High Dose Plerixafor Is Safe and Mobilizes Higher Numbers of CD34+ Cells Compared with Standard Dose Plerixafor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 585-585
Author(s):  
Jeremy M Pantin ◽  
Xin Tian ◽  
Matthew M. Hsieh ◽  
Lisa Cook ◽  
Theresa Donohue ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Adverse Events ◽  
Dose Level ◽  
Peripheral Blood ◽  
Standard Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Cd34 Cells

Abstract Abstract 585 Introduction Plerixafor is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXCR4. This results in therapid release of CD34+ cells into circulation, which can then be collected by apheresis. Plerixafor is FDA approved at the 240 μg/kg dose to be used in conjunction with G-CSF to mobilize autografts for transplantation. Allogeneic grafts can also be mobilized using single agent plerixafor without G-CSF, and following transplantation, result in sustained donor derived hematopoiesis. However, when the 240 μg/kg dose is used, 1/3 of donors fail to mobilize minimally acceptable doses of CD34+ cells. Recently, we demonstrated the safety of administration of a single dose of 480 μg/kg of subcutaneous (sc) plerixafor in humans. We subsequently conducted a randomized cross-over trial comparing CD34+ mobilization in healthy subjects mobilized with a single dose of sc plerixafor given at either a high dose (480 μg/kg) or a conventional dose (240 μg/kg). Methods Twenty normal healthy volunteers were randomized and received either a 240 or 480 μg/kg dose of sc plerixafor followed by at least a 2 week wash out period then were administered the other dose of plerixafor. Circulating numbers of leukocytes and CD34+ cells/μlwere measured at multiple time points for 24 hours following each plerixafor injection and the CD34+ AUC over 24 hours was calculated for each subject at each dose level. Peripheral blood colony forming unit (CFU) assays were performed at baseline and 6 hours after plerixafor dosing. Adverse events were graded using CTCAE version 3.A sample size of 20 subjects was determined to have over 90% power to detect an absolute CD34+ count difference of 10/μl using this crossover design and a two-sidedpaired t-test at the 0.05 level. Results Twenty-three subjects were enrolled and 20 completed administration of both doses. Peak circulating CD34+ cell numbers (median 31.5 vs 25, p=0.0009), circulating CD34+ cell numbers at 24hrs (median 15.5 vs 9, p<0.0001), and the CD34+ AUC over 24 hours (median 543 vs 411, p<0.0001) were all significantly higher following the administration of the 480 μg/kg plerixafor dose compared to the 240 μg/kg dose. The time to peak CD34+ was also slightly longer after the 480 μg/kg dose (median 10 vs 8 hrs, p=0.011). These differences were not related to the order of administration of the 2 different plerixafor doses. Although GM-CFUs from the peripheral blood at 6hrs following plerixafor were significantly higher compared to baseline levels at both plerixafordoses, there was no dose-effect relationship observed between drug dose and fold increase in GM-CFUs. The incidence and severity of AE's did not differ between lower and higher doses of plerixafor and no grade 3 or greater adverse events occurred at either dose level. Conclusion These preliminary data suggest high dose plerixafor can be administered safely and may mobilize more CD34+ cells than standard dose plerixafor. Furthermore, these data suggest mobilization following a single dose of plerixafor and a single apheresis procedure would result in graft collections containing higher CD34+ cell numbers when allogeneic stem cell donors are mobilized with high-dose plerixafor compared to standard-dose. Disclosures: Off Label Use: Plerixafor, a hematopoietic stem cell mobilizer, is indicated 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 (NHL) and multiple myeloma (MM).

Transplantation of Peripheral Blood Stem Cells Mobilized by Chemotherapy and Single Dose Pegylated G-CSF in Patients with Multiple Myeloma: Equivalence of 6 mg and 12 mg Pegfilgrastim.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2868-2868 ◽  
Author(s):  
Ingmar Bruns ◽  
Ulrich Steidl ◽  
Christof Scheid ◽  
Kai Hübel ◽  
Roland Fenk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Single Dose ◽  
Peripheral Blood ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cytotoxic Therapy ◽  
Cd 34 ◽  
Cd34 Cells

Abstract To date the most effective treatment for patients (pts) with multiple myeloma consists of conventional induction chemotherapy followed by either single or tandem high-dose chemotherapy and autologous blood stem cell transplantation. Collection of sufficient numbers of hematopoietic stem cells is essential for high-dose chemotherapy. Current regimens for stem cell mobilization are based on daily subcutaneous injections of human recombinant G-CSF starting shortly after cytotoxic therapy. Here we examined the use of polyethyenglycole (PEG)-conjugated G-CSF (pegfilgrastim) at two different doses in patients with stage II or III multiple myeloma. Patients received induction therapy with 2–4 cycles ID or VAD. Following cytotoxic therapy with cyclophosphamide (4g/m2) we administered either a single dose of 6 mg pegfilgrastim (n=10 pts; median age: 55 years), 12 mg pegfilgrastim (n=12 pts; median age: 51 years) or daily doses of 8,5 μg/kg unconjugated G-CSF (filgrastim) (n=12 pts; median age: 51 years). The growth factor was given on day 4 (range 2–5 days) in the “6 mg pegfilgrastim group”, on day 5 (range 2–7 days) in the “12 mg pegfilgrastim group” and on day 4 (range 3–6 days) in the “filgrastim group” after cyclophosphamide. Numbers of CD34+ cells were determined during leukocyte recovery and harvested by large volume apheresis using a cobe spectra blood cell separator. Pegfilgratim was associated with an earlier leukocyte recovery both at the 6mg dose (median 12 days, range 8–16 days) and the 12mg dose (median 12 days, range 7–16 days) as compared to filgrastim (median 14 days, range 11–15 days, p=0.04). Similarily, the peripheral blood CD34+ cell peak occurred earlier in patients who received pegfilgrastim (median 12 days, range 11–18 days versus median 15 days, range 12–18). On the other hand the peripheral blood CD 34+ peak did not differ significantly between the three groups (median 129/μl with 6 mg pegfilgrastim, range 30–433, median 78/μl with 12 mg pegfilgrastim, range 20– 1055 and median 111/μl with filgrastim, range 28–760, p=0.95). With a median of 1.0x10E7 CD34+ cells per kg (range 5.8x10E6-1.9x10E7) in the “6 mg pegfilgrastim group”, 7.4x10E6 CD34+ cells per kg (median, range 4.9x10E6- 3.8x10E7) in the “12 mg pegfilgrastim group” and 10.8x10E6 CD34+ cells per kg (median, range 5.0x10E6-8.7x10E7) in the “filgrastim group” there were no significant differences in the total number of harvested CD34+ cells. Following high-dose therapy with melphalan (200 mg/m2) and autografting leukocyte and platelet reconstitution was similar within all groups. In summary, a single dose of pegfilgrastim after high dose cyclophosphamide is capable of mobilizing a sufficient number of CD 34+ cells for succesful autografting and sustained hematological reconstitution in patients with multiple myeloma. No difference could be observed between 6 mg and 12 mg of pegfilgrastim. Our data provide the basis for randomized studies evaluating the optimal dose and timing of pegfilgrastim as well as long-term outcome in larger cohorts of patients.

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.

Mobilization as a Preparative Regimen for Hematopoietic Stem Cell (HSC) Transplantation in Rhesus Macaques.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1709-1709
Author(s):  
Andre Larochelle ◽  
Cynthia L. Perez ◽  
Allen Krouse ◽  
Mark Metzger ◽  
Simon Fricker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Dose ◽  
Peripheral Blood ◽  
Rhesus Macaques ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Preparative Regimen ◽  
Hsc Transplantation

Abstract The myeloablative conditioning regimens currently used for hematopoietic stem cell (HSC) transplantation are associated with significant morbidity and mortality. Alternative strategies to promote engraftment of infused HSCs with increased safety warrant investigation. In a murine model, we previously demonstrated that, in absence of irradiation, mobilization with AMD3100 (a CXCR4 antagonist) before marrow transplantation vacated microenvironmental niches and resulted in higher levels of engraftment of transplanted HSCs compared to controls (no AMD3100 treatment before transplantation) (Abkowitz JL et al., Blood (ASH Annual Meeting Abstracts)104 (11): 1187, 2004). In this study, we hypothesized that AMD3100 mobilization before transplantation could also promote HSC engraftment in a large animal model, eliminating the need for toxic myeloablative conditioning. Peripheral blood cells from two rhesus macaques were collected by apheresis 3 hours after administration of a single dose of AMD3100 1mg/Kg. CD34+ cells were enriched and transduced for four days in the presence of cytokines and fibronectin with non-expression Moloney murine leukemia virus-derived retroviral vectors (G1PLI) that carry a bacterial neomycin phosphotransferase resistance gene (neoR). The neoR-marked CD34+ cells were reinfused in the non-myeloablated animals, immediately after AMD3100 mobilization and apheresis repeated on the day of transplantation. NeoR-marking levels of approximately 0.1% were detected in both peripheral blood MNC and granulocytes at two months (animal 2RC102) and four months (animal RQ4791) after transplantation. Previous transplantation studies performed without prior myeloablative conditioning or mobilization preparative regimen resulted in no long-term in vivo gene marking. We mathematically confirmed that this observed level of gene marking is what can be expected when AMD3100 mobilization is used as a conditioning regimen. Previous studies have estimated the number of long-term repopulating HSCs at 6 per 105 CD34+ cells (Abkowitz JL et al, Blood96: 3399, 2000). In animal RQ4791, approximately 4.5X107 CD34+ cells, and therefore 2700 HSCs, were mobilized after AMD3100 administration. The total number of HSCs per animal is thought to be conserved in mammals and has been estimated at 11,000 to 22,000 (Abkowitz JL et al, Blood100: 2665, 2002). Hence, 12–24% of HSCs were mobilized after a single dose of AMD3100, consequently opening 12–24% of microenvironmental niches for engraftment. If 1% of engrafted HSCs are marked, 0.12–0.24% long-term marking levels are expected, correlating well with the observed marking level of 0.1%. These results imply that the number of available niches in large animals, as in murine models, regulates the number of HSCs that engraft. As importantly, mobilization with AMD3100 could provide a non-toxic preparative approach in large mammals, including humans, to improve HSC engraftment in transplantation for genetic and other nonmalignant disorders.

Higher Efficacy of Peripheral Blood Stem Cell Collection in Children Mobilized with High-Dose G-CSF.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5274-5274
Author(s):  
Jan Styczynski ◽  
Robert Debski ◽  
Hanna Gornicka ◽  
Elzbieta Hulek ◽  
Pawel Wojtylak ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Count ◽  
Peripheral Blood ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Peripheral Blood Cd34 ◽  
Group I ◽  
Cd34 Cells ◽  
Stem Cell Collection ◽  
Number Of Cells

Abstract Objective: Analysis of efficacy of PBSC collection after mobilization by high-dose G-CSF in children and young adults, qualified for transplantation of autologous hematopoietic stem cells. Patients and Methods: Total number of 21 patients (23 collection cycles) were included into the study, divided into 2 groups: group I of 10 patients (aged 16m-23y, weight 8.5–61kg) with solid tumors were mobilized with G-CSF (Neupogen) at dose 2x5 μg/kg bw/day (12 collection cycles); group II of 11 patients (aged 3–27y, weight 12.5–68kg) with solid tumors (n=6) or hematological malignancies (n=5), who were mobilized with G-CSF (Neupogen) at dose 2x12 μg/kg bw/day. PBSC collections were performed by COBE Spectra from the day when CD34 cell count exceeded 20/μl. Efficacy of procedure was determined by collection of total 2x106 CD34 cells/kg (minimal required cell dose), or 5x106 CD34 cells/kg (optimal cell dose). Results: Group I: Peripheral blood CD34 cell count exceeded 20/μl in 7/12 (58%) patients at day 4 and 10/12 (83%) at day 6 of G-CSF administration. Total number of CD34 cells of 2x106 /kg kw and 5x106 /kg bw was obtained in 3/12 (25%) and 2/12 (17%) patients after first collection respectively; and in 8/12 (67%) and 4/12 (33%) after second collection, respectively. After 3 days of collection required number of cells was obtained in 9/12 (75%) and 6/12 (50%) patients, respectively. No patient reported side-effects related to G-CSF administration. Group II: Peripheral blood CD34 cell count exceeded 20/μl in 8/11 (73%) patients at day 4 and 11/11 at day 6 of G-CSF administration. Total number of CD34 cells of 2x106 /kg bw and 5x106 /kg bw was obtained in 9/11 (82%) and 3/11 (27%) patients after first collection respectively; and in 11/11 and 6/11 (55%) after second collection, respectively. After 3 days of collection, in all patients, but one, optimal number of cells was obtained. Two patients reported side-effects related to G-CSF administration (headache, bone pain). No differences were found between the rate of speed of PBSC mobilization in analyzed schemes of G-CSF administration, however group of patients mobilized with high-dose G-CSF, showed more efficient stem cell collection after 3 days of procedure (p=0.027; OR=14; 95%CI=1.1–402). Conclusion: Mobilization of PBSC with high-dose G-CSF is a safe and effective method of hematopoietic stem cell collection, enabling high efficacy of this procedure.

scholarly journals Low Dose Umbilical Cord Blood Transplant Results in Skewed Immune Cell Composition Which May Impact Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5672-5672
Author(s):  
Chi Hua Sarah Lin ◽  
Beth Shaz ◽  
Rona Singer Weinberg
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Cell Population ◽  
Peripheral Blood ◽  
Low Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Nsg Mice ◽  
Cd34 Cells

Abstract Introduction Reconstitution of donor-derived immune system after allogeneic hematopoietic stem cell transplantation (HSCT) is essential for recovery and long-term survival. Despite routine use of human umbilical cord blood (hUCB) as a stem cell source for allogeneic HSCT, much remains unknown regarding the kinetics of immune recovery and correlation with different transplant cell dosages. To study the hUCB repopulating potential, different hUCB CD34+ cell dosages were transplanted into immune deficient NSG mice; hematopoietic cells were then collected and engraftment was analyzed. Methods NOD/SCID/IL-2Rγnull recipient (NSG) mice (Jackson Laboratories, Bar Harbor, ME) were kept in pathogen-free facilities. CD34+ cells were isolated from a pool of six hUCB donors using a CD34+ microbead kit (Miltenyi Biotec). Each sublethal irradiated (220 or 300 cGy) 8 week old female NSG mice received either low dose (15x103, N=15) or high dose (75x103, N=15) CD34+ cells transplanted intravenously via retro-orbital route. Animal experiments were performed in accordance with Institutional Animal Care and Use Committee guidelines. Statistical analysis was performed with Prism software (GraphPad Software, Inc) and Excel. Data are presented as mean ± standard error of the mean (SEM). Results To determine the effects of hUCB CD34+ cell dosages on the rate of engraftment, NSG mice were transplanted with low doseor high dose CD34+ cells. The transplanted CD34+ cell dosages were comparable to clinical dosages based on body weight (Mavroudis et al. 1996). The engrafted cells were analyzed for expression of surface markers that define human hematopoietic cells. During the follow up period of up to 18 weeks, the high dose infused group had increased hUCB engraftment compared with the low dose infused group in peripheral blood (Fig 1A), bone marrow (Fig 1B & 1C) and spleen (Fig 1D), which is consistent with reported clinical observations that infused cell dosage is inversely correlated with time to engraftment (Migliaccio et al. 2000 Blood). Interestingly, we observed different lymphoid subset frequencies between low and high dose infused groups at the post-engraftment stage (18 weeks post transplantation) (data not shown). To investigate different lymphoid subset engraftment frequencies in low and high dose hUCB transplanted recipient mice at early engraftment stage, peripheral blood and hematopoietic organs were collected and analyzed up to 10 weeks post transplantation. The low dose infused group had significantly lower CD3+ (T cells) and CD56+ (NK cells) frequency in peripheral blood at 4 and 8 weeks (Fig 2A & 3A). More importantly, CD3+ (T cells) frequency was close to non-detectable in the bone marrow and spleen in the low dose infused group (Fig 2B & 2C), and CD56 (NK cells) frequency was decreased in the low dose infused group compared with the high dose infused group (Fig 3B & 3C). The absolute CD3+ and CD56+ number, displayed as fold difference, were even more dramatically decreased in the femur (Fig 2D & 3D) and the spleen (Fig 2E & 3E) of low dose infused group. Because of the substantial difference in T cell subset frequencies between the two dosage groups in bone marrow and spleen, thymuses were collected and analyzed to study T cell development and maturation. Engraftment of hCD45+ cells in the thymuses were observed in 10 out of 15 animals (66.7%) in the low dose infused group and 12 out of 14 animals (85.7%) in the high dose infused group. Interestingly, in animals with high hCD45+ frequency, the total thymocyte CD3+ frequency was lower in the low dose infused group (Fig 4A). Additionally, the low dose infused group had lower CD3+CD4+ T cell frequency (Fig 4B) and higher CD3+CD4+CD8+ T cell frequency (Fig 4C), suggesting low dose infused group had a decreased mature T cell population and increased immature T cell population in the thymus. In contrast, the low dose hUCB CD34+ cells infused group had increased hCD19 (B cells) frequency in the peripheral blood, bone marrow and spleen (Fig 5A-5C), while the absolute hCD19 (B cells), displayed as fold difference, did not show a statistically significant difference between the two groups (Fig 5D & 5E). Conclusions In summary, our findings suggest that (1) transplanted hUCB cell dosage is inversely correlated with time to engraftment (2) low transplanted hUCB cell dosage resulted in skewed immune cell population which may contribute to delayed immune recovery after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma

2001 ◽  
Vol 40 (06) ◽  
pp. 215-220 ◽  
Author(s):  
S. Bielack ◽  
S. Flege ◽  
J. Eckardt ◽  
J. Sciuk ◽  
H. Jürgens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
High Activity ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Blood Stem Cell ◽  
High Dose ◽  
External Radiotherapy ◽  
Primary Tumor Site ◽  
Hematopoietic Stem

Summary Purpose: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. Patients and Methods: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. Results: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. Conclusion: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors.

scholarly journals Lower Hematopoietic Progenitor Cell Counts and Yields at Subsequent Donations Is Influenced By a Shorter Inter-Donation Interval between the First and Subsequent Mobilizations

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1962-1962
Author(s):  
Sandhya R. Panch ◽  
Brent R. Logan ◽  
Jennifer A. Sees ◽  
Bipin N. Savani ◽  
Nirali N. Shah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Time Interval ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Peripheral Blood Cd34 ◽  
Cell Counts ◽  
Cd34 Cells

Introduction: Approximately 7% of unrelated hematopoietic stem cell (HSC) donors are asked to donate a subsequent time to the same or different recipient. In a recent large CIBMTR study of second time donors, Stroncek et al. incidentally found that second peripheral blood stem cell (PBSC) collections had lower total CD34+ cells, CD34+ cells per liter of whole blood processed, and CD34+ cells per kg donor weight. Based on smaller studies, the time between the two independent PBSC donations (inter-donation interval) as well as donor sex, race and baseline lymphocyte counts appear to influence CD34+ cell yields at subsequent donations. Our objective was to retrospectively evaluate factors contributory to CD34+ cell yields at subsequent PBSC donation amongst NMDP donors. Methods. The study population consisted of filgrastim (G-CSF) mobilized PBSC donors through the NMDP/CIBMTR between 2006 and 2017, with a subsequent donation of the same product. evaluated the impact of inter-donation interval, donor demographics (age, BMI, race, sex, G-CSF dose, year of procedure, need for central line) and changes in complete blood counts (CBC), on the CD34+ cell yields/liter (x106/L) of blood processed at second donation and pre-apheresis (Day 5) peripheral blood CD34+ cell counts/liter (x106/L) at second donation. Linear regression was used to model log cell yields as a function of donor and collection related variables, time between donations, and changes in baseline values from first to second donation. Stepwise model building, along with interactions among significant variables were assessed. The Pearson chi-square test or the Kruskal-Wallis test compared discrete variables or continuous variables, respectively. For multivariate analysis, a significance level of 0.01 was used due to the large number of variables considered. Results: Among 513 PBSC donors who subsequently donated a second PBSC product, clinically relevant decreases in values at the second donation were observed in pre-apheresis CD34+ cells (73.9 vs. 68.6; p=0.03), CD34+cells/L blood processed (32.2 vs. 30.1; p=0.06), and total final CD34+ cell count (x106) (608 vs. 556; p=0.02). Median time interval between first and second PBSC donations was 11.7 months (range: 0.3-128.1). Using the median pre-apheresis peripheral blood CD34+ cell counts from donation 1 as the cut-off for high versus low mobilizers, we found that individuals who were likely to be high or low mobilizers at first donation were also likely to be high or low mobilizers at second donation, respectively (Table 1). This was independent of the inter-donation interval. In multivariate analyses, those with an inter-donation interval of >12 months, demonstrated higher CD34+cells/L blood processed compared to donors donating within a year (mean ratio 1.15, p<0.0001). Change in donor BMI was also a predictor for PBSC yields. If donor BMI decreased at second donation, so did the CD34+cells/L blood processed (0.74, p <0.0001). An average G-CSF dose above 960mcg was also associated with an increase in CD34+cells/L blood processed compared to donors who received less than 960mcg (1.04, p=0.005). (Table 2A). Pre-apheresis peripheral blood CD34+ cells on Day 5 of second donation were also affected by the inter-donation interval, with higher cell counts associated with a longer time interval (>12 months) between donations (1.23, p<0.0001). Further, independent of the inter-donation interval, GCSF doses greater than 960mcg per day associated with higher pre-apheresis CD34+ cells at second donation (1.26, p<0.0001); as was a higher baseline WBC count (>6.9) (1.3, p<0.0001) (Table 2B). Conclusions: In this large retrospective study of second time unrelated PBSC donors, a longer inter-donation interval was confirmed to be associated with better PBSC mobilization and collection. Given hematopoietic stem cell cycling times of 9-12 months in humans, where possible, repeat donors may be chosen based on these intervals to optimize PBSC yields. Changes in BMI are also to be considered while recruiting repeat donors. Some of these parameters may be improved marginally by increasing G-CSF dose within permissible limits. In most instances, however, sub-optimal mobilizers at first donation appear to donate suboptimal numbers of HSC at their subsequent donation. Disclosures Pulsipher: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Bellicum: Consultancy; Amgen: Other: Lecture; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Honoraria. Shaw:Therakos: Other: Speaker Engagement.

The Impact of Different Mobilization Strategies in the Setting of Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3254-3254
Author(s):  
Francesco Mazziotta ◽  
Gabriele Buda ◽  
Nadia Cecconi ◽  
Giulia Cervetti ◽  
Lorenzo Iovino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Partial Response ◽  
Peripheral Blood ◽  
High Dose ◽  
Roc Curve Analysis ◽  
Cd34 Cells ◽  
Significant Difference ◽  
The Impact

INTRODUCTION Multiple myeloma (MM) is considered an incurable disease. Despite the introduction of novel agents allowed deeper response, high-dose chemotherapy and autologous stem cell transplantation (ASCT) remain the standard of care for patients (pts) in good clinical conditions. The most used strategies to mobilize stem cells from bone marrow (BM) into peripheral blood are high-dose cyclophosphamide (HD-CTX) plus G-CSF and G-CSF plus plerixafor (G-CSF+P). The goal of this retrospective study is to investigate whether the two different mobilization strategies have an impact on the clearance of monoclonal PCs in the apheresis products and on pts' outcome. PATIENTS AND METHODS We analyzed 62 pts (median age 61, range 41-75, 37 males and 25 women) diagnosed with MM and treated with ASCT between Mar 2014 and Mar 2018 at our Hematology Division (Pisa, Italy). All pts received induction therapy with at least 4 cycles of bortezomib, thalidomide and dexamethasone (VTD). 9/62 pts obtained a less than partial response (PR) and received lenalidomide-based regimens. After induction, 8 (12,9%) pts achieved complete remission (CR), 26 (41,9%) were in PR, 28 (45,2%) obtained a very good partial response (VGPR). 43/62 fit pts received HD-CTX (2-3 g/sqm) on day 1 followed by G-CSF (30 MU/day) started on day 4 until day 7, increased to 60 MU/day from day 8 until the end of apheresis. In 19/62 pts, after 4 days of G-CSF (60 MU/day) administration and not sufficient mobilization, we added plerixafor (0,24 mg/kgbw) for up to 4 consecutive days. In 43/62 pts we collected apheresis samples (10μl) analyzed through flow citometry to enumerate clonal residual PCs. The panel used to asses clonality included: CD138 Per-Cp, CD38 APC, CD19 PE-Cy7, CD45 APC-Cy7, cytoplasmic immunoglobulin K chain and L chain. RESULTS At the end of the peripheral blood stem cell (PBSC) collection, pts treated with HD-CTX presented a higher CD34+ absolute count (p=0.0489) and achieved the threshold of 5x106 CD34+ cells/kgbw in a significantly (p=0.006) higher percentage. We found a nearly significant (p=0.0517) lower count of CD34+ PBSCs in pts who received lenalidomide-based regimens before the mobilization. Performing flow citometry on apheresis samples, we observed that the number of the harvested clonal PCs showed a significant correlation (p=0.0115) with the occurrence of post-ASCT relapse. ROC curve analysis investigating the predictive effect of the number of pathological PCs on disease relapse showed an area under the curve of 0,6978 (95% CI 0.5392-0.8564; p=0.0267). Neither BM residual PCs detectable on BM biopsies performed before apheresis (r=-0.1323; p=0.609) nor the type of mobilization scheme (p=0.707) had an impact on the proportion of clonal PCs in the graft. Additionally, we did not observe any statistically significant difference in progression free- (PFS) (p=0.8276) and overall survival (OS) (p=0.2475) between the HD-CTX and G-CSF+P groups. DISCUSSION PBSC mobilization has a succession rate > 85%. Despite the use of HD-CTX to increase PBSC yields and decrease tumor burden, there is not clear evidence of a superior mobilization strategy. Additionally, HD-CTX has a not negligible toxicity and approximately 10% of the pts require hospitalization. Conversely, G-CSF+P is a safe and effective approach also in poor mobilizers. In our study, we observed a significative difference in the apheresis yields (p=0.0489) and in the percentage of pts who achieved the threshold of 5x106 CD34+ cells/kgbw (p=0.006) in favor of HD-CTX. Additionally, the detection of harvested residual clonal PCs could be a promising strategy to recognise pts more likely to relapse after ASCT. Nonetheless, we failed to demonstrate a superior effect of HD-CTX in the clearance of harvested clonal PCs, in agreement with the absence of a different pts' outcome amongst the two mobilization strategies. In conclusion, the choice between the two regimens is challenging and requires careful consideration of multiple factors. Overall, young fit pts, especially in the high-risk setting, should be treated with all appropriate modalities including chemiomobilization followed by double-ASCT. Conversely, in pts candidate to a single-ASCT it is reasonable to use G-CSF+P, since HD-CTX does not improve PFS and OS and add toxicity. The absence of an in-vivo purging effect on apheresis products of chemiomobilization further strengthens a chemotherapy-free mobilization. Disclosures Galimberti: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau.

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