SCD-Haplo: Phase II Study of HLA-Haploidentical SCT for Aggressive SCD
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Haploidentical Transplant; Alemtuzumab; Total Body Irradiation; Cyclophosphamide; Sirolimus
Intervention description: All subjects will undergo pre-conditioning treatment with alemtuzumab (0.3 mg/kg Day -5, Day -4, Day -3) and total body irradiation (300cGy), followed by stem cell transplant, and post-transplant treatment with cyclophosphamide (50mg/kg/day) and sirolimus (target trough level of 10-15ng/mL).; On Day -7, the first test dose of alemtuzumab (0.03 mg/kg) will be administered and on Day -6, the second test dose of alemtuzumab (0.1 mg/kg) will be administered. Alemtuzumab (0.3 mg/kg) will be infused daily on Day -5, -4, and -3.; A 300cGy dose of TBI will be administered in a single fraction on Day -2.; Cyclophosphamide (50 mg/kg IBW) IV, over approximately 1-2 hours, is given on Day 3 post-transplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 (approximately 24 hours after Day 3 cyclophosphamide).; Sirolimus will be started on Day +5 (at least 24 hours after the completion of the cyclophosphamide infusion). The starting dose will be 12mg followed by 4mg PO daily. Doses will be adjusted to achieve a whole blood trough level of 4 - 12ng/mL.
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Alemtuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 16 Years
Maximum age: 60 Years
Healthy volunteers: No

Summary:

      Related donor stem cell transplantation using the alemtuzumab/ TBI platform has been shown to
      be a safe strategy to cure severe sickle cell disease. However, due to a lack of suitable
      donors, many patients cannot benefit from this strategy. Alternative donor sources are
      desperately needed to fill this gap. Nearly all patients will have a haploidentical family
      member who would be able to donate. The use of post transplantation cyclophosphamide has
      greatly improved the outcome of haploidentical stem cell transplantation. The investigators
      propose to combine this with alemtuzumab/TBI conditioning.
    

Eligibility criteria:

        Patient Eligibility:

          -  Patients with sickle cell disease are eligible if they have any of the following
             complications:

               -  Stroke or central nervous system event lasting longer than 24 hours

               -  Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring
                  emergency room, acute care center, or hospital admissions.

               -  Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room
                  visits

               -  Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime
                  events

               -  Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy

               -  Bilateral proliferative retinopathy with major visual impairment in at least one
                  eye

               -  Osteonecrosis of 2 or more joints

               -  Sickle cell nephropathy, defined by a GFR < 90mL/min/1.73m2 or the presence of
                  macroalbuminuria (urine albumin > 300 mg/g creatinine)

               -  Pulmonary hypertension, defined by a mean pulmonary artery pressure > 25mmHg

          -  Age 16-60 years

          -  Karnofsky performance status of 60 or higher

          -  Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%

          -  Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥
             50% predicted (after adjustment for hemoglobin concentration)

          -  Estimated GFR ≥ 50mL/min as calculated by the modified MDRD equation

          -  ALT ≤ 3x upper limit of normal

          -  HIV-negative

          -  Patient is pregnant

          -  Patient is able and willing to sign informed consent

          -  Patient has an HLA-haploidentical relative