Treatment.
myeloid block, WHIM
STERILE, ADVERSE EVENT
G-CSF was purchased from Amgen, and plerixafor was provided by the manufacturer, Sanofi-Genzyme. Both drugs come in similarly sized vials and are indistinguishable, clear, colorless, sterile, and nonviscous liquids (1.6 μL at 300 mg/mL for G-CSF and 1.2 μL at 20,000 μg/mL for plerixafor). Either the Pharmaceutical Development Section of the NIH-CC Pharmacy or Integrity Bio Inc. transferred the drugs undiluted under cGMP conditions into unmarked borosilicate syringes in 5 different predefined amounts: 15, 22.5, 36, 54, and 75 μg G-CSF (corresponding to 0.05, 0.075, 0.12, 0.18, and 0.25 mL, respectively) and 800, 1,200, 1,800, 2,600, and 3,800 μg plerixafor (corresponding to 0.04, 0.06, 0.09, 0.13, and 0.19 mL, respectively). These 2 ranges were predefined to deliver target doses ranging from approximately 0.25 to 2.0 μg/kg BiD for G-CSF and approximately 10 to 40 μg/kg BiD for plerixafor for the body weight range anticipated for the study participants. The predefined target dose ranges for both drugs were expected to be sufficient, based on previous experience in treating patients with WHIM, who do not have a myeloid block and have mobilizable leukocyte pools (For patients already taking open-label G-CSF at enrollment, the unmasked prefilled G-CSF syringe amount prescribed to start the screening phase was judged based on the preenrollment dose, the preenrollment ANC response, and patient weight. Those not already taking G-CSF at enrollment started the screening phase using the syringe containing either the lowest or second lowest G-CSF dose. Dose adjustments using the 5 available syringe amounts were made during the screening phase if necessary, guided by periodic blood count assessments, to increase the morning dose trough ANC into the predefined target range of 500–1,500 cells/μL. To start the masked and randomized equilibration phases, the masked principal investigator selected both a prefilled G-CSF syringe dose based on the patient’s screening phase response and a prefilled plerixafor syringe that would deliver a dose within the lower portion of the target dose range, i.e., approximately 10–20 μg/kg BiD. The unmasked pharmacist then dispensed the correct syringe option based on the randomization. The initial G-CSF dose in this phase was, in most cases, the same as the dose the patient had already been receiving at the end of the screening phase. From these starting doses, adjustments were made during the equilibration phase using the same prescribing procedure for the other 4 prefilled syringe amounts for each drug, guided by masked ANC assessments every 2 weeks before the morning dose, until the ANC reached at least 500 cells/μL. Patients who failed to reach this threshold by 8 weeks were declared drug failures and were switched to the second drug. Patients who succeeded during the equilibration phase were continued on the effective dose for a 12-month treatment phase. The dose could be further adjusted within the prespecified range for each drug during the treatment phase if the ANC fell below 500 or above 7,500 or to mitigate an adverse event thought to be related to the drug. Patients unable to tolerate a study drug or who met prespecified failure criteria were switched in the first treatment period to the alternate agent or in the second treatment period to open-label G-CSF.