Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency

Abstract

Background: Granulocyte-colony-stimulating factor (G-CSF)-mobilized autologous hematopoietic progenitor cells (HPCs) may be collected by apheresis of patients with chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) for use in gene therapy trials. CD34+ cell mobilization has not been well characterized in such patients.

Study design and methods: We retrospectively evaluated CD34+ cell mobilization and collection in 73 consecutive CGD and SCID patients and in 99 age-, weight-, and G-CSF dose-matched healthy allogeneic controls.

Results: In subjects aged not more than 20 years, Day 5 preapheresis circulating CD34+ counts were significantly lower in CGD and SCID patients than in controls; mean peak CD34+ cell counts were 58 × 10(6) , 64 × 10(6) , and 87 × 10(6) /L, respectively (p = 0.01). The SCIDs had lower CD34+ collection efficiency than CGDs and controls; mean efficiencies were 40, 63, and 57%, respectively (p = 0.003). In subjects aged more than 20 years, the CGDs had significantly lower CD34+ cell mobilization than controls; mean peak CD34+ cell counts were 41 × 10(6) and 113 × 10(6) /L, respectively (p < 0.0001). In a multivariate analysis, lower erythrocyte sedimentation rate (ESR) at mobilization was significantly correlated with better CD34+ cell mobilization (p = 0.007). In SCIDs, CD34 collection efficiency was positively correlated with higher red blood cell (RBC) indices (mean RBC volume, R(2) = 0.77; mean corpuscular hemoglobin [Hb], R(2) = 0.94; mean corpuscular Hb concentration, R(2) = 0.7; p < 0.007) but not Hb.

Conclusions: CGD and SCID populations are characterized by significantly less robust CD34+ HPC mobilization than healthy controls. The presence of active inflammation or infection as suggested by an elevated ESR may negatively impact mobilization. Among SCIDs, markedly reduced CD34 collection efficiencies were related to iron deficiency, wherein decreased RBC size and density may impair apheresis cell separation mechanics.

Conflict of interest statement

Conflicts of Interest: None

Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1

Panels A and B show CD34+ cell mobilization (CD34+ cell count immediately prior to apheresis) in the CGD and SCID patients and matched controls by age groups ≤ 20 and >20 years, respectively. Patients in both age groups had significantly lower mobilization than controls. Panels C and D show CD34+ cell collection efficiencies among patients and matched controls stratified by the two age groups, respectively. In the ≤ 20 age group, SCID patients had significantly lower apheresis collection efficiencies than CGD patients or controls. Rectangular plots show the middle 50% of patients (25th to 75th percentiles and median). Diamond plots show the mean +/- 95% confidence intervals.

Figure 2. Effect of adding plerixafor to G-CSF on CD34+ cell counts

(A) Day 4 CD34+ cell counts were significantly lower in patients receiving plerixafor plus GCSF compared to those receiving G-CSF alone (p

Figure 3. Correlation of erythrocyte sedimentation rate (ESR) with the presence of infection and/or inflammation (A) and CD34+ cell counts (B)

Subjects with active infection and/or CGD-associated colitis had significantly higher mean ESR compared to those without these events (38 vs 17 mm/hr, p=0.0007). ESR in turn was inversely related to mean peak pre-apheresis circulating CD34+ cell counts (p=0.03).

Figure 4. Effect of iron deficiency on CD34+ cell collection efficiency in SCID subjects

Panels A-D show that red cell indices (x-axes) on the day of collection, including MCV, MCH, and MCHC, and the Combined Cell Index, all correlated significantly with CD34+ cell collection efficiency (y-axis) among SCID patients, as described in the text. Combined Cell Index = RDW×104/(MCH × MCV). The higher the Combined Cell Index, the greater the likelihood of iron deficiency anemia.

Figure 5. Lack of effect of iron deficiency on collection efficiency in CGD subjects

Panels A-B show the absence of any correlation between CD34+ cell collection efficiency (y-axis) and red cell parameters (x-axes), including MCV and the Combined Cell Index in CGD patients. The same was true for other red cell indices including RDW, MCH and MCHC.