Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

• INCLUSION CRITERIA:

RECIPIENTS:

Must fulfill one disease category from below:

DISEASE SPECIFIC:

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 and infarct on cerebral MRI

OR

an abnormal trans-cranial Doppler examination ( greater than or equal to 200m/s);

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 nephritic syndrome OR creatinine clearance less than 60mL/min/1.73m(2) for patients less than or equal to 16 years of age or less than 50mL/min for patients greater than or equal to 16 years of age OR requiring peritoneal or hemodialysis

OR

Age is less than or equal to 5 years of age with the upper limit of normal serum creatinine 0.8mg/dl

Age is greater than 5 years or less than or equal to 10 years of age with the upper limit of normal serum creatinine 1.0mg/dl

Age is greater than 10 years and less than or equal to 15 years of agethe the upper limit of normal serum creatinine 1.2mg/dl

Age greater than 15 years of age with the upper limit of normal serum creatinine 1.3mg/dl

C. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5m/s in patients greater than or equal to 18 years of age at least 3 weeks after a vaso- occlusive crisis, OR

D. Recurrent tricorporal praipism defined as at least two episodes of an erection lasting greater than or equal to 4 hours involving the corpora cavernosa and corpus spongiosa, OR

E. Sickle hepatopathy defined as EITHER ferritin greater than 100mcg/L OR direct bilirubin greater than 0.4 mg/dL at baseline in patients greater than or equal to 18 years of age; OR

F. Any one of the below complications:

1. Vaso-occlusive crisis:

   • Eligible for hydroxyurea at least 3 hospital admissions in the last year
   • Eligible for HSCT More than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea

2. Acute Chest Syndrome (ACS):

   • Eligible for hydroxyurea: 2 prior ACS while greater than 3 years of age and adequately treated for asthma
   • Eligible for HSCT: any ACS while on hydroxyurea*

3. Osteonecrosis of 2 or more joints:

   • Eligible for hydroxyurea: And significantly affecting their quality of life by Karnofsky score 50-60
   • Eligible for HSCT: And on hydroxyurea* where total hemoglobin increase less than 1g/dL or fetal hemoglobin increases less than 2.5 time the baseline level

4. Red cell alloimmunization:

   • Eligible for hydroxyurea: Transfusion dependent

   • Eligible for HSCT: Total hemoglobin increase less htan 1 g/dL while on hydroxyurea*

     • hydroxyurea at maximum tolerated dose

   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 desferoxamine 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 greater than or equal to 4 years
   • 6/6 HLA matched family donor available
   • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
   • Negative serum beta-HCG
   • Pediatric patients less than 16 years of age must decline myeloablative bone marrow transplantation

   DONOR:

   Donor deemed suitable and eligible, and willing to donate per clinical evaluations, who are additionally willing to donate blood for research and undergo a neuropsychological test. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation under a separate NHLBI protocol. Note that participation in this study is offered to all donors, but is not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study.

   EXCLUSION CRITERIA:

   RECIPIENT:

   (Any of the following would exclude the subject from participating)

   ECOG performance status of 3 or more or Lansky performance status of less than 40.

   Diffusion capacity of carbon monoxide (DLCO) less than 35% predicted. (corrected for hemoglobin and alveolar volume)

   Baseline oxygen saturation or less than 85 % or PaOa2 less than 70

   Left ventricular ejection fraction: less than 35% estimated by ECHO.

   Transaminases greater than 5 times the 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

   Major ABO mismatch

   DONOR:

   None