Improving White Blood Cell Collection From Healthy Donors

Bacterial and fungal infections in neutropenic patients or in patients with inherited
disorders of neutrophil function continue to cause substantial morbidity and mortality. In
particular, fungal infections are an increasingly important cause of death in patients
receiving aggressive chemotherapy, in patients undergoing hematopoietic stem cell
transplantation (HSCT), in patients with chronic granulomatous disease, and in patients with
bone marrow failure syndromes such as severe aplastic anemia. The strongest predictor of
progression and death from invasive mold infection in the cancer/ HSCT setting is the
duration of neutropenia. Any modality which increases the granulocyte count during periods of
profound neutropenia and severe infection is thus likely to be of clinical benefit. In the
1970-80 s, collection of granulocyte concentrates by apheresis of healthy donors stimulated
with corticosteroids alone yielded products with an insufficient number of granulocytes to
substantially raise the circulating counts in neutropenic patients. Transfusion of such
components was variably associated with clinical benefit. More recently, the ability to give
donors recombinant human granulocyte colony-stimulating factor (G-CSF) in combination with
corticosteroids (dexamethasone) dramatically increases the circulating neutrophil count prior
to apheresis and results in the collection of granulocyte concentrates containing 2 to 6
times as many cells as those collected using steroids alone. Transfusion of granulocyte
concentrates collected after G-CSF and dexamethasone stimulation of the donor typically
increases the recipient s granulocyte count by 1,000 cells/uL, and the increase in counts is
generally sustained for 24 to 48 hours. Transfusion of daily or every other day granulocytes
derived by apheresis of G-CSF and dexamethasone-stimulated donors has been associated in
observational and retrospective studies with clearance of life-threatening infections in
neutropenic patients, but a single small randomized prospective study did not demonstrate
improved survival in neutropenic infected patients who received granulocytes. Granulocyte
components are not recognized as a licensed blood component by the Food and Drug
Administration (FDA), and neither G-CSF nor dexamethasone is approved by the FDA for use in
allogeneic granulocytapheresis donors. Studies at the NIH Department of Transfusion Medicine
(DTM) have defined the optimal timing and dose of these drugs in granulocyte donors, and
these components have been used for clinical care since 1996. Short term adverse effects of
G-CSF and dexamethasone, including bone pain, myalgias, headache, insomnia and fatigue, are
well known and possible long term effects, including cataracts from serial steroid
administration, have been described. The purpose of the current protocol is to determine the
operational feasibility of managing a volunteer community donor granulocytapheresis program
and to provide informed consent for the administration of filgrastim and dexamethasone to
volunteer donors donating granulocytes by apheresis. Donor accrual and retention, immediate
short term adverse effects of G-CSF and dexamethasone, and any long term effects, will be
assessed in healthy subjects who will be permitted to donate granulocytes a maximum of 12
times per year. Participants will be selected based on general blood donor eligibility
criteria, adequacy of antecubital venous access, and interest in the program. Most subjects
will already have experience as plateletpheresis donors. The toxicity of granulocyte
transfusions and the survival and discharge rates of the transfusion recipients will be
monitored, but the protocol is not designed to evaluate the efficacy of granulocyte
transfusions.

- INCLUSION CRITERIA:

- Donors shall meet all donor eligibility criteria for allogeneic blood donors, as
defined in the most recent editions of the AABB Standards and FDA Code of Federal
Regulations (21CFR640). In addition, donors shall meet the following restrictions:

- Age greater than or equal to18 and less than or equal to 75 years

- If hypertension is present, must be well-controlled on medications

- If peptic ulcer disease has been diagnosed in the past, symptoms must be
well-controlled on medications

- If cataracts have been diagnosed in the past, records from subject s ophthalmologist
must be obtained indicating type of cataract. If PSC was diagnosed in the past,
subject may receive G-CSF but not dexamethasone. The only exception to this is a
history of bilateral cataract extractions due to PSC.

EXCLUSION CRITERIA:

- Information obtained from health history screen that does not meet the allogeneic
donor eligibility criteria of the AABB Standards or the FDA CFR.

- Weight less than 50 kg (110 lbs)

- History of coronary heart disease

- Uncontrolled hypertension (systolic BP >160, diastolic BP >100)

- History of hepatitis or injection drug use

- Diabetes mellitus requiring insulin

- Active, symptomatic peptic ulcer disease

- History of iritis or episcleritis

- Sickle cell disease (sickle trait is acceptable). Testing for hemoglobin S is not
required.

- Lithium therapy

- Pregnancy or nursing (breast feeding)

- Renal function eGFR < 45 ml/min/1.73m(2)