Hematopoietic Stem Cell Transplant for Sickle Cell Disease

Primary Objective

1. To evaluate the safety and feasibility of hematopoietic stem cell transplant (HSCT) after
treatment with fludarabine in adult patients with Sickle Cell Disease (SCD).

Secondary Objective(s), in HSCT for SCD

1. To evaluate the rates of disease-free and overall survival in both MSD and alternate
graft donor (MUD, haploidentical, or cord blood-derived) recipients

2. To evaluate fertility in matched sibling and alternate-donor graft recipients

3. To evaluate GVHD rates in MSD and Alternate Graft Donor recipients in SCD.

4. To evaluate cerebral, pulmonary, renal, and generalized vasculopathy before and after
HSCT in SCD.

5. To evaluate hematopoiesis and erythropoiesis before and before HSCT in SCD.

6. Modulation of SCD Phenotype by Allogeneic Transplantation. Rigorous clinical follow-up
will be performed, per routine care, to evaluate those consequences of SCD that will be
modified by allogeneic transplantation in the short-term (4-12 weeks), in the
medium-term (12-24 weeks) and in the long-term (>24 weeks). Short-term changes would
include disappearance of stress hematopoiesis and erythropoiesis; medium- and long-term
changes would include effects on pain, fertility (TSH, LH), cognition (routine cognitive
assessments), and end-organ damage (including urine albumin-to-creatinine ratios and
tricuspid regurgitant jet velocities, as indicated).

Procedures:

The study will start with at least 10 and up to 25 patients. They will be given the lowest
starting dose of fludarabine. This is done to make sure it is safe. Researchers will watch
the patients during what is called the dose-limiting toxicity (DLT) period. Their safety will
be monitored by a Safety Monitoring Committee, which is made up of people who run research
studies. The study will not take new patients until the DLT period is done.

If at least 3 of the 10 patients enrolled do not benefit, the maximum tolerated dose (MTD)
will be considered exceeded. After the DLT period is complete, patients will receive a stem
cell transplant from a genetically matched donor. Patients will be continued to be monitored
for a year after the transplant.

To prepare for the transplant patients will have to undergo the following treatments:

- an exchange transfusion

- a stem cell graft infusion from either a:

- perfectly matched sibling donor (called MSD),

- perfectly matched but unrelated donor (called MUD),

- a half-matched related donor (called Haploidentical), or

- a cord blood donor

- rabbit antithymocyte globulin (ATG)

- cytoxan (a type of chemotherapy)

- Fludarabine (you get this medicine a few weeks before transplant and again, as part of
the routine chemotherapy treatment). This is the main drug being studies in this
research

- total body irradiation (also called TBI)

- tacrolimus, mycophenolate (MMF) and/or methotrexate (MTX). These drugs will weaken your
immune system. They are given to lower your chances of getting GVHD and rejecting the
donor cells.

Patients will be in the study for approximately 14 months.

Inclusion Criteria:

- Patients must have one of the following inherited hemoglobin gene disorders:

- a. Hemoglobin SS

- b. Hemoglobin SC

- c. Hemoglobin S-Beta-zero-Thalassemia or

- d. Hemoglobin S-Beta-plus Thalassemia with an episode of multi-organ failure
within 5 years of eligibility

Patients must meet one of the following risk criteria:

- Low Risk (Red Light. Stop and consider therapy closely): Must have matched sibling
donor grafts, failed conventional therapy as determined by the PI, and evidence for
morbid disease (one of the following):

- a. 2 or more painful episode/year (requiring Emergency Department or inpatient
care) x 2 years or

- b. 1 or more diagnoses of Acute Chest Syndrome within 5 years, or

- c. 2-year mortality 5-10% or

- d. Baseline LDH>600 IU or

- e. History of sepsis, with or without a WBC>13.5, or

- f. On chronic transfusions

- Moderate Risk (Yellow Light. Reasonable to proceed, but with caution): May have
alternate donor grafts (haploidentical or matched unrelated donor), if MSD is not
available. Must have history of high-level vasculopathy, as defined by at least one of
the criteria below:

- a. Urine Albumin to Creatinine Ratio of >300mg/g or eGFR 50-90 ml/min x 2
evaluations within 3 months or

- b. History of overt clinical stroke, or progressive cerebral vasculopathy
radiographically or

- c. 1 or more diagnoses of Acute Chest Syndrome, multi-organ failure, or sickle
hepatopathy within 7 years, or

- d. Excessively morbid disease manifest as VOCs at a rate of 2 or more per year x
2-years or uncontolled retinal disease attributed to SCD. These patients can be
considered for moderate-risk alternate donor transplants. The palliative nature
of the transplant will be explicit in the consent.

- e. 2-year mortality >10-15%

- i. Baseline WBC>13.5 and on chronic transfusions or baseline LDH>600 or age
>35 years old,

- ii. Baseline TRV ≥3 m/s,

- iii. Chronic transfusion therapy and age >35 years old or male gender,

- iv. Baseline LDH>600 and age >35 years old or history of sepsis

- v. History of sepsis and age >35 years old or male gender.

- f. History of multi-organ failure

- High Risk (Green light, proceed if possible): All donor types are eligible. Must have
high risk disease and a >15% risk of 2-year mortality as defined by at least one of
the criteria below.

- a. Baseline TRV ≥3 m/s and baseline WBC >13.5 or on chronic transfusions or
history of sepsis or age >35 years old,

- b. Baseline WBC>13.5 and chronic transfusions or baseline LDH>600 or age >35
years old

- c. Age >35 years old and chronic transfusions

To determine eligibility as a bone marrow transplant patient:

- Available suitable donor

- a. 6/6 HLA-matched sibling donor (HLA A, B, and DRB1), bone marrow only

- b. 8/8 HLA-matched unrelated donor (HLA A, B, C, DRB1), bone marrow only

- c. 4/8, 5/8, 6/8, 7/8 Haploidentical donor, bone marrow only

- Patients must have adequate hematologic, hepatic, and renal function as defined below:

- Direct bilirubin within 3 X normal institutional limits

- ALT (SGPT) < 3 X institutional upper limit of normal

- Creatinine clearance >21 mL/min/1.73 m^2 for subjects with creatinine clearance
values below 50 mL/min/1.73 m^2, the principal investigator may use discretion
for appropriate fludarabine dose adjustment as noted.

- Patients must have adequate pulmonary function as defined by Pulmonary function:
DLCO r40% (adjusted for hemoglobin) and FEV1r50%.

- Contraception/Child Bearing The effects of Fludarabine, cytoxan, ATG,
tacrolimus/sirolimus and MTX are cumulatively known to be deleterious to the health of
the developing human fetus. For this reason, and because of teratogenic potential, all
women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) for the duration of study
participation and for 12 months after completing treatment.

- Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Red cell alloimmunization to a degree that precludes extended transfusion

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Subjects must not have evidence of impaired liver function due to iron overload, +/-
hepatitis. Patients will be evaluated by liver consult if ferritin >1500, history of
hepatitis,or ALTis ≥3 X Upper limit of normal (ULN). Recommended evaluations could
include liver biopsy if there is evidence for significant hepatic iron deposition or
fibrosis/cirrhosis on T2* MRI of the liver.

- eGFR <21 ml/min

- ≥2.0 liter-per-minute pm home oxygen requirement

- An estimated Left Ventricular Ejection Fraction ≤40% (echo or MUGA)

- Hepatic cirrhosis (Biopsy Proven)

- HIV positive, ineligible because of the increased risk of lethal infections when
treated with marrow suppressive therapy. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

- Pregnant or breastfeeding women are excluded from this study because the
immunomodulatory treatment, preparative regimen, and anti-GVHD therapy contain agents
with the potential for teratogenic or abortifacient effects.

- Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
medication and progression of clinical symptoms) within 1 month prior to starting the
conditioning regimen. Patients with fever or suspected minor infection should await
resolution of symptoms before starting the conditioning regimen.

- Prior allogeneic marrow or stem cell transplantation.