded but trait
condition is acceptable
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