Abstract
Abstract 823
Plerixafor, a reversible inhibitor of the interaction between stromal cell-derived factor 1 (SDF-1) and CXCR4, improves autologous stem cell collection in patients with non-Hodgkin lymphoma (NHL), multiple myeloma, and Hodgkin lymphoma (HL). In Phase II and III trials, plerixafor has been combined with the standard G-CSF regimen and administered as a subcutaneous (sc) injection of 0.24 mg/kg, given 9–11 hours before pheresis. Intravenous (IV) administration of plerixafor may result in a faster rise and higher peak in the peripheral CD34+ cell count, allowing administration of plerixafor the same day as pheresis and improving stem cell collection.
The primary objectives of this Phase I/II study were to determine the maximum tolerated dose (MTD) of IV plerixafor, up to 0.40 mg/kg combined with G-CSF, and to determine the efficacy of IV plerixafor + G-CSF to mobilize ≥ 2 × 106 CD34+ cells/kg from patients with lymphoma. Patients were given an initial dose of plerixafor 0.24 mg/kg sc on day -5, to assess the mobilization of CD34+ cell subsets, and then started mobilization with G-CSF (10 ug/kg SC daily) on days -4 thru -1 and on each day of pheresis. IV plerixafor was given over 30 min. 4 hrs. before each pheresis, beginning day 0. Samples for CD34+ cell subsets were collected after treatment with plerixafor only on day -5, after 5 days of G-CSF on day 0 (G-CSF only), and 4 hrs after plerixafor administration on day 0 (G-CSF + plerixafor). Human CD34+ cells were purified by positive selection with a Magnetic Affinity Cell Selection CD34 isolation kit.
In the Phase I component of the study, 25 adult pts. (median age 49) with NHL (n=15) or HL (n=10) were treated with IV plerixafor at escalating doses (10 pts. at 0.16 mg/kg, 3 at 0.24 mg/kg, 6 at 0.32 mg/kg, and 6 at 0.40 mg/kg). One dose-limiting toxicity (grade 2 chest pain) was observed at 0.32 mg/kg, and no grade 3/4 toxicities occurred at 0.40 mg/kg. 24 of 25 pts. (96%) met the goal collection of ≥ 2.0 × 106 CD34+ cells/kg. 21 of 25 pts. (84%) collected ≥ 5.0 × 106 CD34+ cells/kg in a median 1 day of pheresis, including 6 of 6 pts. in the 400 ug/kg cohort. Peripheral blood CD34+ cell count increased median 27-fold (range, 4–174) after G-CSF + plerixafor IV and 2.1-fold (range, 0.8–7.0) 4 hours after the first dose of IV plerixafor. There was a positive correlation between peripheral blood CD34+ cell count 6 hr. after plerixafor SC on day -5 and both peripheral blood CD34+ cell count after G-CSF mobilization and first day stem cell collection. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) were divided into four distinct subsets based on their cell surface expression of CD45RA and CD123 (IL-3Rα): (1) CD34+CD45RA-CD123+/− primitive HSPCs, (2) CD34+CD45RA+CD123+/− committed progenitors, (3) CD34dimCD45RA+CD123hi plasmacytoid dendritic cell (pDC) progenitors and (4) CD34+CD45RA-CD123hi cells of unknown function. Table 1 shows the CD34+ cell subset distribution following sequential mobilization with plerixafor, G-CSF, and plerixafor + G-CSF (PL+G). G-CSF mobilized grafts were enriched with CD45RA-CD123+/− primitive HSPCs while plerixafor preferentially mobilized the CD34dimCD45RA+CD123hi pDC precursors and CD34+CD45RA-CD123hi cells. We found no significant differences in the CD34+ subset distribution between HL and NHL pts. Flow cytometric analyses showed that the CD34+ subsets preferentially mobilized by plerixafor expressed high levels of cell surface CXCR4.
Plerixafor IV, at doses up to 0.40 mg/kg, is well-tolerated and effective when added to G-CSF for the mobilization of stem cells from patients with lymphoma, with mobilization kinetics and stem cell collections that compare favorably with sc dosing. The Phase II study is proceeding at the 0.40 mg/kg dose. In addition, our data suggest that G-CSF and plerixafor mobilize distinct subsets of human CD34+ HSPCs. The impact of these cells on the engraftment and function of plerixafor mobilized grafts requires further study.
Phenotype of human CD34+ stem cells.
Phenotype . | Plerixafor (n = 18) . | G-CSF (n = 16) . | PL + G (n = 22) . |
---|---|---|---|
34+RA-123+/−, % | 47.8 ± 14 | 78.6 ± 5.9 | 57.9 ± 13 |
34+RA+123+/−, % | 29.2 ± 8.0 | 19.9 ± 5.8 | 34.8 ± 11 |
34dimRA+123hi, % | 18.2 ± 9.2 | 0.8 ± 0.6 | 4.4 ± 2.1 |
34+RA-123hi, % | 3.8 ± 4.4 | 0.7 ± 0.5 | 2.2 ± 2.0 |
Phenotype . | Plerixafor (n = 18) . | G-CSF (n = 16) . | PL + G (n = 22) . |
---|---|---|---|
34+RA-123+/−, % | 47.8 ± 14 | 78.6 ± 5.9 | 57.9 ± 13 |
34+RA+123+/−, % | 29.2 ± 8.0 | 19.9 ± 5.8 | 34.8 ± 11 |
34dimRA+123hi, % | 18.2 ± 9.2 | 0.8 ± 0.6 | 4.4 ± 2.1 |
34+RA-123hi, % | 3.8 ± 4.4 | 0.7 ± 0.5 | 2.2 ± 2.0 |
Rettig:Genzyme Corp.: Consultancy, Honoraria. Vij:Genzyme: Honoraria, Speakers Bureau. Uy:Genzyme: Consultancy, Honoraria, Research Funding.
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