Safety of Blood Stem Cell Mobilization With Plerixafor in Patients With Sickle Cell Disease

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for sickle
cell disease (SCD) patients but its use is significantly limited by the lack of compatible
donors. Gene therapy using autologous hematopoietic stem cell (HSC) transplantation
represents an alternative approach but requires the collection of significant numbers of
cells. Severe adverse events have been observed in SCD patients after mobilization using the
standard agent granulocyte colony-stimulating factor (G-CSF), and bone marrow harvesting is
also associated with side effects. The use of a single administration of plerixafor has been
suggested as an alternative mobilization strategy in SCD but may not mobilize sufficient
number of HSC. In this study, our primary objective is to assess if up to two injections of
plerixafor (starting dose level: 240 µg/kg/dose) are safe in SCD patients and can recruit
enough blood stem cells needed for future gene therapy.

Inclusion Criteria:

- Weight between 50 and 120 kg;

- Karnofsky performance status (KPS) ≥70%;

- Confirmed diagnosis of sickle cell disease with βS/βS or βS/β0 or βS/β+ genotype;

- Must have had one or more of the following events in the 2 year period preceding
enrollment:

- History of ≥2 severe vaso-occlusive pain crises (VOC) (or at least two episodes
in the year preceding the setting up of regular transfusion protocol). A severe
VOC is defined as an episode of pain lasting more than 2 hours severe enough to
require care at a medical facility.

- History of ≥1 episodes of acute chest syndrome despite the institution of
supportive care measures (i.e. asthma therapy and/or hydroxyurea)

- Clinically significant neurological event (stroke) or any neurological deficit
lasting 24 hours. A stroke is defined as a sudden neurological change lasting
more than 24 hours that is accompanied by cerebral magnetic resonance imaging
(MRI) changes.

- Prior treatment with regular RBC transfusion therapy, defined as receiving ≥8
transfusions per year for >1 year to prevent vaso-occlusive clinical
complications (i.e. pain, stroke, and acute chest syndrome)

- Osteonecrosis of two or more joints;

- Anti-erythrocyte alloimmunization (>2 antibodies);

- Presence of sickle cell cardiomyopathy documented by Doppler echocardiography;

- Presence of any significant cerebral abnormality such as stenosis or occlusions
on magnetic resonance imaging (MRA)

- Meet current eligibility requirements for donation for mobilization at the COH DAC;

- Adequate renal function: defined as a creatinine estimated FDR (eGFR) of ≥60 ml/min;

- Adequate liver function: defined by a serum conjugated (direct) bilirubin <2.5x upper
limit of normal (ULN) for age; AST and ALT <5x ULN for age as per laboratory;

- Adequate cardiac function: defined as left ventricular ejection fraction >50%;

- Adequate hematologic parameters: WBC ≥2.5 x 10^9/L; platelet count ≥120 x10^9/L;
hemoglobin >8 g/dL;

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry.

Exclusion Criteria:

- Diagnosed with alpha thalassemia (two or more gene deletions or any α-globin
structural variants);

- Seropositivity for HIV-1/2 (Human Immunodeficiency Virus) or HTLV-1/2(Human
T-Lymphotropic Virus);

- Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking
medication and progression of clinical symptoms) within one month prior to treatment.
Participants with fever should await resolution of symptoms before starting the
treatment;

- Any clinically significant active infection which, in the opinion of the investigator,
would require significant medical intervention;

- Abnormal pulmonary function tests (adults with mild or moderate obstruction or
restriction or diffusion defects are eligible, per Investigator discretion).

- History of pulmonary hypertension, proven by cardiac catheterization;

- History of malignancy or immunodeficiency disorder, (i.e., subjects with prior
malignancy must be disease-free for 5 years), except curatively-treated basal cell
carcinoma or cutaneous squamous cell carcinoma;

- Participation in any study with an investigational agent or medical device within 90
days of screening;

- Major surgery in the past 30 days;

- Prior receipt of any gene transfer product;

- Bone marrow harvest in the past year;

- Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenesis;

- Known hypersensitivity to plerixafor or any excipient contained in Mozobil;

- G-CSF or plerixafor medication within 4 weeks of treatment;

- Pregnant or nursing women;

- Any condition or chronic physical, neurological, or mental illness, which in the
opinion of the investigator, makes participation ill advised.