Mobilization of Hematopoietic Progenitor Cells with Standard- or Reduced-Dose Filgrastim after Vinorelbine in Multiple Myeloma Patients: A Randomized Prospective Single-Center Phase II Study

Vinorelbine combined with filgrastim at a dose of 10?µg/kg of body weight (BW) per day is a reliable and well-tolerated regimen for mobilization of hematopoietic progenitor cells (HPCs) in patients with multiple myeloma. This prospective, randomized, phase II study was initiated to assess the feasibility of a reduced filgrastim dosage. Vinorelbine was combined with either standard-dose filgrastim (10?µg/kg BW per day) or reduced-dose filgrastim (5?µg/kg BW per day). Leukapheresis sessions were planned to start at day 8 and were continued until the predefined target amount of 4?×?10⁶ HPCs/kg BW was collected. The study demonstrated the feasibility of vinorelbine combined with reduced daily filgrastim with a mean of 1.29 leukapheresis sessions necessary per patient (95% confidence interval, .95 to 1.7). All patients could start leukapheresis as planned at day 8, and the collection success rate was 100% for the whole patient collective after a maximum of 2 leukapheresis sessions. No statistically significant differences with regard to the amount of HPCs collected between the 2 groups were observed (P?=?.99). Accordingly, no differences were seen with regard to length of hospitalization for autotransplant (P?=?.34) and duration of neutrophil (P?=?.93) and platelet engraftment (P?=?.42). Patients receiving reduced-dose filgrastim reported significantly lower peak pain values in a numeric analogue scale (P?=?.01), and the costs were significantly lower than in patients undergoing standard-dose chemomobilization (P?=?.001). Vinorelbine 35?mg/m² plus filgrastim 5?µg/kg BW once per day until completion of HPC collection is feasible and appears to be advantageous with respect to the severity of pain intensity and treatment costs.     

Systematic review of randomized controlled trials of hematopoietic stem cell mobilization strategies for autologous transplantation for hematologic malignancies

Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation; however, a proportion of patients fail to collect the minimum number of cells required. We summarized the efficacy and safety of HSC mobilization strategies. We performed a systematic review of randomized controlled trials comparing HSC mobilization strategies before autologous transplantation for hematologic malignancies. The primary outcome was CD34+ cell yield. Secondary outcomes included number of aphereses, proportion of failures, rate of count recovery, and adverse events. We identified 28 articles within 3 broad strategies. Using a cyclophosphamide with growth factor strategy (10 articles), CD34+ cell yield is improved by addition of molgramostim to cyclophosphamide (1.4 vs 0.5 × 10(6)/kg; P = .0165), addition of cyclophosphamide to filgrastim (7.2 vs 2.5 × 10(6)/kg; P = .004), and addition of ancestim to cyclophosphamide and filgrastim (12.4 vs 8.3 × 10(6)/kg; P = .007). Within a growth factor-based strategy (6 articles), addition of plerixafor improves CD34+ cell yield over filgrastim alone in multiple myeloma (MM; 11.0 vs 6.2 × 10(6)/kg; P?< .001) and non-Hodgkin lymphoma (5.69 vs 1.98 × 10(6)/kg; P < .01). With combination or noncyclophosphamide-based chemotherapy (12 articles), higher-dose filgrastim (8.2 vs 4.7 × 10(6)/kg for 16 vs 8/mcg/kg daily of filgrastim, respectively; P < .0001) and addition of rituximab to etoposide and filgrastim (9.9 vs 5.6 × 10(6)/kg; P = .021) improve CD34+ cell yield. Growth factor alone after chemotherapy, ancestim, or plerixafor provide adequate autologous HSC grafts for the majority of patients. Although some strategies result in higher CD34+ cell yield, this potentially comes at the expense of increased toxicity. As all strategies are reasonable, programmatic, and patient-specific considerations must inform the approach to autologous graft mobilization.     

Tbo-Filgrastim: A Review in Neutropenic Conditions

Tbo-filgrastim (filgrastim XM02; Biograstim^®, Ratiograstim^®, Tevagrastim^®) is approved in the EU as a biosimilar of filgrastim (Neupogen^®) for use in all indications for which reference filgrastim is approved, including chemotherapy-induced neutropenia, neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation, mobilization of peripheral blood stem cells (PBSCs), severe chronic neutropenia, and neutropenia in HIV infection. Tbo-filgrastim (Granix^®) is also approved as a biologic in the USA for neutropenia associated with chemotherapy. Tbo-filgrastim has demonstrated bioequivalence to reference filgrastim in terms of its pharmacokinetic and pharmacodynamic profiles. In phase III trials, tbo-filgrastim was equivalent to reference filgrastim in ameliorating severe neutropenia in patients receiving chemotherapy for breast cancer, lung cancer, or non-Hodgkin lymphoma. In addition, the efficacy of tbo-filgrastim for PBSC mobilization in the allogeneic and autologous settings has been demonstrated in several small studies. Tbo-filgrastim was generally well tolerated, with a similar safety profile to that of reference filgrastim. Most adverse events were of mild or moderate severity. Biosimilars such as tbo-filgrastim have the potential to reduce healthcare costs compared with those of reference filgrastim; this may provide patients with more cost-effective treatment options. Current evidence indicates that tbo-filgrastim is a useful alternative to reference filgrastim in patients requiring filgrastim therapy for various neutropenic conditions.     

Orchestration of Chemomobilization and G-CSF Administration for Successful Hematopoietic Stem Cell Collection

Successful collection of peripheral blood stem cells (PBSCs) depends on the optimal orchestration of mobilization chemotherapy, granulocyte colony stimulating factor (G-CSF) application, and CD34⁺ cell number assessment in the peripheral blood (PB). However, determining the optimal timing in accordance to the applied chemomobilization regimen can be challenging. Although most centers apply their own local timing schedules, a reliable timetable including the currently most often used mobilization regimens is lacking. We present a comprehensive analysis of the timing modalities for 11 of the most commonly used chemomobilization regimens. A retrospective analysis was performed on the clinical and PBSC collection parameters (including duration of G-CSF application, time point of CD34⁺ assessment, PB CD34⁺ cell count, number of leukapheresis [LP] sessions, processed blood volume, and CD34⁺ collection results) of 91 representatively selected patients who had undergone stem cell mobilization at 2 collection centers.Six to 10 patients were analyzed per regimen with a variety of diagnoses, including multiple myeloma, malignant lymphoma, and sarcoma. No collection failures (<2?×?10⁶ CD34⁺ cells/kg body weight) were observed. All analyzed patients successfully reached their individual collection goal in adherence to the given schedule of chemotherapy, application of G-CSF, measurement of CD34⁺ cells, and subsequent LP.The presented data on the timing of chemomobilization, G-CSF application, and stem cell collection may be helpful in clinical decision making and contribute to a more transparent and predictable treatment process.     

Pharmacoeconomics of Hematopoietic Stem Cell Mobilization: An Overview of Current Evidence and Gaps in the Literature

Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have been used to mobilize HSCs. Studies have shown that the efficiency of HSC mobilization and collection may vary when different methods of mobilization are used. No studies have shown that survival is significantly affected by the method of mobilization, but some studies have suggested that cost and resource utilization may be different between different mobilization techniques. After the FDA approval of plerixafor with G-CSF to mobilize HSCs many transplant centers became concerned about the cost of HSC mobilization. A panel of experts was convened ant this paper reviews the current literature on the pharmacoeconomics of HSC mobilization.     

Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells

Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 10⁴ cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.     

Etoposide + Granulocyte Colony-Stimulating Factor and Optional Plerixafor in Patients Who Failed Chemomobilization with or without Plerixafor

We conducted a retrospective study of 62 patients undergoing etoposide (2 g/m²) + granulocyte colony-stimulating factor (G-CSF; 10 patients also received additional plerixafor) as a salvage stem cell mobilization regimen after previous unsuccessful chemomobilization with or without plerixafor. The median peak CD34⁺ values after etoposide + G-CSF ± plerixafor was 54.07 CD34⁺/μL compared with 9.6 CD34⁺/μL after previous mobilization attempts (P < .001). The median yield was 6.33 × 10⁶ CD34⁺ cells/kg per 2 apheresis. Etoposide + G-CSF ± plerixafor mobilization regimen resulted in 91.53% successful mobilizations and 89.83% of patients proceeding to autologous stem cell transplantation. All 7 patients who had previously failed plerixafor-based mobilization attempts were successfully mobilized with etoposide + G-CSF ± plerixafor and proceeded to autologous stem cell transplantation. The most common grades 3 to 4 adverse events of etoposide + G-CSF ± plerixafor were febrile neutropenia (69.35%), mucositis (51.62%), and bacteremia (20.97%). No fatal outcomes were observed. Rates of 12-month overall survival and progression-free survival were 88.71% and 70.97%, respectively. Etoposide + G-CSF ± plerixafor is an effective regimen for salvage stem cell mobilization also in patients who failed plerixafor, with most patients undergoing autologous stem cell transplantation. The adverse event rate may warrant a decrease in the dose of etoposide.     

Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens

Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34⁺ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n?=?223) and/or lenalidomide-based (n?=?19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident.     

High-Dose Etoposide Plus Granulocyte Colony-Stimulating Factor as an Effective Chemomobilization Regimen for Autologous Stem Cell Transplantation in Patients with Non-Hodgkin Lymphoma Previously Treated with CHOP-based Chemotherapy: A Study from the Consortium for Improving Survival of Lymphoma

We conducted a multicenter retrospective study to compare the efficacy and toxicity of various chemomobilization regimens: high-dose (HD) cyclophosphamide, HD etoposide (VP-16), and platinum-based chemotherapies. We reviewed the experiences of 10 institutions with 103 non-Hodgkin lymphoma patients who had previously only been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. The mobilization yields for each regimen were analyzed. HD VP-16 mobilized a significantly higher median number of CD34⁺ cells (16.22 × 10⁶ cells/kg) than HD cyclophosphamide (4.44 × 10⁶ cells/kg) or platinum-based chemotherapies (6.08 × 10⁶ cells/kg, P < .001). The rate of successful mobilization (CD34⁺ cell count ≥5.0 × 10⁶ cells/kg) was also significantly higher for HD VP-16 (86%) than for HD cyclophosphamide (45%) or platinum-based chemotherapies (61%, P = .004). The successful mobilization rate on day 1 of 72% for HD VP-16 was significantly higher than the rates for HD cyclophosphamide (13%) and platinum-based chemotherapies (26%, P < .001). In multivariate analysis, HD VP-16 was a significant predictor of successful mobilization (P = .014; odds ratio, 5.25; 95% confidence interval, 1.40 to 19.63). Neutropenic fever occurred in 67% of patients treated with HD VP-16. The incidence was similar for HD cyclophosphamide (58%, P = .454) but was significantly lower for platinum-based chemotherapies (12%, P < .001). However, fatal (grade ≥ 4) infection and treatment-related mortality were not observed in this study. In conclusion, the mobilization yield was significantly influenced by the chemomobilization regimen, and HD VP-16 was a highly effective mobilization regimen in patients with non-Hodgkin lymphoma.     

Impact of Mobilization and Remobilization Strategies on Achieving Sufficient Stem Cell Yields for Autologous Transplantation

The purpose of this article was to examine historic institutional autologous stem cell mobilization practices and evaluate factors influencing mobilization failure and kinetics. In this retrospective study we analyzed clinical records of 1834 patients who underwent stem cell mobilization for autologous transplantation from November 1995 to October 2006 at the Washington University in St. Louis. Successful mobilization was defined as collection of ≥2 × 10⁶ CD34⁺ cells/kg. From 1834 consecutive patients, 1040 met our inclusion criteria (502 non-Hodgkin's lymphoma [NHL], 137 Hodgkin's lymphoma, and 401 multiple myeloma [MM]). A total of 976 patients received granulocyte colony-stimulating factor (G-CSF) and 64 received G-CSF plus chemotherapy (G/C) for the initial mobilization. Although the median CD34⁺ cell yield was higher in G/C group than in G-CSF alone group, the failure rates were similar: 18.8% and 18.6%, respectively. Overall, 53% of patients collected ≥2 × 10⁶ CD34⁺ cells/kg during the first apheresis with either mobilization regimen. Regardless of mobilization regimen used, MM patients had the highest total CD34⁺ cell yield and required less aphereses to collect ≥2 × 10⁶ CD34⁺ cells/kg. Mobilized, preapheresis, peripheral blood CD34⁺ count correlated with first day apheresis yield (r = .877, P < .001) and 20 cells/μL was the minimum threshold needed for a successful day 1 collection. For the remobilization analysis we included patients from the whole database. A total of 269 of 1834 patients underwent remobilization using G/C, G-CSF, and/or GM-CSF, and G-CSF plus plerixafor. Only 23% of remobilized patients achieved ≥2 × 10⁶ CD34⁺ cells/kg and 29.7% failed to pool sufficient number of stem cells from both collections. Patients receiving G-CSF plus plerixafor had lowest failure rates, P = .03. NHL patients remobilized with G-CSF who waited ≥25 days before remobilization had lower CD34⁺ cell yield than those who waited ≤16 days, P = .023. Current mobilization regimens are associated with a substantial failure rate irrespective of underlying disease. Patients who fail initial mobilization are more likely to fail remobilization. These findings suggest that there is a need for more effective first-line mobilization agents.     

Mobilization of Hematopoietic Progenitor Cells for Autologous Transplantation Using Pegfilgrastim and Plerixafor: Efficacy and Cost Implications

Filgrastim (FIL) is the most common growth factor combined with plerixafor for autologous hematopoietic progenitor cell mobilization, but requires daily, multi-injection administration. We adopted a standardized mobilization regimen with pegfilgrastim (PEG) and upfront plerixafor, allowing for a single injection given the long half-life and slow elimination of PEG. Between 2015 and 2017, a total of 235 patients with lymphoma or plasma cell dyscrasias underwent mobilization with PEG 6 mg on day 1 and upfront plerixafor 24 mg on day 3, followed by apheresis on day 4 regardless of peripheral blood CD34⁺ cells. The median CD34⁺ cells/mm³ in peripheral blood on first day of collection was 48 and median collection yield was 7.27?×?10⁶ CD34⁺ cells/kg (range, 0.32 to 39.6?×?10⁶ CD34⁺ cells/kg) after a mean of 1.6 apheresis collections. Overall, 83% of patients achieved the mobilization target, and 95% reached the minimum necessary CD34⁺ cell yield to proceed with transplantation (2?×?10⁶ CD34⁺ cells/kg). Because FIL is weight-based and dosed daily, the cost comparison with PEG is influenced by patient weight and number of apheresis sessions required. A cost simulation using actual patient data indicates that PEG is associated with lower cost than FIL for the majority of patients. Autologous hematopoietic progenitor cell mobilization with PEG and plerixafor is practical, effective, and not associated with increased cost compared with FIL mobilization.     

Temporal Changes in Plerixafor Administration and Hematopoietic Stem Cell Mobilization Efficacy: Results of a Prospective Clinical Trial in Multiple Myeloma

Plerixafor with granulocyte colony-stimulating factor (G-CSF) is effective for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and myeloma; however, labeling requires dosing 11 hours before apheresis. Pharmacodynamic studies show peak blood CD34⁺ cell counts at 10 to 14 hours; limited data are available for later time points. To address the effect of afternoon plerixafor dosing on CD34⁺ cell yields, we conducted a prospective clinical trial in myeloma patients undergoing stem cell collection. Thirty-one patients received plerixafor 17 hours before apheresis; blood CD34⁺ cells were measured before the first plerixafor dose and 1, 3, and 17 ± 1 hours after treatment. The target HSC number (≥10 × 106 CD34⁺ cells/kg) was collected from 22 subjects (73%) in 1 day and from all subjects within 3 days. Hematopoietic engraftment after transplantation and adverse events were similar to previous studies. Plerixafor given 17 hours before apheresis yields desired HSC collection efficiencies after induction treatment in myeloma patients.     

Increased Efficacy of Stem Cell Chemomobilization with Intermediate-Dose Cytarabine Plus Granulocyte Colony-Stimulating Factor (G-CSF) Compared with G-CSF Alone in Patients with Multiple Myeloma: Results of a Randomized Trial

Mobilization of hematopoietic stem cells for patients with multiple myeloma (MM) may be done using either steady-state granulocyte colony-stimulating factor (G-CSF) or a combination of chemotherapy with G-CSF. The goal of this randomized, open-label, phase 3 trial was to compare the efficacy of chemomobilization using intermediate-dose cytarabine (ID-AraC) plus G-CSF with G-CSF alone in patients with MM referred for tandem autologous stem cell transplantation (autoSCT). The percentage of patients with stem cell yield of at least 5?×?10⁶ CD34⁺ cells/kg was the primary endpoint. Ninety patients were enrolled, including 44 assigned to the ID-AraC arm and 46 in the G-CSF arm. The threshold number of CD34⁺ cells was reached in 43 patients (98%) in the ID-AraC arm and in 32 patients (70%) in the G-CSF arm (P?=?.0003). The median number of collected CD34⁺ cells was 20.2?×?10⁶ cells/kg in the ID-AraC arm versus 5.9?×?10⁶ cells/kg in the G-CSF arm (P < .000001). A single apheresis was sufficient to achieve the required number of harvested CD34⁺ cells in 37 patients (86%) in the ID-AraC arm and in 13 patients (41%) in the G-CSF arm (P?=?.00008). The times to both neutrophil and platelet recovery after autoSCT were significantly shorter in the patients mobilized with ID-AraC. This study provides the first evidence of the advantage of chemomobilization over G-CSF monotherapy in terms of efficacy. ID-AraC with G-CSF should be the preferred chemomobilization protocol for patients with MM scheduled to undergo tandem autoSCT.     

Cost-Effectiveness Analysis of a Risk-Adapted Algorithm of Plerixafor Use for Autologous Peripheral Blood Stem Cell Mobilization

Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/μL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 × 10⁶ CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/μL for single or <20/μL for multiple transplantations, or day-1 yield was <1.5 × 10⁶ CD34/kg, or any subsequent daily yield was <0.5 × 10⁶ CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower.     

Peripheral Blood CD34+ Percentage at Hematological Recovery after Chemotherapy Is a Good Early Predictor of Harvest: A Single-Center Experience

Several algorithms for early prediction of poor-mobilizing patients after chemotherapy and granulocyte colony-stimulating factor administration have been proposed. They generally define peripheral blood cut-off levels of CD34+ cells at a fixed day after starting chemotherapy, mostly with cyclophosphamide. To define an algorithm for early addition of plerixafor regardless of the chemotherapy regimen used, we retrospectively analyzed 280 chemomobilization attempts in 236 patients treated at our institution between 2002 and 2012. In multivariate analysis, CD34+ absolute count and CD34+ percentage upon total leukocyte count at day 1 (defined as the first day in which leukocytes reached a value > 1 × 10⁹/L) were the only factors able to predict a total harvest ≥ 2 × 10⁶ CD34+/kg. In patients with day 1 CD34+ lower than 20/μL, the CD34+ percentage was a more reliable predictor of stem cell harvest in the following days than CD34+ absolute count. Upon definition of the best CD34+ cut-off value for identification of poor-mobilizing patients, an algorithm was set up to guide plerixafor administration. It was prospectively validated in 20 patients in 2013 with encouraging results in terms of low incidences of both mobilization failure and plerixafor use. Large prospective trials that define the most cost-effective strategy for just-in-time rescue plerixafor are warranted.     

Effectiveness of an Algorithm-Based Approach to the Utilization of Plerixafor in Patients Undergoing Chemotherapy-Based Stem Cell Mobilization

Autologous stem cell transplantation remains a mainstay of therapy for diseases such as multiple myeloma and relapsed lymphoma. The use of plerixafor has been shown to augment the ability to collect adequate stem cells, but the optimal use of this agent when used with chemotherapy is not yet clear. We utilized an algorithm-based approach with the addition of plerixafor to 54 patients undergoing chemomobilization with reduced-dose etoposide who had a less than optimal preapheresis CD34⁺ cell count. We used a CD34⁺ precount of 20 cells/μL as a threshold to initiate stem cell apheresis. Ninety-four percent of patients were successfully collected and proceeded to transplantation. Fourteen of 51 (28%) patients who successfully collected required plerixafor to augment stem cell yield. Of the patients who successfully collected, 94% (89% of the entire population) were able to collect in 2 or fewer days. Compared with previous data from our institution, the rate of patients collecting > 4 × 10⁶ CD34⁺ cells/kg in a single collection was increased from 39% to 69%. The safety profile of this approach was acceptable. The use of this algorithm-based method to determine when and whether to add plerixafor to chemomobilization was shown to be a successful and cost-effective approach to stem cell collection.     

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs,potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m²) and low dose (15 mg/m²) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m² dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m²) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.     

Mobilization of hematopoietic stem cells in patients undergoing HSCT as a treatment of early diabetes type 1

BackgroundThe immunoablation with autologous hematopoietic stem cell transplantation is a new experimental treatment of early diabetes type 1. The treatment is based on destruction of immune system with cytotoxic drugs which leads to halt of immune reaction directed against beta cells of pancreas. During that treatment young patients with diabetes type 1 who are otherwise healthy undergo mobilization with cyclophosphamide (CY) and G-CSF. They are naïve to cytotoxic drugs and mobilization is their first contact with chemotherapy. We analyzed the efficiency of mobilization with cyclophosphamide and G-CSF in this population.MethodsWe analyzed the medical records of 25 patients with diabetes who underwent mobilization with cyclophosphamide and G-CSF.ResultsThe median white blood cell count on the first day of apheresis was 14.6 × 10³/μL (range 1.5–33.3) in CY + G-CSF mobilized patients. Median absolute CD 34+ cell count in peripheral blood on the first apheresis day was 0.095 127 × 10³/μL (range 0.026–0.477). The median total number of collected CD34+ cells during one or two (if needed) aphereses was 466 × 10⁶ (range 204–816) or 7.24 × 10⁶ CD34+ cells per kg of patient body weight (range 3.03–13.1). There were no poor mobilizers who were unable to collect sufficient cell numbers.ConclusionThe mobilization of hematopoietic stem cells with CY + G-CSF in patients with early diabetes type 1 is efficient and the underlying diabetes does not impair the efficiency of hematopoietic stem cell collection.     

Polymorphism of CD44 Influences the Efficacy of CD34+ Cells Mobilization in Patients with Hematological Malignancies

In the last decade, peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous and allogeneic transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand-receptor interactions of adhesion molecules, such as SDF1/CXCR4, VLA4/VCAM-1, or CD44/osteopontin, play an important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. We enrolled 110 patients (60 females and 50 males) in the study. The median age of the patients was 55 (range, 22 to 69) years. The group consisted of patients with multiple myeloma (n = 74), non-Hodgkin lymphoma (n = 19), Hodgkin lymphoma (n = 15), or acute myeloid leukemia (n = 2). The mobilization procedures comprised chemotherapy and subsequent granulocyte-colony stimulating factor (G-CSF) at a dose of 10 μg/kg daily. The poor mobilizers group was defined according to Italian National Bone Marrow Transplant Registry criteria: patients with peak CD34⁺ in the peripheral blood < 20/μL or total yield < 2 × 10⁶ CD34⁺ cells/kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N = 108) who achieved minimal threshold for collections (CD34⁺ at least 10/μL) proceeded to apheresis. The median total yield of CD34⁺ in this group was 5.6 × 10⁶ cells/kg body weight, whereas the median number of cells collected during the first apheresis was 3.3 × 10⁶ cells/kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for poor mobilizer. The group of poor mobilizers had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT versus TT P = .047). Patients homozygous for T allele had a lower total yield of CD34⁺ cells/kg body weight than the group with allele C (median, 3.7 × 10⁶/kg versus 5.8 × 10⁶/kg; P = .019) and a lower number of CD34⁺ cells gathered during first apheresis (.95 × 10⁶/kg versus 3.3 × 10⁶/kg, P = .04). Multivariate logistic regression analysis revealed that the CD44 TT genotype was the only factor associated with 5-fold higher risk of poor mobilization (P = .037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. In conclusion, our results indicate that among investigated single nucleotide polymorphisms (SNPs), only CD44 rs13347 has an impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting the poor mobilizers population who may benefit from newer modalities using adhesion molecules inhibitors.