Healthy donor hematopoietic stem cell mobilization with biosimilar granulocyte-colony-stimulating factor: safety, efficacy, and graft performance.

BACKGROUND: Biosimilar granulocyte-colony-stimulating factors (G-CSFs) have been available in the European Union since 2008, and Sandoz' biosimilar filgrastim was approved in the United States in March 2015 for all of the reference product's indications except acute radiation syndrome. Biosimilar G-CSFs have been largely embraced by the medical community, except for some reservations about healthy-donor stem cell mobilization, for which use outside of clinical studies was cautioned against by some members of the scientific community. STUDY DESIGN AND METHODS: In a two-center safety surveillance study (National Clinical Trial NCT01766934), 245 healthy volunteer stem cell donors were enrolled. Of 244 donors who began mobilization with twice-daily Sandoz biosimilar filgrastim, 242 received a full (n = 241) or partial (n = 1) course of G-CSF and underwent apheresis. Efficacy and safety were assessed and are reported here. RESULTS: Biosimilar filgrastim was accompanied by the typical G-CSF class-related adverse effects of expected frequency and severity. Median mobilization for CD34-positive stem cells was 97/µL (range, 20-347/µL); after one apheresis (91%) or two aphereses (9%) from all but three donors (1.2%), cell doses in excess of the typical 4 × 106 CD34-positive cells/kg of the recipient had been collected (range, 3-52 × 106 /kg). Biochemical and hematologic alterations were consistent with previous reports; all had normalized by the first follow-up 1 month after mobilization. Stem cell products engrafted with typical probability and kinetics for G-CSF-mobilized stem cell products. CONCLUSION: These data support the use of biosimilar filgrastim for healthy-donor stem cell mobilization as safe and effective.

Unstimulated leukapheresis in patients and donors: comparison of two apheresis systems.

BACKGROUND: Unstimulated mononuclear cell (MNC) apheresis plays a role in the generation of donor lymphocytes (DLIs; healthy donors) and in extracorporeal photopheresis (ECP; patients). The new apheresis system Spectra Optia MNC has been shown in small studies to be capable of performing the desired cell collections, but larger data sets from real-life clinical apheresis procedures are lacking. STUDY DESIGN AND METHODS: Presented are comparative data from DLI collections randomly performed with either the new technology or a clinical standard technology, COBE Spectra MNC, as well as data from patients with chronic graft-versus-host disease undergoing MNC collections alternating between the two apheresis systems to generate products for ECP. Target cell yield and collection efficiency, product volume, nontarget cell contamination, platelet (PLT) attrition, and some process variables such as process volume and time were analyzed. RESULTS: For most relevant apheresis outcomes, differences between the devices were at best marginal. Spectra Optia MNC collections in patients, but not in donors, took 10% longer to achieve the target process volume. Not unexpectedly, given previous observations for granulocyte-colony-stimulating factor-stimulated leukapheresis, the novel device collected smaller products with less red blood cell contamination. PLT attrition with Spectra Optia MNC was markedly lower in donors. ECP apheresis outcome variability was, to a significant degree, donor dependent, irrespective of the device used. CONCLUSION: Based on more than 200 unstimulated apheresis procedures, we conclude that both apheresis systems are safe, robust, and equally suitable for unstimulated MNC collections. Both can be successfully run with manufacturer-recommended settings and algorithms.

Granulocyte collections: comparison of two apheresis systems.

BACKGROUND: Donor granulocyte concentrates are routinely administered to patients with granulocyte function defects or transient neutropenia and (risk of) bacterial or fungal exacerbations, despite lack of definitive clinical proof for patient-relevant outcome improvement. Granulocytes are collected by apheresis from healthy donors treated with granulocyte-colony-stimulating factor and/or steroids for neutrophil mobilization the evening before apheresis, as well as with hydroxyethyl starch during apheresis, to enhance sedimentation of red blood cells (RBCs) and thus to facilitate accessibility of neutrophils for collection. STUDY DESIGN AND METHODS: Granulocyte apheresis procedures are performed with standard apheresis equipment, including with the frequently used apheresis system for peripheral blood "stem cell" collection, COBE Spectra MNC (Terumo BCT), using the same tubing set as for MNC collection, but a different software protocol, PMN. An automated apheresis system for granulocyte collection, Spectra Optia IDL (Terumo BCT), became available in October 2011. Since then, 70 granulocyte apheresis procedures have been performed at our site, 35 each with the new and old systems. RESULTS: Apheresis procedures were well tolerated throughout. The target dose of 1 × 10(10) neutrophils was achieved in all but one collection with Spectra Optia IDL. Spectra Optia IDL collections were approximately 20% more efficient. Products contained more nontarget white blood cells (mononuclear cells), but fewer RBCs and platelets. Although less blood had to be processed with Spectra Optia IDL to achieve the same granulocyte dose, clinically relevant differences between the two apheresis devices were not apparent. CONCLUSION: Both apheresis systems are similarly capable of generating granulocyte concentrates.

Allogeneic donor peripheral blood "stem cell" apheresis: prospective comparison of two apheresis systems.

BACKGROUND: Granulocyte-colony-stimulating factor-mobilized peripheral blood stem cells, collected by white blood cell apheresis, are used for more than 80% of allogeneic and most autologous hematopoietic stem cell transplantations. Optimal donor and recipient outcomes require maximized stem cell collection efficiency and minimized non-target cell contamination. Therefore, improved apheresis technology is desirable. The safety and feasibility of apheresis collections with the novel, electronics-assisted apheresis system Spectra Optia v.5.0 (CaridianBCT) were recently demonstrated. An unpublished optimization trial had furthermore determined that different settings than manufacturer-installed default might result in improved apheresis yields. STUDY DESIGN AND METHODS: The first prospective comparison of allogeneic peripheral blood stem cell apheresis with the Spectra Optia versus the COBE Spectra (CaridianBCT) mononuclear cell (MNC) in a routine clinical setting is reported here; "optimized" machine settings were used. Assessed variables included collection efficiency, product characteristics, donor outcomes, and frequency of operator interventions. Outcomes were additionally compared with historical data from the Spectra Optia in default mode. RESULTS: The mean CD34+ cell collection efficiency CE1 was 7.9% greater with the Spectra Optia than with the COBE Spectra MNC. Variability of outcomes was equally great. Reduced platelet (PLT) attrition necessitated 90% fewer autologous PLT reinfusions. Spectra Optia products contained 50% fewer red blood cells, but 50% more granulocytic lineage cells. Less operator input was required, although 26% of Spectra Optia apheresis procedures required triggering of the first chamber flush. Apheresis yield and collection efficiency were also markedly greater than in default-mode Spectra Optia collections. CONCLUSION: Using optimized machine settings, peripheral blood stem cell apheresis outcomes with the automated apheresis system Spectra Optia exceed results with the COBE Spectra MNC or the Spectra Optia in the default mode.

Automatic interface-controlled apheresis collection of stem/progenitor cells: results from an autologous donor validation trial of a novel stem cell apheresis device.

BACKGROUND: Cryopreserved hematopoietic progenitor cells collected by apheresis from granulocyte-colony-stimulating factor with or without chemotherapy-mobilized patients have become the preferred type of autograft to support treatment of diseases amenable to high-dose chemotherapy. A novel apheresis system, the Spectra Optia v.5.0 (CaridianBCT), was constructed to meet certain shortcomings of manual apheresis systems such as the COBE Spectra MNC (CaridianBCT), including the need for continuous optical or manual monitoring and readjustment of buffy coat position and sensitivity to inconsistent blood flow. By use of optical sensors, which provide real-time automatic interface (buffy coat) and collection line control, the Spectra Optia promises to automatically guide apheresis procedures, potentially freeing up operator time and reducing variability in collection efficiency (CE2). STUDY DESIGN AND METHODS: In a two-center clinical trial, 35 autologous stem cell donors were subjected to apheresis with the Spectra Optia to validate feasibility and effectiveness of apheresis procedures. Results were compared to data from 80 autologous apheresis procedures with the COBE Spectra MNC. RESULTS: Usability and function of the automatic interface management were excellent. CD34+ cell quality, assessed by viability staining, colony-forming unit-culture frequency, and engraftment kinetics, was equally good with both systems. CE2 of the Spectra Optia, calculated as CD34+ contents in the product divided by the number of CD34+ cells presented to the collection port, exceeded that of the COBE Spectra MNC. Spectra Optia product volumes were significantly smaller. Very high white blood cell and platelet counts modestly reduced CE2 with the Spectra Optia. CONCLUSION: The Spectra Optia is a novel automatic apheresis system supporting autologous stem cell collection with at least equal efficiency and superior user-friendliness compared to the COBE Spectra MNC.

Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting with hyperleukocytosis.

BACKGROUND: Patients with acute myeloid leukemia (AML) with hyperleukocytosis of at least 100 x 10(9) per L are at high risk of early death due to pulmonary or cerebral leukostasis. Although the efficacy of leukapheresis in terms of prompt cytoreduction is generally accepted, published data regarding the clinical value of immediate therapeutic leukapheresis are limited and conflicting. STUDY DESIGN AND METHODS: To determine whether leukapheresis has a favorable impact on early mortality, the clinical course of 53 newly diagnosed patients with AML and hyperleukocytosis admitted between 1995 and 2005 was analyzed retrospectively. Before August 2001, 28 patients received chemotherapy without leukoreduction (Cohort A). Thereafter, all AML patients with hyperleukocytosis were scheduled to receive leukapheresis, which was performed in 25 patients (Cohort B). RESULTS: There were no procedure-related adverse events. By Day 21 of therapy, 13 of 53 patients had died, resulting in an overall early death rate of 25 percent. In a multivariate logistic regression model, patients in Cohort B had a significantly lower risk of early death than patients in Cohort A (16% vs. 32%, respectively; p = 0.015). Dyspnea (p = 0.005), elevated creatinine (p = 0.028), and higher lactate dehydrogenase serum levels (p = 0.021) were independent risk factors for early death. With a median follow-up of 24.2 months, the overall survival was similar in both cohorts (Cohort A, 7.5; Cohort B, 6.5 months). Thus, leukapheresis had no impact on patients' long-term survivals. CONCLUSIONS: Our experience suggests that AML patients with hyperleukocytosis receiving leukapheresis had a significantly lower risk for early death by Day 21 than patients treated without leukapheresis. We therefore have adopted leukapheresis as a standard procedure in our department.

Prophylactic and interventional granulocyte transfusions in patients with haematological malignancies and life-threatening infections during neutropenia.

Patients with haematological malignancies and prolonged periods of neutropenia after chemotherapy are at high risk for severe bacterial and fungal infections. Those infections have long time been considered as a contraindication for subsequent haematopoietic stem cell transplantation (HCT). We conducted a prospective, non-randomized study of granulocyte transfusions (GTX) to control acute life-threatening infections (44 episodes) and to prevent recurrence of severe fungal infections during HCT or intensive chemotherapy (23 episodes). GTX achieved control in 82% (36/44) of acute life-threatening infections. No single reactivation of a previous infection occurred under prophylactic GTX (0/23). Median survival was 170 days in the interventional group and 185 days in the prophylactic group; death in both patient groups was mainly due to underlying progressive malignant disease. We conclude that under GTX, the infection-related mortality even in high-risk patients is low. Due to a secondary prophylaxis with GTX, haematopoietic allografts can be safely given to patients with previous fungal infections.

High prevalence of GBV-C/HGV among relatives of GBV-C/HGV-positive blood donors in blood recipients and in patients with aplastic anemia.

BACKGROUND: The prevalence of GB virus C (GBV-C)/HGV is high in individuals with parenteral risk factors. The frequency of GBV-C/HGV in blood donors is significantly lower, however it is still far above other parenterally transmitted viruses like HBV and HCV. Therefore, transmission routes apart from parenteral transmission must be considered. STUDY DESIGN AND METHODS: The purpose of the study was to evaluate the prevalence of GBV-C/HGV in blood donors and relatives of GBV-C/HGV-positive and -negative blood donors. Prevalence was also analyzed in aplastic anemia patients. Samples were tested by RT-PCR and partially by ELISA. Positive isolates were sequenced and phylogenetically analyzed. RESULTS: A total of 5733 blood donors were PCR tested and 90 were positive (1.6%). Of these, 98 relatives could be tested. Viremia was found in 14.3 percent and anti-E2 in 29.5 percent, whereas only 1.1 percent of the relatives of PCR-negative donors were viremic and 8.5 percent were anti-E2 positive. Probable virus transmission could be shown in two couples and in six mother-child pairs by sequencing of isolates indicating horizontal and vertical virus transmission, respectively. Recipients of GBV-C/HGV RNA-positive blood products were shown to be infected at a rate of 58 percent (18/31). Aplastic anemia patients were positive at a rate of 32 percent (17/53). CONCLUSION: The high percentage of 14.3 percent of GBV-C/HGV PCR-positive relatives of GBV-C/HGV-positive blood donors suggests intrafamilial transmission. Sequence analyses revealed vertical and horizontal transmission. Although parenteral transmission is highly efficient for GBV-C/HGV (58% of recipients of GBV-C/HGV RNA-positive blood products and 32% of aplastic anemia patients), it appears that sexual and vertical transmission are the most common transmission routes.