Trends in Collection and Utilization of Autologous Hematopoietic Stem Cells (APBHC) Intended for Transplant in Patients with Multiple Myeloma
Nina SamuelLauren LauferRodrigo TanaguchiJoel RosieneCarlo PalesiRichard ElkindIoannis MantzarisAditi ShastriNoah KornblumR. Alejandro SicaUrvi A. ShahDennis CooperAmit VermaNishi Shah
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Plerixafor
Autologous stem-cell transplantation
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In patients failing successful conventional mobilization of hematopoietic progenitor cells (HPC) plerixafor (Mozobil(®)) seems to be an alternative. We report a series of 14 patients with multiple myeloma or NHL successfully mobilized and harvested by plerixafor together with large-volume leukaphereses (LVL).In a first series (GI), 5 patients were mobilized with G-CSF and plerixafor. In the second series (GII), 9 patients were mobilized by chemotherapy, G-CSF, and plerixafor.In GI and GII, addition of plerixafor led to a significant (p < 0.01) increase of leukocytes and CD34+ cells in peripheral blood (PB). In GII, the median number of CD34+ cells in PB before and after addition of plerixafor was significantly (p = 0.019) higher compared to GI (9 vs. 5 and 50 vs. 24 cells/μl, respectively). In GI and GII, a median number of three or one aphereses was performed. In GII, the median yield (6.7 × 10(6) CD34+ cells/kg) of the first apheresis and the median intra-apheresis recruitment of CD34+ cells were significantly (p < 0.05) higher compared to GI (2.94 × 10(6) CD34+ cells/kg). All patients transplanted, 5 in GI and 8 in GII, exhibited successful engraftment.Plerixafor and G-CSF mobilization or the addition of plerixafor during non-optimal chemotherapy and G-CSF mobilization together with LVL enabled, independent of leukocyte count and even without detectable CD34+ cells before addition of plerixafor, sufficient harvest of HPC numbers for transplantation. Addition of plerixafor during chemotherapy and G-CSF mobilization led to an increased intra-apheresis recruitment and a significantly higher yield of CD34+ cells compared to plerixafor and G-CSF steady-state mobilized patients.
Plerixafor
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Mobilization
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Plerixafor
Mobilization
Leukapheresis
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Plerixafor is widely used as up-front treatment with G-CSF to enhance peripheral blood hematopoietic stem cell output in patients failing previous mobilizations. Less frequently, plerixafor is used to rescue an unsatisfactory mobilization following chemotherapy (CT) and G-CSF. This study investigates if pre-collection factors affect the CD34+ cell harvest in chemotherapy and G-CSF mobilizations rescued by plerixafor. Clinical and hematological data relative to patients, mobilization, and apheresis products were retrospectively examined. The outcome was completing a target cell dose ≥ 2 × 106 CD34+ cells/kg at first apheresis. The effect exerted on the outcome by patient- and disease-related factors was investigated by univariate and multivariate logistic regression analysis. The analysis included data from 42 patients affected by hematological (39 patients) and non-hematological malignancies (three patients). Twenty-nine patients (69%) attained the target cell dose at first apheresis. Twelve out of the remaining 13 patients received an additional plerixafor administration, and all accomplished the transplant dose at a second apheresis procedure. Day -1 CD34+ PB count (OR1.46, 95% CI 1.1–1.9, p = 0.008) and platelet count (OR1.0, 95% CI 1.0–1.0, p = 0.033) predicted the achievement of the target dose at first apheresis, independently of pre-mobilization CT, radiation therapy, and disease status at mobilization. At ROC curve analysis, the best cut-off value predicting the successful collection at first apheresis was 7.5/µL for Day -1 CD34+ cell count (AUC 0.830, 0.69 sensitivity, and 0.92 specificity) and 75 × 109/L for Day -1 platelet count (AUC = 0.736, 0.65 sensitivity and 0.85 specificity). In conclusion, on-demand plerixafor rescue allows a successful stem cell collection, irrespectively of disease type and status, prior CT lines, and radiation exposure. Pre-apheresis CD34+ cells and platelet count predict the need for one or two aphereses.
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Plateletpheresis
Complete blood count
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Mobilization with Neupogen plus Plerixafor versus Neupogen alone yields a product with more CD34+ stem cells, thus reducing the overall time and cost for stem cell collections. Since the mechanism of action is different for these two mobilizing agents, we determined whether or not there are differences in the proliferative potential and cellular composition of the apheresis products collected after mobilization. We compared apheresis products from patients mobilized with both stem cell regimens sequentially (Neupogen only, then Neupogen plus Plerixafor). Stem cells (CD45/34) were enumerated prior to cryopreservation by flow cytometry. The proliferative capacity of thawed apheresis products was evaluated using a HALO assay (Hemogenix), which utilizes luminescence to measure the proliferative capacity of cells by quantifying ATP concentrations. The cellular composition of the thawed samples was evaluated by flow cytometry for various lineage markers and T-cell differentiation markers. The proliferative capacity of apheresis products collected after mobilization with Neupogen was lower compared to products collected after Neupogen plus Plerixafor mobilization (p < 0.05). This correlates with the CD34 content in the products, which tends to be lower in products mobilized with Neupogen (0.25±0.18%) versus Neupogen plus Plerixafor (0.35±0.27%), but the difference is not significant (p = 0.23). However, ATP levels calculated per stem cell were similar (P = 0.34, n = 15 patients) between products mobilized with the two regimens. Phenotypic analyses of the products from 3 patients each mobilized with both regimens were performed. T-helper cells (CD4) were higher (32% vs. 24%, P = 0.02) in the apheresis products mobilized with Neupogen only versus Neupogen plus Plerixafor. There were no other significant differences in phenotypic markers, however, there was a trend toward a lower percentage of lin1dimHLA-DR+CD11c+ dendritic cells (p = 0.08) in the apheresis products mobilized with Neupogen versus Neupogen plus Plerixafor. Evaluation of additional samples will determine if this trend is significant. Although the mechanisms of action of Neupogen and Plerixafor are different, the proliferative capacity of the stem cells generated after treatment with Neupogen alone versus Neupogen plus Plerixafor is similar. However, the cellular composition of the products is different and may affect the quality of the stem cell graft.
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Mobilization
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Leukapheresis
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Apheresis machines are used to deliver a wide range of treatments to patients. Peripheral blood stem cells, mobilized by G-CSF chemotherapy, have become the primary source of grafts in haemopoietic stem cell transplantation. Poor mobilizers require skilled management and the recent introduction of plerixafor has increased the chances of successful mobilizations in this group of donors. Evidence supporting, or otherwise, the use of plasma exchange to treat various disorders is accumulating. Photopheresis is increasingly being used to treat cutaneous lymphoma and GVHD. Therapeutic apheresis can be associated with complications and patient inconvenience, and these require attention by skilled operators.
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Therapeutic plasma exchange
Photopheresis
Leukapheresis
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BACKGROUND: This report describes the specific kinetics of the peripheral blood (PB) CD34+ cell concentration in a selected group of very poor stem cell mobilizer patients treated with granulocyte–colony‐stimulating factor (G‐CSF) and plerixafor and determines the kinetics' impact on apheresis. STUDY DESIGN AND METHODS: All patients had previously experienced at least two failures of mobilization (without use of plerixafor). The present salvage therapy consisted in the administration of 10 µg/kg/day G‐CSF for 5 days added to a dose of plerixafor administered at between 5 a.m. and 6 a.m. on Day 5. The PB CD34+ cell counts were tested every 3 hours thereafter. Apheresis was initiated as soon as the PB CD34+ cell count reached 10 × 10 6 /L. RESULTS: A PB CD34+ cell count higher than 10 × 10 6 /L was observed as soon as 3 hours after plerixafor administration in 10 of the 11 patients who reached this threshold at some point in the monitoring process. Interestingly, all patients presented an early decrease in the PB CD34+ cell count 8 to 12 hours after plerixafor administration (below 10 × 10 6 /L for seven patients). CONCLUSION: Had such patients been tested for PB CD34+ cell mobilization according to conventional criteria (i.e., 11 hr after plerixafor administration), apheresis would not have been performed at the optimal timing. For very poor stem cell mobilizer patients, early monitoring of PB CD34+ cell count may be required for the optimal initiation of apheresis.
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Abstract Plerixafor (Mozobil) in combination with granulocyte colony‐stimulating factor (G‐CSF) has shown to increase mobilization of peripheral blood stem cells (PBSC) as compared to G‐CSF alone in patients undergoing autologous stem cell transplantation (ASCT). However, up to 25% of patients treated with G‐CSF alone still fail mobilization. Adding plerixafor to poor mobilizers allows to rescue these patients from mobilization failure and to reduce the number of apheresis sessions. The goal of this retrospective study was to capture the impact of plerixafor on treatment outcome and on apheresis department efficiency. The latter was measured in terms of time‐slots lost, that is, the number of apheresis sessions scheduled but not carried out due to poor mobilization, and the number of elective apheresis sessions performed for patients undergoing extracorporeal photopheresis (ECP). Hospital records of patients treated before and after introduction of plerixafor were collected and analyzed. With plerixafor, the mobilization failure rate dropped from 12% to 4% and the mean number of time‐slots lost per patient dropped from 1.39 to 0.89. Additional drug costs due to plerixafor were partially balanced by a reduction in apheresis sessions, resulting in an additional cost of 759€ per ASCT candidate. More importantly, with the use of plerixafor, the availability of time‐slots turned from erratic to predictable such that freed capacity could be dedicated to other apheresis procedures. As a result, the number of ECP sessions increased from 0 in 2005 to 685 sessions in 2014.
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Stem cells harvested from peripheral blood are the most commonly used graft source in hematopoietic stem cell transplantation. While G-CSF is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients undergoing autologous transplantation. Plerixafor (AMD3100, Genzyme Corporation) is a bicyclam molecule that antagonizes the binding of the chemokine stromal cell-derived factor-1 (SDF-1) to its cognate receptor CXCR4. Plerixafor results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF. In clinical studies of autologous stem cell transplantation, the combination of plerixafor and G-CSF allows the collection of large numbers of stem cells in fewer apheresis sessions and can salvage those who fail G-CSF mobilization alone.
Plerixafor
CXCR4 antagonist
Hematopoietic stem cell
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