SALT: Alternative Donor Bone Marrow and Cord Blood Transplantation for High Risk Sickle Cell Disease

Unfortunately, less than 1/4th of patients with severe SCD will have a matched sibling donor
that can serve as a BMT donor. This research protocol proposes to study the safety and
usefulness of "alternate donor transplant" (using donors other than matched siblings). We
will offer this treatment to children with severe sickle cell disease that do not have a
matched sibling BMT donor. Alternative donors can be family members who are slightly less
than completely matched, unrelated volunteer donors who are completely matched, and donated
banked umbilical cord blood that is completely or nearly completely matched.

Alternative donor transplant has been performed commonly in patients with cancer, and also
provides curative therapy for several non-malignant diseases (severe immunodeficiency,
marrow failure and metabolic storage diseases). Alternate donor transplants carry higher
risks of complications, including graft-versus-host disease, infection, and graft failure.
Therefore, we will be selective about which patients are invited to participate, limiting
eligibility to those patients that have had a severe SCD related problem (rather than those
who are doing well and are likely to have few SCD related problems), but excluding patients
who have such severe organ damage that they are more likely to die during transplant, and
limiting eligibility to a young age group. A multi-step review algorithm that includes
internal, local and external expert review has been constructed to provide a thorough, safe
and ethical accrual process. We will treat patients using drugs and methods commonly used in
alternate donor transplant for other diseases such as leukemia, and incorporate lessons
learned from our previous experience in BMT for sickle cell by modifying supportive care
measures. Special attention will be given to evaluation of post-BMT effects in this
population, as well as potential reasons for adverse effects (such as graft failure).

We think that Atlanta is a particularly good place to study this kind of transplant for
several reasons. One reason is experience: our program has transplanted more children with
SCD than any other single institution in North America, with excellent outcomes.
Additionally, SCD patients in our area often have been treated on a special red cell
transfusion program that limits the number of people donating the blood; we think this is
likely to reduce the chance of graft failure.

Inclusion Criteria:

- Hemoglobin SS, hemoglobin SC, or hemoglobin S0 thalassemia

- Donor available: Partially (5/6) HLA-matched relative (PMRD), matched (6/6)
unrelated marrow donor or umbilical cord (5/6 or 6/6) of appropriate size (see 6.3.2)
, using high-resolution HLA typing. Donor must not be homozygous for HgbS and must
meet standard donor eligibility criteria of the Blood and Marrow Transplant Program.

- Severe SCD, defined by one of the following (modified Walters criteria):

oPrevious (6 months prior) central nervous system event lasting longer than 24 hours, plus
objective imaging evidence of CNS vasculopathy, with or without residual neurologic
findings oFrequent (3 per year for 2 years) painful vaso-occlusive episodes (defined as
episode lasting 4 hours and requiring hospitalization or outpatient treatment with
parenteral narcotics) oRecurrent (3 in lifetime) acute chest syndrome events which have
necessitated exchange transfusion or chronic transfusion therapy. Must have failed a
good-faith trial of hydroxyurea (failure defined as a reduction of less than 50% in the
incidence of vaso-occlusive events over a period of at least 18 months) or have
demonstrated an inability to take the drug due to side effects.

oAny combination of 3 acute chest syndrome episodes and vaso-occlusive pain episodes
(defined as above) yearly for 3 years. Must have failed a good-faith trial of hydroxyurea
(failure defined as a reduction of less than 50% in the incidence of vaso-occlusive events
over a period of at least 18 months) or have demonstrated an inability to take the drug
due to side effects.

oStage I or II sickle lung disease oRed-cell alloimmunization (2 antibodies) on chronic
transfusion therapy

Exclusion Criteria:

oSuitable HLA-identical relative donor is available oBiopsy proven chronic active
hepatitis, portal fibrosis, or cirrhosis, or serologic evidence of active hepatitis.

oSCD chronic lung disease stage III (see Appendix) oSevere renal dysfunction defined as
<50% of predicted normal GFR for age. oSevere cardiac dysfunction defined as shortening
fraction < 25%. oSevere residual neurologic impairment other than hemiplegia alone,
defined as full-scale IQ 70, quadriplegia or paraplegia, inability to ambulate, inability
to communicate without assistive device, or any impairment resulting in decline of Lansky
performance score to <70%.

oCNS event occurring within 6 months prior to transplant oKarnofsky or Lansky functional
performance score < 70% (see Appendix) oConfirmed HIV seropositivity. oPatient with
unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity
to tolerate bone marrow transplantation.

oPatient or patient's guardian(s) unable to understand the nature and risks inherent in
the BMT process.

oHistory of lack of compliance with medical care that would jeopardize transplant course.