Plerixafor Injection Research Articles

CD34+ Subclasses of Blood Stem Cell Grafts Collected After Plerixafor Injection in Non-Hodgkin Lymphoma (NHL) Patients Mobilizing Poorly with Chemotherapy Plus G-CSF

Abstract 2990 Background:Mobilization of blood stem cells is difficult in a subgroup of patients with standard methods. Plerixafor, a CXCR4 antagonist, has been used for stem cell mobilization in combination with G-CSF for some years. Mobilization method used may affect not only efficacy of stem cell mobilization and collection but also graft content which on the other hand may have effect on post-transplant outcomes. No data is available on CD34+ subclasses in grafts collected after plerixafor administration in patients who mobilize poorly with chemotherapy plus G-CSF.Patients and Methods: Altogether blood stem cell grafts collected from 26 NHL patients were studies. Thirteen patients (8 M, 5 F, median age 51 yrs) were mobilized with a combination of chemotherapy and G-CSF ad received plerixafor due to poor mobilization followed by stem cell apheressis. Thirteen patients (10 M, 3 F, median age 56 yrs) were mobilized with chemotherapy plus G-CSF without plerixafor and served as controls. Samples from the first collection after plerixafor and from the first apheresis of control patients were studied by flow cytometry using the following antibodies: CD34, CD38, CD 117, CD133, CD19 and CD45. Viability of CD34+ cells after freezing was assessed with 7-aminoactinomycin D staining. Also in vitro growth of granulocyte/macrophage progenitors (GM-CFU) were assessed from all grafts. Patients were followed after high-dose chemotherapy in regard to hematopoietic reconstitution. Results:The number of viable cells in the grafts was comparable between the plerixafor and the control groups (Table 1). The number of the most primitive stem cells (CD34+CD38−CD133+) was higher in plerixafor mobilized grafts (Table 1). Most of the CD34+ cells were myeloid progenitors, as defined by their CD117 antigen co-expression. No differences in GM-CFU were observed between the groups. All except one patient had received high-dose therapy. The median number of CD34+ cells collected from the patients was comparable (3.1 vs. 3.3 × 106/kg). The median time to reach neutrophils > 10 × 109/L was 10 days from the stem cell infusion in both groups and time to unsupported platelets was also comparable (16 d vs. 13 d). Platelet counts at 1 month, 3 months and 6 months were comparable between the groups. Absolute lymphocyte counts were higher in plerixafor group but the differences were not statistically significant. One early toxic death occurred in the plerixafor mobilized group and one death due to disease recurrence in both groups with a median follow-up of 301 and 348 days from stem cell infusion in prelixafor and control groups, respectively. Conclusions:Plerixafor added to chemomobilization in NHL patients resulted in higher number of the most primitive CD34+ cells in the graft with comparable in vitro growth and engraftment potential after BEAM chemotherapy when compared to patients mobilized without plerixafor. Longer follow-up of higher patient numbers are needed to evaluate whether differences in graft content have an effect on patient outcomes.TableCD34+ subclasses and in vitro growth in graft collected after plerixafor injection in NHL patients mobilizing poorly with chemotherapy plus G-CSF and in patients mobilized without plerixafor.Mobilization without plerixafor, median (range), n=13Mobilization with plerixafor, median (range), n=13pCD34+ cell content of the graft (x 106/kg)1.80 (0.31–4.74)1.45 (0.4–4.40)0.858Proportion of CD34+, CD133-, CD38+ cells from all CD34+ cells (%)26.3 (13.0–44.5)25.9 (7.9–44.9)0.663Proportion of CD34+, CD133+, CD38+ cells from all CD34+ cells (%)70.7 (54.1–86.6)68.4 (51.9–90.0)0.473Proportion of CD34+, CD133-, CD38- cells from all CD34+ cells (%)0.4 (0.1–0.7)0.4 (0.1–2.1)0.407Proportion of CD34+, CD133+, CD38- cells from all CD34+ cells (%)1.6 (0.0–5.9)3.5 (1.0–11.6)0.010The most primitive stem cell (CD34+, CD133+, CD38-) content of the graft (x 106/kg)0.02 (0.00–0.12)0.07 (0.01–0.15)0.005GM-CFU (x 104/kg)16.2 (3.0–63.3)23.1 (6.0–43.0)0.817GM-CFU, granulocyte macrophage colony forming unit Disclosures:Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Effect of Plerixafor on Graft Lymphocyte Subsets in NHL Patients Mobilizing Poorly with Chemotherapy Plus G-CSF

Abstract 1929A combination of chemotherapy plus G-CSF (chemomobilization) is commonly used to mobilize CD34+ cells to circulation. Mobilization of CD34+ cells is poor or suboptimal in 20–30 % of patients. Plerixafor, a CXCR4 antagonist, increases the mobilization of CD34+ cells and may also have effect on graft composition subsequently collected. There are no data on lymphocyte subsets in the grafts collected after chemomobilization plus pre-emptively given plerixafor.We have analyzed lymphocyte subsets (CD3, CD4, CD8, NK cells, CD19) in grafts collected on the next morning after plerixafor injection in 13 chemomobilized patients with non-Hodgkin lymphoma. As controls we had the first collections from 13 NHL patients mobilized with chemotherapy plus G-CSF and with yield of 2–6 × 106/kg CD34+ cells with 1–2 aphaereses.The median CD34+ content of the analyzed grafts was 1.45 × 106/kg in the plerixafor group compared to 1.8 × 106/kg in the controls (p=n.s.). The number of T-cell subsets and NK cells were significantly higher in plerixafor mobilized grafts (Table 1). CD19+ B cells were infrequent in both groups.Table 1Lymphocyte subsets of the grafts.Stem cell collection with plerixafor, median (range)Stem cell collection without plerixafor, median (range)Significance pGraft volume (ml)100 (43–190)80 (45–140)0.280Graft sample preservation time (days)299 (31–450)291 (103–397)0.898CD34+ cell content (x 106/ kg) after 7-AAD1.45 (0.40–4.40)1.80 (0.31–4.74)0.858CD3+ cell content (x 106/kg)75.3 (14.6–327.3)21.3 (9.1–159.4)0.004CD4+ cell content (x 106/kg)32.7 (10.6–132.8)12.4 (6.9–51.5)0.002CD8+ cell content (x 106/kg)33.4 (4.2–200.5)8.8 (2.2–125.0)0.006CD19+ cell content (x 106/kg)0 (0–0)0 (0–0)NANK cell content (x 106/kg)5.1 (0.2–30.40)1.5 (0.3–8.0)0.045CD4+/CD8+ cell ratio0.98 (0.34–3.04)1.41 (0.28–5.06)0.2287-AAD, 7-Aminoactinomycin D; NK, natural killer.All except one patient has received high-dose therapy with blood stem cell support. The median CD34+ cell dose was 3.1 × 106/kg in plerixafor treated group and 3.3 × 106/kg in the control group, respectively. Time to neutrophil engraftment was comparable between the groups. There were two patients in the plerixafor group with late platelet engraftment (1 and 6 months).Addition of plerixafor to chemomobilization in poor mobilizers results in increased content of T lymphocytes and NK cells in the graft but do not appear to mobilize B lymphocytes. Whether higher T cell and NK cell content are associated with more rapid immune reconstitution and survival should be evaluated in larger patient series with longer follow-up. Disclosures:Jantunen:Genzyme: Honoraria. Kuittinen:Roche: Consultancy.

Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin + Rituximab Followed by Stem Cell Transplantation in Relapsed/Refractory DLBCL Patients: Safety and Efficacy

Abstract 2718 Background:Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to cytotoxic calicheamicin. In a prior study, INO combined with rituximab (INO+R) had an overall response rate (ORR) of 78% in patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) who were not candidates for high-dose therapy and autologous stem cell transplant (HDT-aSCT). An ORR of ∼20% was seen in pts with refractory aggressive lymphoma. Objectives:Safety and activity of INO+R followed by HDT-aSCT in relapsed/refractory DLBCL pts. Primary endpoint: ORR. Secondary endpoints: successful peripheral blood stem cell (PBSC) collection, aSCT rate, progression free survival (PFS), and overall survival (OS). Patients, Treatment:CD20+/CD22+ B cell DLBCL, HDT-aSCT eligible, ≥2 adverse prognostic factors (prior R exposure, early relapse/persistent disease with prior therapy, sIPI ≥2). R 375 mg/m2 on day (d) 1, INO 1.8 mg/m2 on d 2 every 21 d, up to 6 cycles; PBSC mobilization with G-CSF (+/− plerixafor injection) on d ≥8, cycle 2. Chemo-priming if insufficient PBSC collected by G-CSF and after response observed. INO+R responders with >2×106 CD34+ cells/kg proceed to HDT-aSCT. Results:63 pts were enrolled; 61 received INO+R in this ongoing trial. Median age was 60 y (range 19–75 y); 46% had 1 prior therapy, 41% had 2, and 11% had ≥3. Pts had adverse prognostic factors: 100% prior R treatment; 78% sIPI ≥2 (range 0–4); 25% had no response to most recent prior therapy, 60% responded with early relapse/failure (<12 mo). Median time to treatment failure with most recent prior therapy was 5.9 mo. All previously treated with anthracyclines and alkylating agents. Pts received median of 3 INO+R cycles (range 1–6). For 54 evaluable pts, ORR after INO+R was 35% (24% complete response, 11% partial response), 13% stable disease, 50% progressive disease (PD). Response to most recent therapy was predictive of response: pts with responses >12 mo, early relapse/failure (<12 mo), or no response had ORR of 90% (n = 10), 30% (n = 30), and 8% (n = 12), respectively. To date, 16 pts collected >2×106 CD34+PBSC/kg (range 2.1–7.1 ×106/kg): 7 mobilized with G-CSF, 6 with G-CSF + plerixafor, 3 with G-CSF + chemo-priming (2 also received plerixafor). Five pts collected <2×106 CD34+ PBSC/kg, including 1 with PD prior to collection attempt and 1 with insufficient counts to initiate apheresis (<5 CD34+ cells/mL): 3/5 pts had 2 prior regimens (1 also had prior aSCT); 2 had 1 prior regimen (1 with bone marrow involvement). For INO+R treated pts, 18 (30%) underwent HDT-aSCT. Consolidation treatment, most commonly BEAM, started 44.5 d (median) after INO+R (range 25–89 d). Of these 18 pts, 14 had successful engraftment. One pt had persistent thrombocytopenia ∼6 mo after HDT-aSCT (platelets 19000/mL), and 3 did not engraft before death: 1 due to neutropenic sepsis at d 23, 1 due to PD at d 25, 1 due to cytomegalovirus (CMV) complications at d 124. For INO+R treated pts, 6- and 12-mo PFS rates are 31% and 13%, respectively (median 2.6 mo, 20 pts censored); median OS is 10 mo (35 censored). PFS was independent of the number of prior regimens, but dependent on prior therapy response: pts with prior responses >12 mo had longer PFS than those with early relapse/failure or no response (median 12.8, 2.1, 2.7 mo, respectively). Pts who underwent HDT-aSCT had 6- and 12-mo PFS rates of 79% and 35%, respectively (median 10 mo); median OS not reached.Common adverse events during INO+R treatment: thrombocytopenia (68%), nausea (46%), lymphopenia (41%), increased aspartate aminotransferase (38%), fatigue (38%), neutropenia (30%), pyrexia (29%), and vomiting (24%). Two pts had veno-occlusive disease, each occurred after HDT-aSCT: 1 recovered without intervention, the other did not recover, ultimately dying from CMV complications (above). In addition, 26 other deaths occurred: 22 due to PD, 2 due to infection after HDT-aSCT (1 neutropenic sepsis pre-engraftment, 1 sepsis post-engraftment), 1 due to neutropenic sepsis (death 77 d after last INO dose), and 1 attributed to complications of pre-existing chronic obstructive pulmonary disease (death 101 d after last INO dose). Conclusion:In this selected high-risk population with relapsed/refractory DLBCL, INO+R shows activity and a 12-mo PFS rate of 35% after aSCT. The safety profile was most notable for some toxicities (hematologic, infectious, and hepatic) after aSCT. Further follow-up is required to assess long-term impact after aSCT. Disclosures:Wagner-Johnston:Sanofi Aventis: Consultancy. Goy:Pfizer Inc: Honoraria, Research Funding. Rodriguez:Pfizer Inc: Research Funding; Genentech: Research Funding; Ortho-Biotech: Research Funding. Hamlin:Seattle Genetics: Consultancy, Honoraria, Research Funding; Calistoga: Consultancy; Spectrum: Consultancy; Pfizer Inc: Research Funding. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Suh:Wyeth advisory member: Consultancy. Jiang:Pfizer Inc: Consultancy, Employment. Sullivan:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment, Equity Ownership. Gisselbrecht:Pfizer Inc: Research Funding; Baxter: Consultancy, Honoraria; Allos: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding.

Emergence of small‐molecule CXCR4 antagonists as novel immune and hematopoietic system regulatory agents

AbstractThe chemokine CXCR4 receptor is a G‐protein‐coupled receptor that has multiple functions in normal physiologies involving the hematopoietic and immune systems. Although the CXCR4 receptor was initially discovered as one of the co‐receptors involved in human immune deficiency virus (HIV) cell entry, it has also been linked to many central immune system functions through the direct regulation of cell trafficking and adhesion, and is present in many cell types within the body. The receptor ligand combination of CXCL12 (SDF‐1) and CXCR4 underlies pathologies such as HIV infection, cancer metastasis and drug resistance, leukemia progression, rheumatoid arthritis, and lupus. This alternative and widespread functionality has allowed researchers to discover new potential uses for substances that are CXCR4 antagonists. This has resulted in approval of the first CXCR4 antagonist, plerixafor injection (AMD3100), for hematopoietic stem cell mobilization. Newer agents are under clinical evaluation for HIV, cancer, and stem cell mobilization. As these agents are further investigated, new uses and therapeutic interventions for CXCR4 antagonists will be discovered. Drug Dev Res 72:598–602, 2011. © 2011 Wiley Periodicals, Inc.

Plerixafor to rescue failing chemotherapy-based stem cell mobilization: it’s not too late

Plerixafor can rescue the outcome of failing chemotherapy-based stem cell mobilization. However, the optimal time for plerixafor injection in this setting has not been determined. This was investigated by retrospective analysis of data from 48 mobilizations with plerixafor, chemotherapy, and granulocyte-colony stimulating factor (G-CSF). The required yield of 2.0×106 CD34+ cells/kg was collected from 71% of patients; the median total yield was 4.1 × 106 CD34+ cells/kg. Patients to whom plerixafor was administered late (≥15 days) after chemotherapy, after a long duration (≥13 days) of treatment with G-CSF, or when the white blood cell count was high (≥20 × 109/L) were mobilized as efficiently as other patients. Plerixafor was shown to rescue mobilizations at a comparable rate in patients with critically low levels of peripheral blood CD34+ cells (<3/µL) and those with higher concentrations. These data suggest that late administration of plerixafor in the course of chemotherapy-based mobilization does not contribute to the failure of this strategy.

Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab In Relapsed DLBCL Patients Followed by Stem Cell Transplantation: Preliminary Safety and Efficacy

Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab In Relapsed DLBCL Patients Followed by Stem Cell Transplantation: Preliminary Safety and Efficacy

Harvesting of Peripheral Blood Stem Cells Using Plerixafor (MOZOBIL) and Granulocyte-Colony Stimulating Factor in Patients Who Had Never Undergone Stem Cell Collection.

Abstract 4236 IntroductionThe collection of peripheral blood stem cells (PBSC) can be tedious and expensive. Moreover, PBSC yields can be severely compromised in patients who previously received chemotherapy. The use of plerixafor (MOZOBIL) for PBSC mobilization has been shown to significantly improve CD34 stem cell yields in patients whom PBSC collections have been adequate. However, this requires the patient to undergo further PBSC harvesting sessions; adding to the patient's inconvenience, exposure to adverse events and costs. We therefore investigated whether using plerixafor at the outset of PBSC mobilization would improve patient acceptability; reduce PBSC collection days and accordingly the patient's costs. Patients and MethodsThree adult patients who had never undergone PBSC harvesting were mobilized using subcutaneous (SC) granulocyte-colony stimulating factor (G-CSF) 10 μg/kg daily starting 4 days prior to PBSC harvesting; plus SC plerixafor 240 μg/kg 10 hours prior to PBSC harvesting. Both G-CSF and plerixafor were continued for as long as was required for PBSC collections. Two patients had multiple myeloma (MM) and were both in stringent complete remission (sCR). The third patient suffered from adult-onset spinomuscular atrophy (SMA) and stem cells were required for possible re-infusion therapy. Importantly, the bone marrows of all 3 patients were assessed to be normal prior to PBSC mobilization and collection. The target PBSC CD34 yield was 2 million CD34 cells/kg per PBSC collection. ResultsAs can be seen, the CD34 yields (expressed as x million CD34 cells/kg) exceeded expectations:PatientDiagnosisCell SeparatorDay 1Day 2Day 3Patient #1MMCOBE Spectra2.794.354.21Patient #2MMCOBE Spectra3.433.12not donePatient #3SMASPECTRA Optia8.105.565.50All patients tolerated the procedure very well and were discharged within 24 hrs of completing the final PBSC collection. The only adverse event was grade 1 restless legs syndrome in Patient #1 following the first injection of plerixafor. It was improved with oral diazepam and did not recur. Both patients with MM reported a sense of “rejuvenation” 2-3 weeks after PBSC collection. All patients were pleased with the relatively complication-free procedure. ConclusionsUpfront collection of PBSCs using G-CSF/plerixafor is both highly effective and safe. There is great patient acceptability as well as much fewer PBSC collection days and an accompanying reduction in procedure costs. The added advantage of using the SPECTRA Optia cell separator is worth further investigations. Disclosures:Off Label Use: Plerixafor (MOZOBIL) - Use in patients who had never undergone stem cell collection..

Preferential Mobilization of CD34+ Plasmacytoid Dendritic Cell Precursors by Plerixafor.

Abstract 32 Background:Plerixafor (Mozobil®) is a CXCR4 antagonist that was recently approved by the Food and Drug Administration for use in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs) in patients with non-Hodgkin's lymphoma and multiple myeloma undergoing autologous transplantation. As part of our ongoing clinical evaluation of plerixafor, we observed that the drug efficiently mobilized a CD34dim population of HSCs. Here, we characterize the CD34dim population and assess its relative frequency following mobilization with G-CSF and/or plerixafor in apheresis samples and in non-mobilized cord blood samples. Methods: Aliquots of apheresis products were obtained from 16 healthy donors following treatment with a single injection of plerixafor or 5 days of G-CSF (10 μg/kg/day). In a separate study, five patients with lymphoma were mobilized sequentially with plerixafor (240 μg/kg), G-CSF (10 μg/kg/day), and plerixafor + G-CSF. These patients received an injection of plerixafor on day −5. Twenty-four hours later, patients were treated with G-CSF for 4 days. On the fifth day (day 0), patients received a dose of G-CSF and a dose of plerixafor followed four hours later by apheresis. Samples were collected after treatment with plerixafor on day −5 as well as immediately before and 4 hrs after plerixafor administration on day 0. Cord blood units were obtained from the St. Louis Cord Blood Bank. Human CD34+ cells were purified by positive selection with a Magnetic Affinity Cell Selection CD34 isolation kit. We used Affymetrix Human Genome U133+2 arrays to generate gene expression profiles for 24 samples of CD34+ cells collected following mobilization of healthy donors with either Plerixafor (n=12) or G-CSF (n=12). Results: Human CD34+ cells can be divided into three distinct subsets based on their cell surface expression of CD45RA and CD123 (IL-3Rα): (i.) CD34+CD45RA−CD123+/− primitive HSCs, (ii.) CD34+CD45RA+CD123+/− committed progenitors, and (iii.) CD34dimCD45RA+CD123hi cells. Table 1 shows the relative frequencies of each of these CD34+ cell subsets in apheresis products obtained from healthy donors mobilized with G-CSF or plerixafor as well as in cord blood units. Strikingly, we observed that each graft type was significantly enriched for one of the CD34+ cell subsets compared to the other two grafts. G-CSF mobilized grafts contained more CD45RA−CD123+/− primitive HSCs, cord blood units were enriched with CD45RA+CD123+/− committed progenitors and plerixafor mobilized products had significantly more CD34dimCD45RA+CD123hi cells. Table 1 also shows the CD34 cell subset distribution following sequential mobilization of lymphoma donors with plerixafor, G-CSF, and plerixafor + G-CSF (PL+G). This data agrees with the results we obtained from healthy donors and confirms that G-CSF grafts are enriched with CD34+CD45RA−CD123+/− cells while plerixafor preferentially mobilizes the CD34dimCD45RA+CD123hi subset. Extensive FACS and functional analyses determined that the CD34dim population represents a plasmacytoid pro-DC2 (for progenitor of pre-dendritic cell type 2) progenitor compartment as indicated by their CD45RA+CD123hiBDCA−2+BDCA−4+CD36+CXCR4hiCD4dimCD25−CD13− phenotype and inability to form CFU-GM colonies in vitro. Finally, we found that the gene signature of plerixafor-mobilized CD34+ cells is distinct from that of G-CSF-mobilized CD34+ cells. Plerixafor-mobilized CD34+ cells expressed significantly more of the specific transcriptional regulator of plasmacytoid DC (pDC) development, E2-2, as well as additional transcriptional factors (SpiB, IRF7, IRF8) and cell surface markers (BDCA-2, ILT7) that are specific to the pDC lineage. Conclusions: This data suggest that the CD34dimCD45RA+CD123hi cells preferentially mobilized by plerixafor are precursor pDCs. Further study is required to determine the impact these cells have on the engraftment and function of plerixafor mobilized grafts after hematopoietic stem cell transplantation.Table 1Phenotype of human CD34+ stem cellsPhenotypeHealthy DonorsLymphoma PatientsPlerixafor (n=7)G-CSF (n=9)Cord (n=4)Plerixafor (n=5)G-CSF (n=5)PL + G (n=5)34+RA−123+/−, %67.1 ± 7.381.6 ± 9.566.5 ± 3.639.4 ± 8.877.5 ± 2.659.6 ± 1334+RA+123+/−, %18.7 ± 4.116.7 ± 9.230.5 ± 4.537.5 ± 7.920.6 ± 2.234.2 ± 1234dimRA+123hi, %12.2 ± 5.31.0 ± 0.82.2 ± 0.819.6 ± 4.01.4 ± 0.74.4 ± 0.9Values represent Mean ± SD Disclosures:DiPersio:Genzyme Corp.: Honoraria.

A Randomized Clinical Trial Comparing Cytokine Administration Sites for Mobilization of Peripheral Hematopoietic Progenitor Cells for Patients with Hematological Malignancies Undergoing Autologous Stem Cell Transplantation.

Abstract 4230 BackgroundThe optimal injection site for cytokine administration when used to mobilize peripheral blood stem cells for collection is unclear. There are known differences in the pharmacokinetics of subcutaneously injected drugs based upon site adiposity. We hypothesized that injection in lower adipose-tissue-containing sites in the extremities would result in a reduced reservoir effect leading to lower exposures of granulocyte colony stimulating factor (G-CSF) and therefore reduced stem cell collection following cytokine mobilization. MethodsWe completed a prospective single institution IRB-approved randomized study to determine the efficiency and tolerability of different injection sites among patients with multiple myeloma or lymphoma undergoing stem cell mobilization and apheresis. The primary end-points were the total number of CD34+ cells collected and the number of days of apheresis required to collect target numbers (5 × 10E6 CD34+ cells/kg for patients with lymphoma; 10 × 10E6 CD34+ cells/kg for patients with myeloma). Forty patients were randomized to receive cytokine injections in their abdomen (group A) or extremities (group B). Randomization was stratified based upon diagnosis (myeloma; N=29 vs. lymphoma; N=11), age (≤50; N=13 vs. >50; N=27), and mobilization strategy (cytokines alone; N=27 vs. chemomobilization; N=13). Both group A and B were balanced with respect to the stratification criteria. Filgrastim was planned at a dose of 10 ug/kg/day for patients undergoing chemomobilization or 15 ug/kg/day for patients undergoing cytokine-only mobilization. Actual mean cytokine doses were 11.78 ug/kg/day using chemomobilization and 12.96 ug/kg/day using cytokines alone due to rounding to nearest vial size. Patients recorded the injection site for G-CSF and symptoms daily. ResultsOf those enrolled, 90% were evaluable with 18 patients in each group. Four were deemed non-evaluable due to failure to proceed to the planned mobilization procedure (1 in group A and 2 in group B) or lack of consistent injection site (1 patient). In addition, one patient in group B received a non-protocol specified injection of plerixafor due to poor mobilization and collected a total of 13.62 × 10E6 CD34+ cells/kg in 2 days of apheresis. Among the 36 evaluable subjects, 1 subject in each group failed collection with a total of < 2.0 × 10E6 CD34+ cells/kg collected. Mean BMI at the time of mobilization was not different between groups A and B (27.25 ± 4.7 versus 29.39 ± 5.7, respectively; p=NS). Mean numbers of CD34+ cells (±SD) collected were not different between groups A and B (9.15 ± 4.7 versus 9.85 ± 5 × 106/kg, respectively; p=NS). The mode and median duration of apheresis was 2 days for both groups. Subjects from both groups reported similar toxicities of pain and discomfort at the injection site. ConclusionsBased upon the analysis, G-CSF administration site (extremities versus abdomen), does not affect the number of CD34+ cells collected by apheresis or the duration of apheresis needed to reach the target cell dose. Disclosures:Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

Plerixafor approved for autologous hematopoietic stem-cell transplantation

Genzyme Corporation announced December15 that FDA has approved the marketing of plerixafor injection, or Mozobil, for use in patients with non-Hodgkin’s lymphoma or multiple myeloma who will undergo autologous hematopoietic stem-cell transplantation. According to the product’s FDA-approved labeling, plerixafor is indicated, in combination with granulocyte colony-stimulating factor (G-CSF), to increase the number of circulating hematopoietic stem cells available for collection and subsequent autologous transplantation. Plerixafor is a CXCR4 chemokine-receptor antagonist that blocks the binding of stromal-cell-derived factor 1-alpha and interferes with the sequestering of hematopoietic stem cells in the bone marrow, the labeling states. According to Genzyme, the use of plerixafor in combination with G-CSF may potentially reduce the number of times a patient needs to undergo apheresis before autologous hematopoietic stem-cell transplantation. The use of plerixafor causes an increase in circulating leukocytes and may cause a decrease in platelets. The labeling warns that white blood cell and platelet counts should be monitored in patients treated with the drug.

Targeted antagonism of CXCR4 mobilizes progenitor cells under investigation for cardiovascular disease

Bone marrow (BM)-derived cells may repair cardiovascular injury but populations of interest circulate in small numbers. Cytokines such as granulocyte-colony-stimulating factor mobilize cells under investigation for this purpose, including CD133+ but require injections over multiple days and may promote inflammation. The purpose of this study was to evaluate the effects of a novel CXCR4 inhibitor (plerixafor), previously shown to mobilize CD34+ stem cells, on CD133+ mobilization and markers of inflammation. Healthy subjects received a single subcutaneous injection of plerixafor in escalating doses: 240 mcg/kg (n = 3), 320 mcg/kg (n = 5) and 400 mcg/kg (n = 7). CD133+ and CD133+/VEGFR-2+ cells were measured by flow cytometry at baseline, then 4-6 h following plerixafor injection. Markers of inflammation in serum were measured at baseline, then again 10 h following injection of the 400 mcg/kg dose. Across all doses, white blood cells increased on average three-fold from baseline values. CD133+ cells increased on average 24-fold (from 616 +/- 141 cells/mL to 14 713 +/- 4423 cells/mL, P = 0.0064) without clear evidence of a dose effect. CD133+/VEGFR-2+ cells ranged from 0 to 20 cells/mL at baseline and from 0 to 124 cells/mL following plerixafor administration, although the rarity of these cells precluded a statistical analysis of this population. C-reactive protein and serum amyloid type A were not increased after the 400 mcg/kg dose. Pro-inflammatory cytokine levels were undetectable before and after plerixafor, except for macrophage inflammatory protein-1 beta, which increased slightly but significantly after the 400 mcg/kg dose of plerixafor (P = 0.0156). CD133+ cells are mobilized into the circulation following a single injection of the CXCR4 antagonist plerixafor, without clear evidence for systemic activation of inflammation. This effect may be of importance in cell-based approaches for treating cardiovascular diseases.

Pharmacokinetics and Pharmacodynamics of Plerixafor in Patients with Non-Hodgkin Lymphoma and Multiple Myeloma

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) studies in healthy volunteers demonstrated that plerixafor (AMD3100), a CXCR4 antagonist, administered either alone or with granulocyte colony-stimulating factor (G-CSF), resulted in dose-dependent mobilization of CD34 + cells in the peripheral blood. The purpose of this study was to evaluate the safety and the PK and PD of plerixafor with G-CSF in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). This was a phase II, open-label, single-arm study conducted in 2 centers in Canada. Patients aged 18 to 70 years with NHL or MM eligible for autologous transplantation were eligible. A total of 22 patients (8 with NHL and 14 with MM) were enrolled in the study. The patients were given G-CSF (10 μg/kg/day subcutaneously [s.c.]) for 4 days in the morning and plerixafor 240 μg/kg s.c. on the evening before each day of apheresis. Apheresis was initiated 10 to 11 hours after each evening dose of plerixafor and after the morning dose of G-CSF. This regimen was repeated for up to 5 days or until ≥ 5 × 10 6 CD34 + cells/kg were collected. The objectives were to determine the safety and efficacy of plerixafor in patients with NHL and MM, and the PK and PD of a single 240-μg/kg dose of plerixafor administered after 4 days of G–CSF mobilization in these patients. The median absolute peripheral blood CD34 + cell count increased from 24.0 cells/μL before plerixafor administration to 75.0 cells/μL before the first apheresis (10 to 11 hours after treatment with plerixafor). The median number of CD34 + cells collected in a median of 1 day was 5.7 × 10 6 cells/kg in the patients with NHL and 12.0 × 10 6 cells/kg in those with MM. All patients underwent transplantation with prompt and durable engraftment. The PK profile of plerixafor was characterized in 13 patients (5 with NHL and 8 with MM). Overall, the PK parameters were comparable in the patients with NHL and those with MM. Plerixafor was rapidly absorbed after s.c. administration with no observable lag time, with peak plasma concentrations occurring 0.5 hour after administration in most patients. Plerixafor was rapidly cleared, with a median terminal half-life of 4.6 hours. The median maximum increase in the number of circulating cells from baseline was 4.2–fold (range, 3.0- to 5.5-fold), with the maximum fold increase occurring approximately 10 hours after plerixafor injection for all patients. The plerixafor PK and PD profiles in the study patients were consistent with those in healthy volunteers and support the current dosing regimen and timing of apheresis. Plerixafor was safe and effective in mobilizing CD34 + cells for transplantation.