Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Beta-Thalassemia

Status:Active, not recruiting
Conditions:Orthopedic, Anemia, Hematology
Therapuetic Areas:Hematology, Orthopedics / Podiatry
Age Range:2 - 80
Start Date:September 9, 2009
End Date:September 10, 2020

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- Bone marrow transplantation (BMT), which involves transplanting a donor s marrow stem
cells, is capable of curing some congenital anemias. BMT usually involves high-intensity
treatment with chemotherapy and radiation to kill abnormal cells, which affects all
systems of the body.

- People with anemias often have damage to other organs such as the kidneys, which can be
further damaged by the chemotherapy. Only approximately 20 percent of patients have a
full-matched donor, making treatment for many people with anemias unavailable. However,
90 percent of patients may have a half-matched donor, but using a half-matched donor
increases the toxicity of BMT.


- To determine if a research BMT with half-matched donor cells, low-intensity radiation,
immunosuppressant drugs, and no chemotherapy will be effective in patients with sickle
cell disease and Beta-thalassemia.

- To determine the effectiveness of cyclophosphamide, an immunosuppressant drug, in
preventing rejection of the donor cells.


- Recipients are individuals at least 18 years of age who have been diagnosed with sickle
cell disease and Beta-thalassemia, and who have a family member who is a haploidentical
(i.e., half match) tissue match.

- Donors are healthy individuals between the ages of 2 and 80 who are found to be suitable


- Donors will undergo apheresis, which involves withdrawing blood from one arm vein,
passing it through a machine that removes bone marrow stem cells, and returning the
remaining blood through the vein in the other arm. Donors will receive a drug that
causes the stem cells to be released into the bloodstream prior to the apheresis

- Recipients will undergo routine physical and laboratory examinations, including bone
marrow sampling at the beginning of the study. After transplantation, physical and
laboratory examinations will occur on a weekly or twice weekly basis at the outpatient
clinic. Recipients will be examined every 6 months starting 100 days posttransplant for
5 years.

- Recipients will receive low-dose radiation in two treatments 1 and 2 days before the
transplant. They will also be given immunosuppressant therapy with alemtuzumab and
sirolimus. Another immunosuppressant drug, cyclophosphamide, will be given in the future
as needed to subsets of the recipients to prevent rejection of donor cells.

- Recipients will receive the donor stem cells through a previously inserted central line.
The process takes up to 8 hours.

- Recipients will receive blood transfusions as necessary to prevent anemia and bleeding
during the posttransplant period. They may also receive intravenous antibiotics to
prevent infection.

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being
investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number
of transplant centers. Our ongoing protocol for patients with severe congenital anemias,
particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent
preliminary results. None of the patients who engrafted had sickle-related events or any
evidence of graft versus host disease (GVHD). There was no significant toxicity associated
with the conditioning regimen.

Our main limitation has been a lack of HLA-matched sibling donors in the majority of
patients. We performed a study in which patients with severe SCD who lacked a suitable donor
underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority
of patients were not found to have an appropriate alternative donor. We therefore seek to
develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that
family members can serve as donors and greatly expand the donor pool.

In this protocol, we propose PBSC transplantation in patients with SCD and thalassemia,
considered at high risk for complications from or ineligible for standard bone marrow
transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor
using a novel immunosuppressive regimen without myeloablation in an attempt to further
decrease the transplant-related morbidity/mortality. The low intensity nonmyeloablative
conditioning regimen will consist of a relatively low radiation dose for therapeutic
radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), and Cyclophosphamide (Cytoxan ) as
a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical
remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte
colony-stimulating factor (G-CSF)-mobilized PBSC will be used to establish hematopoietic and
lymphoid reconstitution.

The primary endpoint of this study is the percentage of patients who have sustained donor
type hemoglobin without significant GVHD for patients with SCD, or who are
transfusion-independent and without significant GVHD for patients with thalassemia. Other
endpoints include degree of donor-host chimerism necessary for long term graft survival and
disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection,
transplant-related morbidity, as well as disease-free and overall survival.


Recipients (must fulfill one disease category in 5.1.1 and all of 5.1.2)

5.1.1 Disease specific Patients with sickle cell disease (HB SS, SC, or SBeta(0)-thal) at high risk for
disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, C,
or D) or potentially modifiable complication(s) not ameliorated by hydroxyurea (E):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an
infarct on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy; OR

B. Sickle cell-related renal insufficiency defined by a creatinine level greater than or
equal to 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell
nephropathy OR nephrotic syndrome OR creatinine clearance less than 50mL/min OR requiring
peritoneal or hemodialysis; OR

C. Pulmonary hypertension defined as tricuspid regurgitant jet velocity (TRV) of greater
than or equal to 2.5 m/s at baseline (without vaso-occlusive crisis); OR

D. Sickle hepatopathy defined as EITHER ferritin greater than 1000mcg/L OR direct bilirubin
greater than 0.4 mg/dL AND platelet count less than 250,000/microL at baseline (without
vaso-occlusive crisis)

E. Any one of the below complications:

-Complication: Vaso-occlusive crises;

Eligible for hydroxyurea*: At least 3 hospital admissions in the last year.

Eligible for HSCT: More than 1 hospital admission per year while on maximal tolerated dose
of hydroxyurea*

-Complication: Acute chest syndrome

Eligible for hydroxyurea*: 2 prior ACS

Eligible for HSCT: any ACS while on hydroxyurea*

*hydroxyurea at maximum tolerated dose for at least 6 months Patients with thalassemia who have grade 2 or 3 iron overload, determined by the
presence of 2 or more of the following:

- portal fibrosis by liver biopsy

- inadequate chelation history (defined as failure to maintain adequate compliance with
chelation with deferoxamine initiated within 18 months of the first transfusion and
administered subcutaneously for 8-10 hours at least 5 days each week)

- hepatomegaly of greater than 2cm below the costochondral margin

5.1.2 Non-disease specific: Age greater than or equal to 18 years Haploidentical relative donor available Ability to comprehend and willing to sign an informed consent Negative Beta-HCG


Recipient (any of the following would exclude the subject from participating)

5.2.1 6/6 HLA-matched with or without an ABO minor mismatched sibling donor

5.2.2 ECOG performance status of 3 or more

5.2.3 Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
medication and progression of clinical symptoms) within one month prior to starting the
conditioning regimen. Patients with fever or suspected minor infection should await
resolution of symptoms before starting the conditioning regimen.

5.2.4 Major anticipated illness or organ failure incompatible with survival from PBSC

5.2.5 Pregnant or lactating

5.2.6 Major ABO mismatch



5.3.1 Haploidentical relative donor

5.3.2 Weight greater than or equal to 20 kg (insofar that the weight difference between
recipient and donor does not exceed a reasonable likelihood of being able to obtain an
adequate cell dose from the donor within two aphereses)

5.3.3 Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood
counts and blood pressure within DTM standards)

5.3.4 No history of congestive heart failure or unstable angina, and no history of stroke)

5.3.4 Ability to comprehend and willing to sign an informed consent; assent obtained from


Donor: (any of the following would exclude the donor from participating)

5.4.1 Pregnant or lactating

5.4.2 HIV positive

5.4.3 Hemoglobin S greater than or equal to 50 percent, or beta

thalassemia intermedia
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Phone: 800-411-1222
Bethesda, MD
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