Nonmyeloablative Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease and Beta-thalassemia in People With Higher Risk of Transplant Failure
Nonmyeloablative Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease and Beta-thalassemia in People With Higher Risk of Transplant Failure
Background:

 - Some sickle cell disease or beta-thalassemia can be cured with transplant. Researchers want
 to test a variation of transplant that uses low dose radiation and a combination of
 immunosuppressive drugs. They want to know if it helps a body to better accept donor stem
 cells.

 Objectives:

 - To see if low dose radiation (300 rads), oral cyclophosphamide, pentostatin, and sirolimus
 help a body to better accept donor stem cells.

 Eligibility:

 - People 4 and older with beta-thalassemia or sickle cell disease that can be cured with
 transplant, and their donors.

 Design:

 -  Participants and donors will be screened with medical history, physical exam, blood
 test, tissue and blood typing, and bone marrow sampling. They will visit a social
 worker.

 -  Donors:

 -  may receive an intravenous (IV) tube in their groin vein.

 -  will receive a drug injection daily for 5 or 6 days to move the blood stem cells from
 the bone marrow into general blood circulation.

 -  will undergo apheresis: an IV is put into a vein in each arm. Blood is taken from one
 arm, a machine removes the white blood cells that contain blood stem cells, and the rest
 is returned through the other arm.

 -  Participants:

 -  may undergo red cell exchange procedure.

 -  will remain in the hospital for about 30 days.

 -  will receive a large IV line that can stay in their body from transplant through
 recovery.

 -  will receive a dose of radiation, and transplant related drugs by mouth or IV.

 -  will receive blood stem cells over 8 hours by IV.

 -  will take neuropsychological tests and may complete questionnaires throughout the
 transplant process.

 -  must stay near NIH for 4 months. They will visit the outpatient clinic weekly.

 -  will have 5 follow-up visits for 3 years after transplant, then annually.
Our ongoing nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplant protocol
 (03-H-0170) for patients with severe sickle cell disease (SCD) and B-thalassemia from
 HLA-matched family donors has excellent results thus far. Our long term leukocyte engraftment
 rate is 85-90% with the same disease-free survival. None of the engrafted patients had acute
 sickle-related events, significant toxicity associated with the conditioning regimen, or any
 evidence of graft versus host disease (GVHD).

 While these results rival the transplant outcomes from low risk transplant patients with
 B-thalassemia, there are areas for improvement. The first is the 10-15% graft rejection rate,
 where a majority of these individuals were male donor and female recipient pairs. Another
 limitation is the significant delay in donor red cell engraftment in one recipient who had
 pre-existing allo-antibody to donor red cells from previous transfusions. Also we have
 excluded another group of individuals with preformed antibodies, recipients having major ABO
 incompatibility to the donors.

 To overcome these limitations (and reduce the transplant failure rate) in this new protocol,
 we will continue our nonmyeloablative approach in the patients with SCD and B-thalassemia
 with HLA-matched family donors, but using an increased intensity regimen in a subset
 considered at high risk for transplant failure. This modified regimen consists of pentostatin
 and oral cyclophosphamide, which we hypothesize will reduce both the T cells that mediate
 leukocyte rejection and the B/plasma cells that produce anti-donor erythrocyte antibodies.
 The main transplant backbone will remain as alemtuzumab, low dose total body irradiation of
 300 cGy, and sirolimus; the transplant graft will remain as unmanipulated G-CSF mobilized,
 T-cell replete, PBSC product for hematopoietic and lymphoid reconstitution.

 The primary endpoint of this study is the percentage/number of patients who have sustained
 donor type hemoglobin at 1 year post transplant for male donors - female recipients. The
 primary endpoint for those with pre-existing antibodies is the presence of donor red cells
 with reticulocytes greater than or equal to 30 k/uL at 2 years post-transplant. Other
 endpoints include the toxicity of the pentostatin-cyclophosphamide regimen, the 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. Since SCD and B-thalassemia are
 non-malignant disorders of red cells, severe GVHD, lack of donor erythrocyte (prolonged donor
 red cell aplasia), or graft rejection is collectively considered transplant failure.
-  INCLUSION CRITERIA- recipients (must fulfill one disease category in 1.0 and all of
 2.0)

 1.0 Disease specific

 1.1 Patients with sickle cell disease (Hb SS, SC, or S beta-thal) at high risk for
 disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, C,
 D, or E) or potentially modifiable complication(s) not ameliorated by hydroxyurea (F):

 -  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. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 m/s 40, 41
 at baseline; OR

 -  D. Recurrent priapism defined as at least 2 episodes of an erection lasting >4 hours
 involving the corpora cavernosa and corpus spongiosa; OR

 -  E. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4
 mg/dL at baseline

 -  F. Any one of the below complications:

 -  Complication/ Eligible for hydroxyurea*/ Eligible for HSCT

 -  Vaso-occlusive crises/ At least 3 hospital admissions in the last year/ More
 than one hospital admission in the last year while on maximal tolerated dose
 of hydroxyurea (at MTD for at least 6 months)

 -  Acute chest syndrome/ 2 prior ACS/ any ACS while on hydroxyurea (at MTD for
 at least 6 months)

 -  Osetonecrosis of 2 or more joints/ And significantly affecting their quality
 of life by Karnofsky score 50-60/ And on hydroxyurea where total hemoglobuin
 increases less than 1 g/dL or fetal hemoglobin increases less than 2.5 times
 the baseline level

 -  Red cell alloimmunization/ Transfusion dependent/ Total hemoglobin increases
 less than 1g/dL while on hydroxurea (hydroxurea for at least 6 months)

 1.2 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

 2.0 Non-disease specific:

 2.1 Age greater than or equal to 4 years

 2.2 6/6 HLA matched family donor available

 2.3 Ability to comprehend and willing to sign an informed consent

 2.4 Negative beta-HCG, when applicable

 EXCLUSION CRITERIA - recipient (any of the following would exclude the subject from
 participating)

 1. ECOG performance status of 3 or more

 2. 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.

 3. Major anticipated illness or organ failure incompatible with survival from PBSC
 transplant

 4. Pregnant or lactating

 5. We will measure anti-A, anti-B, and/or other red cell antibody titers from the first
 cohort to determine the feasibility of transplanting patients with pre-existing
 antibodies (major ABO mismatch or other anti-donor red cell antibody). The information
 gathered from this cohort of patients will help to determine if the titer or antibody
 to a specific antigen needs to be incorporated in the exclusion criteria.

 INCLUSION CRITERIA - adult donor

 1. 6/6 HLA matched family donor

 2. Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood
 counts and blood pressure within DTM standards no history of congestive heart failure
 or unstable angina, and no history of stroke)

 3. Ability to comprehend and willing to sign an informed consent; assent obtained from
 minors

 EXCLUSION CRITERIA - adult donor: (any of the following would exclude the donor from
 participating)

 1. Pregnant or breastfeeding

 2. HIV positive

 3. Hemoglobin S greater than or equal to 50%, or B-thalassemia intermedia

 INCLUSION CRITERIA - pediatric donor

 Pediatric donors will undergo apheresis as a Standard of Care procedure under NHLBI
 protocol 94-H-0010. These donors must meet the NIH Department of Transfusion Medicine (DTM)
 requirements for apheresis donation.

 pdiatric donors will be enrolled onto this study in order to provide a research blood
 sample. These donors must have met standard inclusion requirements for apheresis donation
 first.