SCD-Haplo: Phase II Study of HLA-Haploidentical SCT for Aggressive SCD

Sickle cell anemia is an inherited form of anemia, a condition in which there aren't enough
healthy red blood cells to carry adequate oxygen throughout the body. These patients are at
increased risk of death, stroke, frequent pain crises, acute chest syndrome as well as
chronic conditions including: lung damage, retinopathy, kidney damage, leg ulcers, and
pulmonary hypertension.

There's no cure for most people with sickle cell anemia. However, treatments can relieve
pain and help prevent co-morbid conditions associated with sickle cell anemia. Hydroxyurea
is the only FDA approved drug to help alleviate symptoms associated with sickle cell
disease. The mortality rate is still high in patients using hydroxyurea and a significant
percentage of patients still have aggressive disease despite the hydroxyurea treatment.
Hydroxyurea therapy also does not seem to prevent the development of many of the
complications of sickle cell disease such as pulmonary hypertension.

Historically, stem cell transplantation in sickle cell disease was mainly done in the
pediatric population. The options were more limited for adults with sickle cell disease with
aggressive disease despite hydroxyurea. Most rely on chronic red blood cell transfusions
which carry significant risks of infection, iron overload, and alloimmunization.
Alloimmunization refers to the production of antibodies which occurs in up to 50% of
patients with sickle cell disease who are on chronic transfusion therapy making further
transfusions difficult with a high potential for hemolytic transfusion reactions.

Recently the use of a non-myeloablative stem cell transplantation regimen (relying on
immunotherapy instead of chemotherapy) for sickle cell disease in adults showed 88%
engraftment rates (30 out of 34 patients) with no GVHD and 0% mortality. However, these
transplants used only fully HLA-matched siblings, which are unavailable to all but
approximately 14-28% of patients who could benefit from such a transplant at UIC.

A recent study at Johns Hopkins carried out a similar haploidentical (half matched)
transplant with 14 sickle cell patients who lacked fully HLA-matched donors. Approximately
two years following transplant, 57% of patients successfully engrafted (8 or 14 patients).
There were no deaths and only one episode of acute GVHD of the skin which resolved without
therapy.

The investigators plan to offer stem cell transplantation to sickle cell patients with
aggressive disease who only have a partially matched HLA sibling donor. Haploidentical
transplants are considered only for patients with no other standard options available who
would normally be treated with supportive (palliative) care or given the option to
participate in a clinical trial. Donors who are HLA-haploidentical will be the source of
hematopoietic stem cells. Potential donors can include any relative (e.g. parents,
offspring, siblings, cousins, aunts/uncles, grandparents).

The related donor stem cell transplantation using the alemtuzumab/TBI platform has been
shown to be a safe strategy to cure severe sickle cell disease. However, due to a lack of
suitable donors, many patients cannot benefit from this strategy. Alternative donor sources
are desperately needed to fill this gap. Nearly all patients will have a haploidentical
family member who would be able to donate. The use of post transplantation cyclophosphamide
has greatly improved the outcome of haploidentical stem cell transplantation. The
investigators propose to combine this with alemtuzumab/TBI conditioning.

The investigational component of this study is the combination of the Alemtuzumab
(immunotherapy) and Total Body Irradiation conditioning regimen and the HLA Haploidentical
Transplant with post-transplant Cyclophosphamide. Investigators plan to study the
engraftment rates (transplant success rates) at Day 60 in sickle cell patients undergoing an
HLA haploidentical stem cell transplant with post transplant high dose cyclophosphamide.

Patient Eligibility:

- Patients with sickle cell disease are eligible if they have any of the following
complications:

- Stroke or central nervous system event lasting longer than 24 hours

- Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring
emergency room, acute care center, or hospital admissions.

- Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room
visits

- Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime
events

- Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy

- Bilateral proliferative retinopathy with major visual impairment in at least one
eye

- Osteonecrosis of 2 or more joints

- Sickle cell nephropathy, defined by a GFR < 90mL/min/1.73m2 or the presence of
macroalbuminuria (urine albumin > 300 mg/g creatinine)

- Pulmonary hypertension, defined by a mean pulmonary artery pressure > 25mmHg

- Age 16-60 years

- Karnofsky performance status of 60 or higher

- Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%

- Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥
50% predicted (after adjustment for hemoglobin concentration)

- Estimated GFR ≥ 50mL/min as calculated by the modified MDRD equation

- ALT ≤ 3x upper limit of normal

- HIV-negative

- Patient is pregnant

- Patient is able and willing to sign informed consent

- Patient has an HLA-haploidentical relative