Hematopoietic Stem Cell Mobilization for Gene Therapy: The Combination of G-CSF+Plerixafor in Patients with Beta-Thalassemia Major Provides High Yields of CD34+ Cells with Primitive Signatures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4412-4412
Author(s):  
Elena Baiamonte ◽  
Rita Barone ◽  
Rosalia Di Stefano ◽  
Melania Lo Iacono ◽  
Barbara Spina ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Total Yield ◽  
Thalassemia Major ◽  
Vitro Assay ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
Cd34 Cells

Abstract Hematopoietic stem cell engineering is a promising therapy to cure b-thalassemia, in particular for patients who lack a suitable BM donor for allogeneic transplantation. Since the engrafted gene-corrected stem cells will not have any selective advantage over the unmodified ones, the effectiveness of the therapy in this setting largely depends on the infusion of high numbers of gene-modified cells and on the conditioning regimen. The quality of the infused cells is also crucial for the clinical outcome and the duration of the therapeutic effect. HSPCs mobilization, particularly when G-CSF and plerixafor are used in combination, has been proved to be the optimal approach to harvest a large number of CD34+cells in patients with hematological malignancies and in healthy volunteers. However adult heavily-transfused thalassemia patients have intrinsic characteristics that may adversely affect both the safety and the efficacy of mobilization. We conducted a clinical trial to investigate the safety and effectiveness of mobilizing HSPCs with G-CSF+plerixafor in adult patients affected by β-thalassemia major with the aim to reach a cell dose of ≥8x106 CD34+cells/Kg. We studied the kinetic of CD34+cells during mobilization and performed a comprehensive characterization of their molecular and functional properties. All patients completed the mobilization according to the protocol (G-CSF 10 μg/kg/day for four days, followed by plerixafor 240 μg/kg in the evening on day 4) and no serious adverse events occurred. Leukapheresis was done 10-12 hours after plerixafor (on day 5). Three of the four patients reached the target cell dose or more in single-apheresis collections, even one patient where a significant dose reduction of G-CSF was halved due to early hyperleukocytosis. For one patients the number of cells collected in the first apheresis was slightly below the established target and therefore, according to the protocol, she was subjected to a second apheresis on day 6, after an additional dose of plerixafor. The total yield from the combined apheresis in this patient was 13.0 CD34+cells /Kg. CD34+ cell yields per single apheresis in our patients were comparable to those in healthy donors (12 pts) mobilized in our hospital with G-CSF alone. A significant increase in the mean peripheral blood CD34+ cells (12.1± 8.2 fold), was unanimously observed after plerixafor addiction. The frequencies of the more primitive CD34+cell subtypes (CD34+CD38- and CD34+CD38-133+) as well as the clonogenic capacity tested in short term in vitro assay were found significantly increased too. Comprehensive microarray analysis of genes expressed in the CD34+ cells purified from the same patient upon mobilization with G-CSF alone (G/CD34+cell) and with G-CSF+plerixafor (G+pl/CD34+cell) highlighted a different HSCs repertoire. According to the mechanism of plerixafor mobilization, CXCR-4 gene expression was found 5-fold higher in G+pl/CD34+cells. CXCR-4 gene is known to be expressed on the surface of more primitive CD34+ HSCs with long-term repopulating potential and plays a central role in the regulation of adhesion of them to native niche in the BM. A substantial number of genes with previously shown implication in mechanisms of homing and engraftment (CXCR4, CD82, DPP4, ROBO4), or genes linked to stress resistance (CXCL4, SOD2, IL8, PPBP) as well as several chemokines genes involved in cell mobility (CXCL2, CXC3, CXCR2) were also found to be up-regulated in G+pl/CD34+cells. Overall, the yields, the primitive signatures of CD34+cells indicate the G-CSF+plerixafor mobilized peripheral blood as optimal graft that should favor HSPCs engraftment after transplantation. This findings has therapeutic implications not only for b-thalassemia but also for other hematopoietic stem cell gene therapy applications. This work was funded by the F and P Cutino Foundation - Project RiMedRi CUP G73F1200015000. Disclosures No relevant conflicts of interest to declare.

Unrelated peripheral blood and cord blood hematopoietic stem cell transplants for thalassemia major

2004 ◽  
Vol 75 (4) ◽  
pp. 209-212 ◽  
Author(s):  
Patrick Huat-Chye Tan ◽  
William Ying Khee Hwang ◽  
Yeow Tee Goh ◽  
Poh Lin Tan ◽  
Liang Piu Koh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Thalassemia Major ◽  
Hematopoietic Stem ◽  
Cell Transplants ◽  
Stem Cell Transplants ◽  
Hematopoietic Stem Cell Transplants

Bortezomib Given in Sequence with Anthracycline and Thalidomide-Containing Regimens Does Not Adversely Affect Stem Cell Mobilization and Engraftment in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 541-541
Author(s):  
Geoffrey L. Uy ◽  
Nicholas M. Fisher ◽  
Steven M. Devine ◽  
Hanna J. Khoury ◽  
Douglas R. Adkins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Cell Mobilization ◽  
High Dose Melphalan

Abstract Bortezomib (VELCADE®) is a selective inhibitor of the 26S proteasome proven to be safe and effective in the treatment of relapsed or refractory multiple myeloma (MM). While high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) remains the standard of care, there is considerable interest in incorporating bortezomib into the initial treatment of MM. However, the role of bortezomib in frontline therapy for MM will depend in part on its effects on subsequent stem cell mobilization and engraftment. We conducted a pilot study of bortezomib administered pretransplant followed by high-dose melphalan with AHSCT. Two cycles of bortezomib 1.3 mg/m2 were administered on days 1, 4, 8, and 11 of a 21-day treatment cycle. One week after the last dose of bortezomib, stem cell mobilization was initiated by administering filgrastim 10 mcg/kg/day subcutaneously on consecutive days until stem cell harvest was completed. Stem cell collection began on day 5 of filgrastim via large volume apheresis (20 L/day) performed daily until a minimum of 2.5 x 106 CD34+ cells/kg were collected. Patients were subsequently admitted to the hospital for high-dose melphalan 100 mg/m2/day x 2 days followed by reinfusion of peripheral blood stem cells 48 hours later. Sargramostim 250 mcg/m2/day subcutaneously was administered starting day +1 post-transplant and continued until the absolute neutrophil count (ANC) ≥ 1,500/mm3 for 2 consecutive days. To date, 23 of a planned 40 patients have been enrolled in this study with 19 patients having completed their initial therapy with bortezomib followed by AHSCT. Patient population consists of 16 male and 7 female patients with the median age at diagnosis of 58 years (range 38–68). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (16), IgA (7) with stage II (9) or stage III (14) disease. Prior to receiving bortezomib, 11 patients were treated with VAD (vincristine, Adriamycin and dexamethasone) or DVd (Doxil, vincristine and dexamethasone), 5 patients with thalidomide and 5 patients with both. Two patients did not receive any prior chemotherapy. All patients successfully achieved the target of 2.5 x 106 CD34+ cells/kg in either one (15/19 patients) or two (4/19 patients) collections with the first apheresis product containing a mean of 5.79 x 106 CD34+ cells/kg. Analysis of peripheral blood by flow cytometry demonstrated no significant differences in lymphocyte subsets before and after treatment with bortezomib. Following AHSCT, all patients successfully engrafted with a median time to neutrophil engraftment (ANC ≥ 500/mm3) of 11 days (range 9–14 days). Platelet engraftment (time to platelet count ≥ 20,000/mm3 sustained for 7 days without transfusion) occurred at a median of 12 days (range 9–30 days). Eleven patients were evaluable for response at 100 days post-transplant. Compared to pre-bortezomib paraprotein levels, 3 patients achieved a CR or near CR, 7 maintained a PR while 1 patient developed PD. We conclude that pretransplant treatment with 2 cycles of bortezomib does not adversely affect stem cell yield or time to engraftment in patients with MM undergoing AHSCT. Updated results and detailed analysis will be available at the time of presentation.

Temporal Changes in Plerixafor Administration Do Not Impact Hematopoietic Stem Cell Mobilization Efficacy: Results of a Prospective Clinical Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2988-2988
Author(s):  
R. Donald Harvey ◽  
Sagar Lonial ◽  
Heather Renfroe ◽  
Rajni Sinha ◽  
Christopher R Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Published Data ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Dosing Interval ◽  
Cell Counts ◽  
Cd34 Cells

Abstract Abstract 2988 Objectives: Plerixafor (AMD3100, Mozobil) with filgrastim (G-CSF, Neupogen) is approved for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and multiple myeloma (MM). Plerixafor pharmacokinetics (PK) and pharmacodynamics (PD) are well described, with linear, dose-dependent PK following subcutaneous (SC) administration, peak concentrations 30–60 mins post-injection and an elimination half-life (t1/2) of 5.3 hr. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, peak CD34+ cell counts occur 10–14 hours following administration, however, data is limited in the 14–24 hr timeframe. Plerixafor labeling requires SC dosing approximately 11 hours prior to apheresis, which translates into dosing 10 :00 PM the night before apheresis, and 54% of MM patients collect ≥ 6 × 106 CD34+ cells/kg following a single apheresis procedure. The current regimen is inconvenient for patients and requires additional health care resources. Based on PK and PD, we hypothesized that plerixafor given at 3 :00 PM (17 hr prior to apheresis) would yield equivalent CD34+ HSC yield to 10 :00 PM dosing in MM patients. Methods: In a Simon's two-stage design, we enrolled MM patients undergoing cytokine-only HSC mobilization. All subjects received filgrastim 7.5 mcg/kg SC BID for 4 days followed by plerixafor (0.24 mg/kg SC daily) for up to 4 days beginning at 3 :00 PM the day prior to the first day of a 24-liter apheresis procedure at 8 :00 AM. Target CD34+ HSC collection for stem cell transplant (SCT) was ≥ 10 × 106 CD34+ cells/kg. Blood samples for CD34+ fluorescence-activated cell sorting analysis were collected prior to the first plerixafor dose and at 1, 3, and 17 ± 1 hr, then daily prior to apheresis as needed. Results: Thirty patients (17 female, median age 59 years [range 44–70]) were evaluable; 27 received 1 pre-mobilization regimen (RVD n=20, VTD n=2, VD n=2, V/PLD/D n=1, VT n=1, RD n=1) for a median of 4 (1–6) cycles. Three received 2 regimens [CMF × 6 (breast cancer), then VTD × 5; RD × 4, then RVD × 4; and V/PLD × 1 with maintenance R]. Six patients received prior radiation. Mean (± SD) CD34+ cell counts in peripheral blood pre-plerixafor and 1, 3, and 17 hr post-first dose increased through the dosing interval (Figure). Twenty-two (73%) patients collected target cell numbers in 1 day of apheresis, 7 (23%) in 2 days, and 1 (3%) in 3 days. Twenty-seven (90%) patients collected ≥ 6 × 106 CD34+ cells/kg in 1 day. Institutional data with filgrastim 7.5 mcg/kg SC BID for 4 days alone in MM in 22 subjects showed a day 1 collection of ≥ 10 × 106 CD34+ cells/kg in 18% of patients (Renfroe H, et al. Transfusion Feb 2011). Adverse events were generally mild and consistent with known side effects of the combination [gastrointestinal disorders (diarrhea, nausea) and injection site reactions]. To date, 16 (53%) patients have proceeded to autologous SCT with melphalan conditioning and all patients have engrafted, with median time to an ANC ≥ 500/mm3 of 13 (range 11–15) days and platelets ≥ 20, 000/mm3 of 16 (range 11–21) days. Conclusion: This is the first prospective trial demonstrating the safety and efficacy of plerixafor given 17 hr prior to apheresis. Pharmacodynamic data showed the peripheral blood CD34+ cell population increased throughout the dosing interval, with a 4.6-fold increase over pre-plerixafor counts at 17 hr. Comparison with historical institutional controls and published data suggests this regimen yields at least equivalent, if not superior, collection rates with one apheresis procedure. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding.

A Comparison of Toxicity and Mobilization Efficacy Following Two Different Doses of Cyclophosphamide for Mobilization of Hematopoietic Stem Cells in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4229-4229
Author(s):  
Connie A. Sizemore ◽  
Justin LaPorte ◽  
Melissa Sanacore ◽  
H. Kent Holland ◽  
Joan Mccollum ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Febrile Neutropenia ◽  
Hematopoietic Stem Cell ◽  
Hospital Utilization ◽  
Off Label Use ◽  
Hematopoietic Stem ◽  
Off Label ◽  
Cell Dose ◽  
Cd34 Cells

Abstract Abstract 4229 Background Cyclophosphamide (Cy) (2-7 g/m2) has been shown to be an effective regimen for hematopoietic stem cell (HSC) mobilization in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). However, the optimal dose to be used, which maximizes HSC collection yields while minimizing febrile neutropenia and other toxicities, remains controversial. Two historical cohorts of MM patients who received G-CSF and Cy at dose of either 4g/m2 (Cy4) or 2g/m2 (Cy2) were compared. Methods A total of 72 patients undergoing first mobilization with Cy and G-CSF at a single institution between June 2006 and December 2008 were retrospectively analyzed. The initial Cy4 patient cohort (n=35) was mobilized with Cy 4gm/m2 starting on Day 1 followed by G-CSF 10ug/kg/day starting on Day 7 and continuing until completion of apheresis. Beginning in Feb 2008, the Cy dose was reduced to 2gm/m2 and the G-CSF start date was moved to day 4 (Cy2 n=37). Apheresis was initiated at physician discretion based on patient specific factors. Minimal and optimal yield was defined as collection of ≥2 × 106 and ≥6-10 × 106 CD34+ cells/kg respectively. Prophylactic antibiotics were given for ANC <500 to reduce risk of febrile neutropenia. Results Minimal cell dose required for ASCT (≥2 × 106 CD34+ cells/kg) was achieved in 97% vs. 86.5% of Cy4 and Cy2 patients, respectively. Of the 5 patients failing to mobilize on Cy2, four of these subsequently mobilized adequately following G-CSF and plerixafor. Median number of apheresis collections required was significantly lower in the Cy4 patients (1 vs.3, p=0.0065). The proportion of patients collecting the minimal and optimal cell dose in 2 or fewer days of apheresis was 94% vs. 86.5% (p= 0.4304) and 77% vs. 35% (p=0.0004), in the Cy4 and Cy2 patients respectively. However, mobilization with Cy4 was associated with a significantly higher incidence of hospital admissions due to febrile neutropenia (40% vs. 5%, p=0.0005), which is what prompted the change from Cy4 to Cy2. Conclusions Although Cy4 and Cy2 are both effective HSC mobilizing regimens, mobilization efficacy and toxicity vary greatly. Cy4 results in higher HSC yields requiring fewer apheresis procedures, but this benefit is offset by increased morbidity and hospital utilization. Based on the suboptimal results with Cy 4g/m2 and Cy 2g/m2 mobilization, newer mobilization strategies are clearly needed for MM patients. We are currently exploring a chemotherapy-free approach utilizing G-CSF +/- plerixafor, with the aim of optimizing HSC yields while minimizing toxicity and costs (apheresis collections, hospital utilization, etc.). In our current algorithm, all MM patients receive G-CSF at a dose of 10ug/kg/day, with a day 4 peripheral CD34+ cell count determining requirement for plerixafor on the evening prior to apheresis collection(s). Disclosures: Off Label Use: Cyclophosphamide is being used as off label use for hematopoietic stem cell mobilization.

High Incidence of Hematopoietic Stem Cell Mosaicism in Fanconi Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 993-993
Author(s):  
Jakub Tolar ◽  
Margaret L. MacMillan ◽  
Sat Dev Batish ◽  
Cindy Eide ◽  
Yeva Flit ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Peripheral Blood ◽  
Somatic Mosaicism ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Cellular Marker

Abstract Determination of the degree of somatic mosaicism providing functional correction of Fanconi anemia (FA) hematopoiesis has direct implications for gene therapy for FA: it may help assess the percentage of FA hematopoietic cells corrected by gene therapy approaches that are needed to achieve clinically meaningful effects. Hypersensitivity to DNA interstrand cross-linking agents, such as diepoxybutane (DEB) and mitomycin C (MMC), is a cellular marker for diagnosis of FA. However, in some FA patients a population of DEB-resistant PHA-stimulated lymphoblasts (PHA-L) was observed, and this population sometimes varied over time. To assess the significance of this finding on hematopoietic function, we evaluated the MMC sensitivity of bone marrow mononuclear cells (BMMC) and DEB sensitivity of PHA-L and cultured lymphoblastoid cell lines (LCL) in 42 consecutive FA patients referred to the University of Minnesota. In cases where LCL were DEB-resistant, cultured fibroblasts were also studied. BMMC were cultured in the presence of increasing concentrations of MMC. PHA-L and LCL were cultured in DEB at 0.1 mcg/ml. Wild type BM progenitors (N = 17 subjects) proliferated regardless of increasing MMC concentrations (albeit at decreased efficiency at the highest concentrations) as follows: 0 MMC (normalized to 100%), 5 nM MMC (99% [standard deviation, SD, 16%]), 10 nM MMC (90% [SD 22%]), 25 nM MMC (77% [SD21%]), and 50 nM MMC (44% [SD 30%]). Of the 42 FA patients, BMMC failed to proliferate at 0 nM MMC in 10 patients and at 5 nM MMC in 20 patients. Twelve FA patients had MMC resistant BMMC: cells cultured in 5, 10, 25 and 50 nM MMC grew 44% (SD 28%), 35% (SD 24%), 24% (SD 30%) and 17% (SD 32%) of colony numbers in MMC free culture, respectively. Six of these 12 subjects were PHA-L mosaics as determined by DEB sensitivity testing. Four patients with no growth of BMMC at 0 or 5 nM MMC were also somatic mosaics in their PHA-L and LCL. Thus there was no clear correlation between somatic mosaicism as demonstrated by DEB testing in peripheral blood and sensitivity of BMMC to growth in MMC. Clinically, two patients with hematopoietic somatic mosaicism developed severe marrow aplasia, one of which received hematopoietic stem cell transplantation. Four of the mosaic patients had normal or near normal peripheral blood counts with one patient having clonal hematopoiesis by HUMARA assay and only low levels of metaphases with multiple breaks in multiple DEB studies. While patients with hematopoietic somatic mosaicism had mixed populations of DEB sensitive cells in their peripheral blood, all their fibroblast cultures were DEB sensitive. In summary, these data show that the presence of somatic mosaicism per se does not necessarily prevent bone marrow failure. Moreover, the data suggest that patients with stigmata of FA may have chromosomal breakage studies showing few cells (or no cells) with the characteristic changes of FA; in these cases, skin fibroblasts should be tested as well.

Safety and Efficacy of Hematopoietic Stem Cell Remobilization with Plerixafor (Mozobil®) + G-CSF In Pediatric Patients with Malignant Disorders

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2245-2245 ◽  
Author(s):  
Shalini Shenoy ◽  
Barbara Asselin ◽  
Jignesh Dalal ◽  
Rakesh Goyal ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Solid Tumors ◽  
Hematopoietic Stem Cell ◽  
Pediatric Patients ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
Cd34 Cells ◽  
The Us ◽  
Equity Ownership

Abstract Abstract 2245 Background: High dose chemo/radiotherapy followed by autologous hematopoietic stem cell (HSC) transplantation (HSCT) is indicated in several pediatric malignant disorders such as neuroblastoma and relapsed Hodgkin's disease. Ideally, 2–5 × 106 CD34+ cells/kg should be infused during autologous peripheral blood (PB) HSCT to support timely and durable engraftment and improve transplant outcomes. In patients who have received repetitive cycles of intensive chemotherapy, this target is not always achieved with standard mobilization regimens. Plerixafor, a novel CXCR4 antagonist, when combined with granulocyte colony-stimulating factor (G-CSF), can safely and predictably mobilize adequate numbers of CD34+ HSC to support transplantation in adult patients with myeloma and lymphoma. We report on the safety and efficacy of PB HSC mobilization with plerixafor + G-CSF in pediatric patients with cancer. Methods: This is a retrospective analysis of all children with various malignant disorders who were enrolled in the US plerixafor compassionate use program (CUP; NCT00291811). Patients who had previously failed HSC mobilization (defined as the inability to collect ≥2 x106 CD34+ cells/kg or achieve an adequate PB CD34+ cell count, typically ≥10 CD34+ cells/μl) with growth factor +/− chemotherapy were treated with plerixafor + G-CSF. The goal was to collect ≥2 × 106 CD34+ cells/kg for autologous HSCT. G-CSF (10μg/kg SC) was administered daily for 5 days. Plerixafor (0.24 mg/kg SC) was given in the evening on Day 4, ~11 hours prior to apheresis. Plerixafor, G-CSF and apheresis were repeated daily until ≥2 × 106 CD34+ cells/kg had been collected. Results: A total of 16 patients with non Hodgkin's lymphoma (3), Hodgkin's disease (1), CNS tumors (4), Ewing's sarcoma (4), neuroblastoma (2), osteogenic sarcoma (1) and desmoplastic small cell tumor (1) underwent the procedure. The median age was 14 years and 7 (44%) patients were male. In previous mobilization attempts, 5 patients failed to collect the minimum transplantable cell dose with a median yield of 0.44 x106 (range: 0.17–2.2 × 106) CD34+ cells/kg. Apheresis was never attempted in11 patients due to low PB CD34+ cell levels; median cells/μl was 1.0 (range, 0.01–12) in 9 patients with available data. Initial mobilization regimens included growth factor alone in 6 patients and growth factor + chemotherapy in 9 patients (data unavailable for 1 patient). When re-challenged for mobilization with plerixafor + G-CSF, 14 (88%) patients successfully collected ≥2 × 106 CD34+ cells/kg; this included all 4 (100%) patients with lymphoma and 10 (83%) patients with solid tumors. The median time to collect the target cell dose was 1.5 days (range 1–5 days). The median CD34+ cell yield from all patients was 3.5 × 106 cells/kg (range 0.96 – 9.80 × 106); patients with lymphoma and solid tumors collected a median of 7.2 (range 3.2 – 7.9) × 106 and 3.3 (range 0.96 –9.8) × 106 CD34+ cells/kg, respectively. Eleven (69%) patients proceeded to transplant including all 4 (100%) patients with lymphoma and 7 (58%) patients with solid tumors. One patient with neuroblastoma received a tandem transplant. The median infused cell dose was 4.18 × 106 CD34+ cells/kg (range 1.7 – 7.6 × 106). The median time to neutrophil and platelet engraftment was 14 and 33 days, respectively. Plerixafor-related adverse events were mostly mild, and observed in 5 (31%) patients. They included administration site reactions (4), vomiting (2), nausea (1) and oral paraesthesia (1). No patient experienced a serious adverse event. Conclusions: Treatment with plerixafor + G-CSF safely and effectively mobilized HSC in the majority of pediatric patients with malignant disorders after failure of standard mobilization with growth factor ± chemotherapy. Successful stem cell mobilization allowed consideration of autologous HSCT when indicated. Mobilization with plerixafor was safe and resulted in prompt engraftment. Many of these patients could not have proceeded to transplant without this intervention. Disclosures: Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. McCarty: Genzyme, Amgen: Honoraria, Research Funding. Angell: Genzyme Corporation: Employment, Equity Ownership. Huebner: Genzyme Corporation: Employment, Equity Ownership.

An Effective Hematopoietic Stem Cell Mobilization Algorithm for Adding Plerixafor to G-CSF for Multiple Myeloma Patients Undergoing Autologous Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4389-4389 ◽  
Author(s):  
Justin LaPorte ◽  
Scott R. Solomon ◽  
Asad Bashey ◽  
H. Kent Holland ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Cell Count ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Small Sample ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
The Absolute

Abstract Abstract 4389 Background: Autologous hematopoietic stem cell transplantation (ASCT) has become an integral part of the treatment for multiple myeloma (MM). In addition, it is standard practice to collect enough stem cells for more than one transplant. Therefore, it is critical to have an effective mobilization strategy in order to efficiently collect sufficient numbers of CD34+ cells. Administering granulocyte-colony stimulating factor (G-CSF) alone to MM patients can produce sufficient CD34+ yields in the majority of patients. However, some patients may require > 4 apheresis days to achieve those yields. In addition, some patients may fail to collect enough CD34+ cells for ASCT. Plerixafor was approved in 2008 to be used in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood. Plerixafor can increase the average daily CD34+ yields by 3-fold. However, since the majority of patients can collect with G-CSF alone, a plerixafor algorithm was developed in 2009 to judiciously administer plerixafor only to those patients at higher perceived risk for mobilization failure. Administration of plerixafor is based on a peripheral blood CD34+ count drawn after 3 days of G-CSF and subsequent CD34+ collection yields. Methods: G-CSF 10mcg/kg/day (given daily or divided into twice daily) was administered subcutaneously from day 1 to 4. On day 4, a peripheral absolute CD34+ cell count was drawn. If the absolute CD34+ cell count was ≥ 12 cells/mm3 then apheresis started on day 5. If the absolute CD34+ cell count on day 4 was < 12 cells/mm3 plerixafor 240mcg/kg was administered subcutaneously the evening prior to apheresis beginning on day 5. During apheresis, if the CD34+ yield was < 1.0×106 CD34+/kg or 50% less than the previous collection, plerixafor was initiated. The minimum collection yield for all patients was 4.0×106 CD34+/kg. The maximum number of apheresis days was 5. Previous therapy was also examined. Results: From October 2009 to May 2011, 68 multiple myeloma patients were mobilized with G-CSF +/− plerixafor. Ninety-three percent (63/68) of patients achieved the minimum collection yield of 4.0×106 CD34+/kg. Ninety-nine percent (67/68) of patients achieved a yield of at least 2.0×106 CD34+/kg. Forty-four percent (30/68) of the patients required at least 1 dose of plerixafor with the majority requiring it prior to the first apheresis (83%). The median days of apheresis was 2 (range 1–5). The overall average yield on the first apheresis day was 4.35×106 CD34+/kg (95% CI +/− 0.64). The overall average total yield was 8.71×106 CD34+/kg (95% CI +/− 0.93). Sixty percent (41/68) and 76% (52/68) of patients collected ≥ 6.0×106 CD34+/kg in ≤ 2 days and ≤ 4 days of apheresis, respectively. The average daily yield (ACD34) for G-CSF alone can be predicted by ACD34 = 0.0377+ 0.07456xCD34 (see figure). ACD34 after plerixafor + G-CSF can be predicted by the equation 3(0.0377 + 0.07456xCD34) = ACD34. Of the patients that received previous radiation therapy (9) or cyclophosphamide (2), plerixafor was utilized in 78% and 100%, respectively. Previous lenalidomide therapy was present in 50% of the patients and it did not correlate to any increase in plerixafor usage. Conclusion: Adding plerixafor to G-CSF based upon a day 4 CD34+ count and collection yields is an effective strategy to mobilize CD34+ cells. Ninety-three percent of the of the patients were able to collect a minimum of 4.0×106 CD34+/kg cells and 99% collected > 2.0×106 CD34+/kg, in a median of two collections. Limitations to the study include a small sample size and an arbitrarily determined threshold to administer plerixafor. Also, the length of lenalidomide could not be retrospectively determined. A cost-based analysis is currently being performed to help determine the best day 4 CD34 cutoff for future studies. Disclosures: No relevant conflicts of interest to declare.

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