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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Nonmyeloablative Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia in Individuals With Higher Risk of Transplant Failure

Conditions
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Sickle Cell Disease, Thalassemia, Stem Cell Transplantation, Graft vs Host Disease

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Sirolimus
* Drug: Cyclophosphamide
* Drug: Pentostatin
* Procedure: Radiotherapy


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA- recipients (must fulfill one disease category in 1 and all of 2) Disease specific Patients with severe sickle cell disease (not limited to 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 or sickle specific therapy (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 therapeutic dose of hydroxyurea or sickle cell therapy Acute chest syndrome/ 2 prior ACS/ any ACS while on hydroxyurea 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 2. Patients with beta-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 Non-disease specific: -Age greater than or equal to 4 years -6/6 HLA matched family donor available Ability to comprehend and willing to sign an informed consent Negative beta-HCG, when applicable EXCLUSION CRITERIA -recipient (any of the following would exclude the subject from participating) -ECOG performance status of 3 or more -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. -Major anticipated illness or organ failure incompatible with survival from PBSC transplant -Pregnant or lactating INCLUSION CRITERIA -donor -6/6 HLA matched family donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood for research. Matched related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all matched related donors, but is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study. EXCLUSION CRITERIA -donor -None

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: male donor - female recipient<br>The first cohort of patients will be male donor - femalerecipients to see if this new regimen will yield higher rate of durable donor leukocyte chimerism. We will also measure anti-A, anti-B, and/or other red cell antibody titers from this initial cohort to determine the feasibility of transplanting patients with pre-existing antibodies (major ABO mismatch or other anti-donor red cell antibody) | Drug: Alemtuzumab<br>* Immunosuppressant<br>Drug: Sirolimus<br>* Immunosuppressant<br>Drug: Cyclophosphamide<br>* Immunosuppressant<br>Drug: Pentostatin<br>* Immunosuppressant<br>Procedure: Radiotherapy<br>* Immunosuppressant and myelosuppressant<br>|
| Experimental: patients with preexisting antibodies<br>patients with preexisting antibodies (major ABO mismatch or otheranti-donor red cell antibody). The primary endpoint forthis group will be different than the first cohort. It is very likely that red cell aplasia (6 months to 2 years posttransplant) and prolonged duration of red cell transfusion are expected in this second group, thus a later time point to determine treatment success is justified. | Drug: Alemtuzumab<br>* Immunosuppressant<br>Drug: Sirolimus<br>* Immunosuppressant<br>Drug: Cyclophosphamide<br>* Immunosuppressant<br>Drug: Pentostatin<br>* Immunosuppressant<br>Procedure: Radiotherapy<br>* Immunosuppressant and myelosuppressant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine regimen failure rate, defined as graft rejection, severe GVHD (acute GVHD grade 3 or higher or extensive chronic GVHD), or prolonged donor red cell aplasia (>2 years post-HSCT) | 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 =30 k/uL at 2 years post-transplant. | greater than or equal to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the level of chimerism required to maintain both graft survival as well as hematologic normalcy using a regimen containing pentostatin, cyclophosphamide, alemtuzumab, and low total body irradiation. |  | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, Allogeneic Hematopoietic Stem Cell Transplant, Pentostatin (Nipent), Cyclophosphamide, Alemtuzumab (Campath)