Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders

Conditions:HIV / AIDS, Anemia
Therapuetic Areas:Hematology, Immunology / Infectious Diseases
Age Range:Any - 54
Start Date:May 24, 2006

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HLA-Haploidentical Related Marrow Grafts for the Treatment of Primary Immunodeficiencies and Other Nonmalignant Disorders Using Conditioning With Low-Dose Cyclophosphamide, TBI and Fludarabine and Postgrafting Cyclophosphamide

This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and
total-body irradiation followed by donor bone marrow transplant and cyclophosphamide,
mycophenolate mofetil, tacrolimus, and sirolimus in treating patients with primary
immunodeficiency disorders or noncancerous inherited disorders. Giving low doses of
chemotherapy and total-body irradiation before a bone marrow transplant helps prepare the
patient's body to accept the incoming donor's bone marrow and decrease the risk that the
patient's immune system will reject the donor's stem cells. When the healthy stem cells from
a donor are infused into the patient they may help the patient's bone marrow make stem cells,
red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a
donor can make an immune response against the body's normal cells called graft versus host
disease. Giving cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus after the
transplant may help decrease this from happening.


I. Determine safety of nonmyeloablative conditioning and hematopoietic cell transplantation
(HCT) from human leukocyte antigen (HLA)-haploidentical related donors for patients with
nonmalignant inherited disorders who do not have an HLA-matched related or unrelated donor.


I. Determine whether nonmyeloablative conditioning and HCT from an HLA-haploidentical related
donor graft can establish mixed chimerism (> 5% cluster of differentiation [CD]3+ donor
T-cell chimerism) in patients with nonmalignant inherited disorders.

II. Transplant related mortality at day 100.

III. Incidence and severity of graft-versus-host disease (GHVD).

IV. Immune reconstitution.

V. Infections during the first 200 days after HCT.


NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously
(IV) over 1 hour on days -6 to -2; cyclophosphamide IV over 1 hour on days -6 and -5; and
undergo total body irradiation on day -1.

TRANSPLANTATION: Patients undergo allogeneic bone marrow transplant on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on days 3
and 4, and mycophenolate mofetil orally (PO) every 8 hours on days 5-30 then twice daily
(BID) to day 40, and then if there is no evidence of active GVHD and donor engraftment is >
95% (or by principal investigator [PI] approval) taper until approximately day 96, or faster
at discretion of PI. Patients also receive tacrolimus IV continuously over 22-24 hours
starting on day 5 post-transplant and continue on tacrolimus through day 100 followed by a
taper to approximately day 180 if there is no evidence of GVHD and their graft is doing well.
Patients may convert to oral tacrolimus given BID or three times daily (TID) when the patient
is able to take medications orally and has a therapeutic drug level. In addition, patients
will receive sirolimus orally beginning on day 5 through day 180 followed by a taper to
approximately day 210 if there is no evidence of GVHD and their graft is doing well.

After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months,
and then annually thereafter.

Inclusion Criteria:

- Primary immunodeficiency disorder or other nonmalignant inherited disease (except
Fanconi anemia) treatable by allogeneic HCT

- Patients with pre-existing medical conditions or other factors that renders them at
high risk for regimen related toxicity or ineligible for conventional myeloablative
HCT and who do not have HLA-matched related or unrelated donors

- Patients with a related donor who is identical for one HLA haplotype

- Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows:

- Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30%
residual hematopoietic cells

- Two out of three of the following (in peripheral blood): neutrophils < 0.5 x
10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L

- SAA diagnostic criteria may be applied to assessment at initial diagnosis or
follow-up assessments

- DONOR: Related donors who are identical for one HLA haplotype

- DONOR: Bone marrow will be the only allowed stem cell source

Exclusion Criteria:

- Fanconi anemia

- Suitably HLA-matched related or unrelated donors

- Patients with metabolic storage diseases who have severe central nervous system (CNS)
involvement of disease, defined as intelligence quotient (IQ) score < 70

- Cardiac ejection fraction < 30% (or, if unable to obtain ejection fraction, shortening
fraction < 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram
(echo), symptomatic coronary artery disease, or other cardiac failure requiring
therapy; patients with a history of, or current cardiac disease should be evaluated
with appropriate cardiac studies and/or cardiology consult; patients with a shortening
fraction of < 26% must be seen by cardiology for approval

- Poorly controlled hypertension despite anti-hypertensive medications

- Patients with clinical or laboratory evidence of liver disease will need to be
evaluated for the cause of the liver disease, its clinical severity in terms of liver
function and the degree of portal hypertension; patients will be excluded if they are
found to have fulminant liver failure, cirrhosis of the liver with evidence of portal
hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of
bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic
dysfunction evidenced by prolongation of the prothrombin time, ascites related to
portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic
viral hepatitis with total serum bilirubin > 3 mg/dl, or symptomatic biliary disease

- Positive for human immunodeficiency virus (HIV)

- Females who are pregnant (beta-human chorionic gonadotropin positive [beta-HCG+]) or

- Fertile men or women who are unwilling to use contraceptives during HCT and up to 12
months post-treatment

- Patients with fungal pneumonia with radiological progression after receipt of
amphotericin formulation or mold-active azoles for greater than 1 month will not be
eligible for this protocol

- DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the
host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous

- DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1
x 10^8 nucleated cells/kg recipient ideal body weight)

- DONOR: HIV-positive donors

- DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion

- DONOR: < 6 months old and > 75 years old
We found this trial at
Nashville, Tennessee 37203
Principal Investigator: Haydar A. Frangoul
Phone: 615-329-7339
Nashville, TN
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Nashville, Tennessee 37232
Principal Investigator: James Connelly
Phone: 615-936-1762
Nashville, TN
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Seattle, Washington 98109
Principal Investigator: Lauri M. Burroughs
Phone: 206-667-2396
Seattle, WA
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