Donor-type red blood cell transfusion to deplete isoagglutinins prior to allogeneic stem cell transplantation from ABO major incompatible bone marrow donors.

ABO incompatibility affects approximately 40% of allogeneic stem cell transplants in Caucasian patient populations. Because bone marrow (BM), the preferred graft from paediatric sibling donors and for non-malignant diseases, has a red blood cell (RBC) content similar to blood, anti-donor isoagglutinins must either be depleted from the recipient or RBCs removed from the graft. To achieve tolerability of unmanipulated BM grafts, we used controlled infusions of donor ABO-type RBC units to deplete isoagglutinins before the transplant. This retrospective study evaluates the outcomes of 52 ABO major incompatible BM transplants performed at our centre between 2007 and 2019. The use of donor-type RBC transfusions was well tolerated. They effectively reduced isoagglutinins levels, typically achieving target titres after one (60%) or two (29%) transfusions. The approach allowed for successful and uneventful infusions of unmanipulated BM which provided timely engraftment. The transplant outcomes were not inferior to those of a matched-pair control group of patients with ABO-identical donors.

Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial.

BACKGROUND: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF. METHODS: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1-2 h infusion of 500-2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. RESULTS: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. CONCLUSIONS: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476).

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.

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.

Clinical evaluation of a polymerase chain reaction assay to detect Aspergillus species in bronchoalveolar lavage samples of neutropenic patients.

The increasing incidence of invasive aspergillosis, a life-threatening infection in immunocompromised patients, emphasizes the need to improve the currently limited diagnostic tools. Using a recently developed two-step polymerase chain reaction (PCR) assay to detect 10 fg of Aspergillus DNA, corresponding to 1-5 colony-forming units (CFU)/ml of spiked samples in vitro, we prospectively examined 197 bronchoalveolar lavage (BAL) samples from 176 subjects, including 141 neutropenic, febrile patients with lung infiltrates, at risk for invasive fungal disease. Underlying diseases of these patients were haematological malignancies; 93 patients suffered from acute leukaemias. Thirty-one of these immunocompromised patients (17.6%) were PCR positive, correlating with positive BAL culture, positive histology from lung surgery or from autopsy, positive computerized tomography scans or positive galactomannan enzyme-linked immunosorbent assay. Six patients (4.3%) of this group had positive PCR results without any correlation to clinical or other diagnostic data, probably owing to contamination of the samples by ubiquitous Aspergillus spores. The samples of two patients (1.4%) with a subsequent histologically proven mould infection were PCR negative. All 102 immunocompromised patients (72.3%) with a negative PCR showed no evidence of invasive fungal disease. From 35 patients without immunodeficiency, four (11.4%) showed positive results, without evidence of invasive or non-invasive pulmonary aspergillosis. In this haematological population, the sensitivity and specificity values of the test reached 93.9% and 94.4%, the positive predictive value 83.8%, the negative predictive value 98.1%. Our data support the considerable clinical value of this PCR assay for confirming and improving diagnosis of pulmonary aspergillosis in high-risk patients.