Acute GVHD Suppression Using Costimulation Blockade to Expand Non-malignant Transplant

Prior treatment

• Patient with a 7/8 URD donor and HLA antibody testing (see below) demonstrating an antibody directed against a donor disparate HLA molecule.

Other illness

• Severe cardiac dysfunction defined as shortening fraction \< 25%.
• Clinical stroke within 6 months of anticipated transplant
• HIV infection
• Uncontrolled viral, bacterial, fungal, or protozoal infection at the time of study enrollment.
• History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.

Lab values

• Pulmonary dysfunction defined as diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) \< 40% of predicted. In a child unable to perform pulmonary function testing, a chronic need for supplemental oxygen will serve as the exclusionary criterion.
• Renal dysfunction defined as estimated glomerular filtration rate (GFR) of \<60 ml/min/1.73m2.

Other

• HLA matched related donor
• Bridging (portal to portal) fibrosis or cirrhosis of the liver
• Karnofsky or Lansky functional performance score \< 50%
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT.
• Patient or patient's guardian(s) unable to understand the nature and risks inherent in the HSCT process.
• Patient is pregnant or lactating.

• Patients with sickle cell disease (stratum 1) must be between the ages of 3-20.99 years and patients with other diseases (stratum 2) between the ages of 0-20.99 years at the time of admission for transplant.
• Must have one of the following diseases:
  • Glanzmann thrombasthenia
  • Chronic granulomatous disease
  • Severe congenital neutropenia (with resistance to granulocyte colony-stimulating factor (GCSF) or chronic requirement of GCSF doses ≥10 mcg/kg)
  • Leukocyte adhesion deficiency
  • Shwachman-Diamond syndrome
  • Diamond-Blackfan Anemia (DBA; transfusion dependent, including steroid failure or inability to wean steroids)
  • Thalassemia major
  • FA
  • Dyskeratosis congenita
  • Chediak Higashi syndrome
  • Acquired (immune; non-inherited, non-congenital) SAA
  • Any genotypic form of SCD with severe disease, defined as one or more of the following criteria:
  • Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
  • Asymptomatic cerebrovascular disease, as evidenced by one the following:
  • Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm. Lesions must be visible on T2-weighted MRI sequences.
  • Cerebral arteriopathy, as evidenced by abnormal TCD testing (confirmed elevated velocities in any single vessel of time-averaged mean of the maximum velocity (TAMMV) \> 200 cm/sec for non-imaging TCD) or by significant vasculopathy on magnetic resonance angiograph (MRA; greater than 50% stenosis of \> 2 arterial segments or complete occlusion of any single arterial segment).
  • Frequent (3 or more per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting 4 hours or more and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.
  • Recurrent (3 or more in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
  • Any combination of 3 or more acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.
  • Other inherited or congenital marrow failure syndromes complicated by SAA
  • Other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy.
  • Congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years).
  • Other inherited or congenital granulocyte disorders resulting in at least three inpatient hospitalizations in the past three years for infection.
• Must have an unrelated adult donor (marrow or PBSC) who is a 7 or 8/8 match
• All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Must have been evaluated and adequately counseled regarding treatment options by a pediatric hematologist.
• Negative serum pregnancy test for females of childbearing potential only. Pregnancy must be excluded before the start of treatment with study drugs and prevented thereafter by reliable contraceptive methods.