Weighty Choices: Selecting Optimal G-CSF Doses for Stem Cell Mobilization to Optimize Yield
Authors: Farhadfar Nosha , Hsu Jack W. , Logan Brent R. , Sees Jennifer A. , Chitphakdithai Pintip , Confer Dennis L. , Pulsipher Michael A. , Shah Nirali N. , Switzer Galen E. , Shaw Bronwen E. , Wingard John R. 
Published: October 2019

Abstract
Introduction. There is little information on the effect of donor body mass index (BMI) on mobilization response to Filgrastim (G-CSF), especially in the unrelated donor setting. Obesity has been associated with chronic low-grade inflammation due to chronic activation of the innate immune system. Obesity-induced pro-inflammatory cytokines can interfere with bone marrow SDF1/CXCR4 axis and promote mobilization of progenitor cells leading to persistent leukocytosis and an increase in number of circulating progenitor cells. Given a higher number of circulatory progenitor cells in obese individuals compared to non-obese, a reduced G-CSF dose in obese donors may elicit adequate response, thus reducing the adverse events associated with peripheral blood stem cell (PBSC) collection. The aim of this study is to evaluate the impact of donor BMI on G-CSF mobilized peripheral blood progenitor cell yield in healthy donors. This study also examines whether there is a G-CSF dose threshold above which there is a significant increase in skeletal pain and other acute toxicities from mobilization without an appreciable increase in progenitor cell yield.
Methods. The primary outcome was examination of CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF administration as a measure of collection yield. The secondary outcomes were the incidence of skeletal pain and highest toxicity level across selected body symptoms (fatigue, nausea, anorexia, insomnia, dizziness) at 24 hours after first G-CSF dose, day 1 to 5 of G-CSF administration, 2 days and 1-week post collection. The population studied was domestic unrelated G-CSF mobilized PBSC donors reported to the NMDP/CIBMTR between 2006 and 2016. G-CSF dosing was based on the NMDP weight-based dosing schema rounded to the nearest vial content. Donors were divided into normal, overweight, obese, and morbidly obese categories based on BMI. Multivariate analysis of collection yields between cohorts were done using linear regression analysis. Stepwise variable selection was used to add variables to the model: BMI group and G-CSF dose was forced into the final model as the variables of interest. Pain and acute toxicities at each time point were described using frequencies and compared between groups using chi-squared test or Fisher's exact test after adjusting for donor and baseline characteristics.
Results. Examination of 20, 884 PBSC donors mobilized by G-CSF revealed a significant increase in collection yield in obese and morbidly obese compared to normal and overweight donors. Median CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF was 29.6, 36.4, 40.8 and 42.9 in normal, overweight, obese and morbidly obese donors, respectively (p<0.001). Based on the subgroup analyses evaluating impact of average daily dose of G-CSF on the collection yield for each BMI group, an increase in average daily G-CSF dose was associated with an increase in stem cell yield in normal and overweight BMI donors. In contrast, an increase in the average daily G-CSF dose beyond 780 mcg per day in obese and 900 mcg per day in morbidly obese did not increase the yield (Table 1).
Figure 1 shows the time course and degree of toxicities in different BMI categories. Obese and morbidly obese were more likely to experience grade 2-4 pain and toxicities compared with normal or overweight in both the peri-collection and early post-donation recovery period but by one week after donation most toxicities abated and there was no difference. Donors with a higher BMI were more likely to experience grade 2 to 4 skeletal pain 24 hours post first G-CSF dose, 2 days post donation and at day 1 to 5 G-CSF administration. In addition, donors with higher BMI were more likely to have grade 2-4 toxicities (fatigue, anorexia, insomnia) at day 1 to 5 of G-CSF and 2 days after collection. However, within each BMI group, incremental increase in G-CSF dose was not associated with greater pain or other toxicities.
Conclusions. Our data indicates a correlation between average daily G-CSF dose and CD34+ cell yield in normal and overweight donors. However, in obese and morbidly obese donors, there was no benefit in CD34+ yield with increasing average daily G-CSF dose above 780 mcg and 900 mcg respectively. Therefore, there appears to be a maximum effective G-CSF dose for mobilization in obese and morbidly obese donors where higher doses of G-CSF add no additional benefit and may result in additional complications.

Disclosures
Pulsipher: Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Adaptive Biotech: Consultancy, Research Funding; CSL Behring: Consultancy.