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

Study ID
STU 012013-015

Cancer Related

Healthy Volunteers

Study Sites

James Pond

Principal Investigator
Prapti Patel


The design of the study incorporates the following features:

1) This is a phase ii study to determine the safety and therapeutic potential of a new transplant approach (disease-free survival, graft versus myeloma effect) and to evaluate its toxicity profile (immediate toxicity, graft-versus-host disease, graft rejection, mortality) in a patient population with severe congenital anemias.

2) The patient cohort to be studied: Those patients with severe sickle cell disease and thalassemia who have risk factors for high mortality and morbidity related to their disease (see inclusion criteria in section and

3) Transplant Conditioning Regimen - immunosuppression without myeloablation: Patients will receive conditioning sufficient to allow donor lympho-hematopoietic engraftment without complete marrow ablation. if the graft is rejected, the patient will reconstitute autologous marrow function. We will use a combination of low dose irradiation, alemtuzumab (Campath[RegisteredTM]), and sirolimus.

4) Peripheral blood hematopoietic progenitor cell (PBPC) transplant: an unmanipulated peripheral blood stem cell collection from a filgrastim (G-CSF) stimulated HLa-matched donor should improve the chance of engraftment because of the high stem cell dose ([GreaterThanorequalTo]5 x 106/kg CD34+ cells) and the presence of donor lymphocytes. To reduce the risk of GVHD, patients will receive sirolimus before and after the transplant. The sirolimus will be tapered as necessary to minimize any graft versus host disease while still maintaining adequate chimerism.

Primary endpoint:

The primary endpoint is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with sickle cell disease and transfusion-independence for patients with thalassemia.

This trial is designed to estimate treatment success, which is anticipated to be about 80%. The study started with a sample size of 25 and this will allow us to estimate the success of engraftment. For example, if the estimated rate is .80, the 95% confidence interval would be approximately (.64, .96). This would allow us to rule out rate of treatment success of less than .64. if the estimated rate is .70, the 95% confidence interval would be approximately (.52, .88) and we could rule out rate of treatment success below .50. if the lower bound of the 95% confidence interval is raised to 0.7, the number of subjects needed to accrue with respect to success rate is listed below. Thus a revised accrual ceiling of 50 would allow more certainty of the eventual success rate.

Participant Eligibility

Inclusion criteria x Recipient

Must fulfill one disease category in 3.1.1 and all of 3.1.2

Disease specific:

Sickle Cell Disease - Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end-organ damage (A, B, C,D, or E) or potentially reversible 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 an abnormal trans-cranial Doppler examination (>=200m/s); OR

B. Sickle cell related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance < 50mL/min OR requiring peritoneal or hemodialysis. OR

C. Pulmonary hypertension as defined by tricuspid regurgitant jet velocity (TRV) of >= 2.5m/s at least 3 weeks after a vaso-occlusive crisis; OR

D. Recurrent tricorporal priapism defined as at least two 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; OR

F. Any one of the below complications
1. Vaso-occlusive crises
2. Acute chest syndrome
3. Osteonecrosis of 2 or more joints
4. Red cell alloimmunization

Thalassemia - 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 desferroxamine 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 2 cm below the costochondral margin

Non-disease specific:

Ages >= 18 but <= 45

6/6 HLA matched family donor available

Ability to comprehend and willing to sign an informed consent, assent obtained from minors

Negative serum pregnancy test

Inclusion criteria x Donor

6/6 HLA identical family donor

Weight > 20 kg (in so far 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)

Fit to receive G-CSF and give peripheral blood stem cells (normal blood counts, normotensive, and no history of stroke)

Ability to comprehend and willing to sign an informed consent