Cord Blood Transplantation for Sickle Cell Anemia and Thalassemia

BACKGROUND:

During the past decade, a number of advances have been made in the treatment of patients
with sickle cell anemia and thalassemia. Among these advances is allogeneic bone marrow
transplantation, which is the only current treatment that offers a potential for cure. In
sickle cell anemia, transplantation has been performed in patients who have had advanced
organ damage. In thalassemia, transplantation has been performed before having any evidence
of iron-related tissue damage. Due to concerns over engraftment and graft versus host
disease (GVHD), transplants for patients with hemoglobinopathies have been limited to
situations in which a human leukocyte antigen (HLA) compatible donor existed. Unfortunately,
an HLA-matched related donor is often not available. Umbilical cord blood (UCB), a recently
recognized source of hematopoietic stem cells, has been used to successfully transplant bone
marrow to over 500 patients. The potential advantage of cord blood over other donor sources
of stem cells is the minimal risk of high-grade GVHD (even without complete HLA
compatibility).

DESIGN NARRATIVE:

This study will establish a national sibling donor cord blood (SDCB) program, evaluate its
use in a multi-center pilot study of transplantation, and develop a Web-based data
management system to support these two projects. A multi-center pilot study was conducted on
cord blood transplantation in children with either sickle cell disease or thalassemia. The
investigators tested the hypothesis that a novel immunosuppressive conditioning regimen
(fludarabine, cyclophosphamide, and busulfan) and post transplant therapy (mycophenolate
mofetil and cyclosporine) would improve engraftment rates and prevent disease recurrence.
The effect of SDCB transplantation on hematologic parameters and GVHD was monitored.
Enrollment in the study was suspended on December 29, 2003. The protocol was revised,
replacing the previous conditioning regimen of fludarabine, busulfan, and cyclophosphamide
with a more conventional regimen of rabbit anti-thymocyte globulin (Sangstat), busulfan, and
cyclophosphamide. The revised protocol is open for enrollment.

Inclusion Criteria:

- Suitable UCB collection from an HLA-identical sibling

- Sickle cell anemia (Hb SS or S beta thalassemia) with significant disease
manifestations as defined by at least one of the following criteria:

1. A history of painful events defined as three or more painful events in the 2
years prior to enrollment. Pain may occur in typical sites associated with
vaso-occlusive painful events and cannot be explained by causes other than
sickle cell disease. The pain must last at least 4 hours and require treatment
with either parenteral narcotics, an equianalgesic dose of oral narcotics (if
pain is treated in a local facility where parenteral narcotics are not routinely
used to treat painful events), or parenteral nonsteroidal anti-inflammatory
drugs. Painful events managed at home will be considered only if there is
documentation of the event in a clinical record that may be reviewed by an
investigator.

2. Acute chest syndrome (ACS) with two or more episodes of ACS with the development
of a new infiltrate on chest radiograph and/or having a perfusion defect
demonstrable on a lung radioisotope scan

3. Any combination of painful events and episodes of ACS that total three events in
the 2 years before transplantation

4. Any clinically significant neurologic event (stroke or hemorrhage) or any
neurologic defect lasting more than 24 hours

5. Abnormal cerebral MRI and abnormal cerebral MRA

6. An episode of dactylitis in the first year of life with significant anemia (Hbg
less than 7 g/dL), or leukocytosis in the second year of life such that the risk
of a severe adverse outcome before 18 years of age exceeds 54% (as defined by
the cooperative study of sickle cell disease (CSSCD) infant cohort study)

7. History of positive trans-cranial Doppler studies (average greater than 200
cm/sec)

- Beta thalassemia major with significant disease manifestations as defined by the
following criteria: Beta thalassemia genotype consistent with clinical diagnosis of
beta thalassemia major (could include patients with E-beta thalassemia genotype) and
requiring eight or more red blood cell (RBC) transfusions a year and iron chelation
therapy. Younger patients who are at risk of transfusional iron overload but who have
not yet initiated iron chelation therapy will be eligible.

- Adequate physical function as measured by the following criteria:

1. Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection
fraction at rest must be greater than 40% and must improve with exercise, or
shortening fraction greater than 26%

2. Hepatic: Less than 5 times the clinical baseline of AST and less than 2.5 times
the clinical baseline mg/dL of total serum bilirubin (clinical baseline is
determined from the mean of the four most recent test results)

3. Renal: Serum creatinine within normal range for age or if serum creatinine is
outside normal range for age then renal function (creatinine clearance or GFR)
greater than 50% of the lower limit of normal (LLN) for age

4. Pulmonary: Asymptomatic, or, if symptomatic, DLCO, FEV1, FEC (diffusion
capacity) greater than 45% of predicted (corrected for hemoglobin); if unable to
obtain PFT, oxygen saturation greater than 85% on room air