Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias Including Sickle Cell Disease and Thalassemia
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Sickle Cell Disease and Thalassemia
- Sponsor
- University of Texas Southwestern Medical Center
- Locations
- 1
- Primary Endpoint
- Treatment Success at One Year
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
The design of the study incorporates the following features:
- 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.
- 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
- 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®), and sirolimus.
- 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 (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.
Detailed Description
A human lymphocyte antigen (HLA)-matched sibling donor will receive filgrastim (G-CSF) 10 to16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of PBPC on day 5 (and day 6 if required). The product will be collected by leukophoresis with a goal of ≥ 10 x 106 CD34+ cells/kg, with a minimum of 5 x 106 CD34+ cells/kg. The patient will receive a preparative regimen of Alemtuzumab to be infused on days -7 to -3, followed by 300 cGy TBI given as a single dose on day -2. Sirolimus at a dose of 5mg/day to maintain trough levels between 10-15ng/ml will be started on day -1. The PBPC graft targeted to deliver 10 x 106 CD34+ cells/kg (at minimum, 5 x 106 CD34+ cells/kg) will be infused on day 0 On days +14, +30, +60 and +100 the chimeric status of patients will be assessed by microsatellite analysis of the peripheral blood. More frequent monitoring may be required. Sickle cell patients with pulmonary hypertension will meet with a Pulmonary Medicine Consult to determine appropriate management prior to SCT. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen. Iron chelation must be discontinued \> 48 hours before initiating the conditioning regimen. Hydroxyurea must be discontinued one day prior to initiating the conditioning regimen.
Investigators
Prapti Patel
PI
University of Texas Southwestern Medical Center
Eligibility Criteria
Inclusion Criteria
- •Inclusion criteria - Recipient
- •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
- •Vaso-occlusive crises
Exclusion Criteria
- •Exclusion criteria - Recipient
- •Any of the following would exclude the subject from participating
- •ECOG performance status of 3 or more or Lanksy performance status of \<40
- •Diffusion capacity of carbon monoxide (DLCO) \<50% predicted (corrected for hemoglobin and alveolar volume)
- •Baseline oxygen saturation of \<85% or PaO2 \<70
- •Left ventricular ejection fraction: \<40% estimated by ECHO
- •Transaminases \> 5x upper limit of normal for age
- •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
- •Major anticipated illness or organ failure incompatible with survival from PBSC transplant
- •Pregnant or lactating
Outcomes
Primary Outcomes
Treatment Success at One Year
Time Frame: Treatment Success at one year
This is defined as full donor type hemoglobin on hemoglobin electrrophoresis for patients with sickle cell disease and transfusion-independence for patients with thalassemia.
Secondary Outcomes
- Level of chierism required to maintain Graft Survival and hematologic normalcy(Measured on days 14, 30, 60 and 100)