Allograft for Sickle Cell Disease and Thalassemia
Allograft for Sickle Cell Disease and Thalassemia
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

 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®), 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 (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.
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.
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

 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 - 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

 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

 Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry, for
 the duration of study participation, and for 90 days following completion of therapy.
 Should a woman become pregnant or suspect she is pregnant while participating in this
 study, she should inform her treating physician immediately.

 A female of child-bearing potential is any woman (regardless of sexual orientation,
 having undergone a tubal ligation, or remaining celibate by choice) who meets the
 following criteria:

 -  Has not undergone a hysterectomy or bilateral oophorectomy; or

 -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
 has had menses at any time in the preceding 12 consecutive months)

 Major ABO mismatch

 Exclusion criteria - Donor

 Any of the following would exclude the donor from participating

 Pregnant or lactating

 Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry, for
 the duration of study participation, and for 90 days following completion of therapy.
 Should a woman become pregnant or suspect she is pregnant while participating in this
 study, she should inform her treating physician immediately.

 A female of child-bearing potential is any woman (regardless of sexual orientation,
 having undergone a tubal ligation, or remaining celibate by choice) who meets the
 following criteria:

 -  Has not undergone a hysterectomy or bilateral oophorectomy; or

 -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
 has had menses at any time in the preceding 12 consecutive months)

 HIV positive

 Hemoglobin S > 50%, or beta thalassemia intermediate