Burgstaler, Edwin A.

ABSTRACTApheresis is performed worldwide for an increasing number of indications. The development of common data elements (CDE) for apheresis related areas may facilitate conduct of new research, enhance quality initiatives including benchmarking, and improve patient care. This report describes the systematic development of the Uniform Apheresis Case Report Form (UACRF) as part of the Apheresis in the United States (ApheresUS) program. A consensus panel of 17 diverse experts in apheresis, related specialties, and electronic case report form (eCRF), and database development was assembled. The panel met via online conferencing from November 17, 2020 to December 1, 2021. A draft document was posted online for public comment from October 11, 2021 to November 10, 2021. Feedback was collected using an online survey tool. The consensus panel revised the UACRF. This version was converted to an eCRF with additional changes made to improve usability in this format. The final version of the UACRF was created on August 24, 2023. The UACRF contains 16 modules: procedure and subject eligibility, patient demographics, general procedure information, laboratory parameters, vascular access, common procedure elements, eight procedure specific modules (mononuclear cell collection and seven therapeutic modalities), outcomes, and site information. A total of 137 data elements were created, including 57 with one or more subelements. The UACRF is the first systematic attempt to develop CDE for therapeutic apheresis and white blood cell collections. Further validation of the UACRF is necessary to confirm the tool's ability to collect the relevant data elements and determine the usability of the form.

AbstractPurposeWe have used a hematopoietic progenitor cell (HPC) algorithm (standard [STD]) that restricted the inlet flow rate to 65 mL/min for peripheral white blood cell count (PWBC) >35 × 109/L (STD). In this study, we evaluated a technique that allows 85 mL/min, regardless of the PWBC count (high). For patients with PWBC >35 × 109/L, a prospective, randomized comparison of the high flow rate vs the STD PWBC‐based flow rate (65 mL/min) was performed, comparing CD34+ and lymphocyte yields, collection efficiencies (CE1), mononuclear cells (MNC), and granulocytes, red blood cell (RBC), and platelet content.MethodsThe Fenwal Amicus version 4.5 with a heparinized ACD‐A anticoagulant (AC) delivered at a 26:1 AC ratio was used. Paired comparisons between high and STD techniques were assessed with Wilcoxon signed rank tests, with P < .05 considered significant. Data are summarized as medians.ResultsForty patient pairs (autologous) were compared. Diagnoses included primarily multiple myeloma (60%) and lymphoma (37.5%). High had significantly higher median average inlet rates (69 vs 55 mL/min), whole blood processed (20 vs 16 L), and cycles (15 vs 14) than STD. There were no significant differences in pre‐procedure counts. Collection contents were (high/STD): 306/328 × 106 CD34+ cells, 48/59% CD34+ CE1 (significant), 0.2/0.2 × 109/kg lymphocytes, 45/57% lymphocyte CE1, 63/59 × 109 WBC, 15/16 × 109 granulocytes, and 1.9/1.7 × 1011 platelets.ConclusionsThe simpler, standardized high flow technique did not significantly increase or decrease CD34+ cells or lymphocyte yields, but did significantly decrease CD34+ CE1. The effects on cross‐cellular content were minimal and not clinically significant.

Introduction Day 15 absolute lymphocyte count (ALC-15) recovery after autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) is recognized as a prognostic factor for survival. ALC-15 recovery is directly dependent on the amount of collected and infused autograft-absolute lymphocyte count (A-ALC). Our group published a double-blind phase III study which showed that patients infused with an A-ALC ≥ 0.5 x 109 cells/kg experienced superior survival post-APBHSCT. Based on the results from our phase III study, on April 1, 2017, our Bone Marrow Transplant Program changed our standard clinical practice to collect an A-ALC ≥ 0.5 x 109 cells/kg in addition to stem cells for lymphoma patients undergoing APBHSCT. To continue to assess the prognostic ability of A-ALC, we evaluated the overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients that underwent APBHSCT after April 1, 2017 compared with a matched-control group in a 1:1:1 ratio with DLBCL patients infused with an A-ALC &lt; 0.5 x 109 cells/kg or an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1, 2017. Methods Eight-five consecutive DLBCL patients after our practice changed on April 1, 2017 received an A-ALC ≥ 0.5 x 109 cells/kg. For each DLBCL patient infused with an A-ALC ≥ 0.5 x 109 cells/kg after April 1, 2017, the set of potential controls was restricted to those DLBCL patients infused with an A-ALC &lt; 0.5 x 109 cells/kg and an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017 . Within this group of potential controls, the subjects were chosen who best matched for the cases in terms of clinical risk variables, including gender, age, stage, lactate dehydrogenase (LDH), performance status, extra-nodal disease, International prognostic index (IPI), and disease status prior to APBHSCT (complete or partial response), using the GREEDY algorithm. Cases were defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg starting from April 1 2017. Control 1 was defined as DLBCL patients infused with an A-ALC &lt; 0.5 x 109 cells/kg prior to April 1 2017. Control 2 was defined as DLBCL patients infused with an A-ALC ≥ 0.5 x 109 cells/kg prior to April 1 2017. We truncated the survival follow-up to 3 years starting from the date of transplant to match follow-up time between cases and controls. Both matched cases and control groups patients received BEAM conditioning. This retrospective study was approved by the Mayo Clinic Institutional Review Board according to the regulation of the Declaration of Helsinki. Results Cases, control 1 and control 2 were balanced to the clinical risk variables; age (p = 0.8); gender (p = 0.9); LDH (p = 0.6); stage (p = 0.3); performance status (p = 0.5); extra-nodal disease (p = 0.2); IPI (p = 0.6); and clinical status prior to transplant (p = 0.2). Figure 1A showed the OS and figure 1B the PFS. Both the cases and control 2 showed superior OS and PFS in comparison to control 1. Cases and control 2 showed overall similar OS and PFS. Multivariate analysis including all patients continue to depict the A-ALC ≥ 0.5 x 109 cells/kg as an independent predictor for OS (HR = 0.382, 95%CI=0.241-0.605, p &lt; 0.0001) and PFS (HR = 0.437, 95%CI = 0.279-0.629, p &lt;0.0001). Subgroup analysis, including all patients, shows superior OS and PFS for patients infused with an A-ALC ≥ 0.5 x 109 cells/kg for each of the following clinical variables: age [&gt; 60 years: OS (p &lt;0.0001); PFS (p &lt;0.0001) or ≤ 60 years: OS (p &lt;0.01); PFS (p , 0.02)]; extra-nodal disease [&gt; 1: OS (p &lt;0.008); PFS (p &lt;0.01) or ≤1: OS (p &lt; 0.001): PFS (p &lt;0.0005)]; IPI [&gt; 2: OS (p &lt;0.01); PFS (p &lt;0.02) or ≤ 2: OS (p &lt;0.0008); PFS (p &lt;0.0006)]; LDH [abnormal: OS (p &lt;0.006); PFS (p &lt;0.005) or normal: OS (p &lt;0.002); PFS (p &lt;0.002)]; performance status [&gt; 1: OS (p &lt;0.04); PFS (p &lt;0.03) or ≤ 1: OS (p &lt;0.0001); PFS (p &lt;0.0001)]; stage [I/II: OS (p &lt;0.006); PFS (p &lt;0.006) or III/IV: OS (p &lt;0.002); PFS (p &lt;0.001)]; response prior to transplant [complete response: OS (p &lt;0.0007); PFS (p &lt;0.0001) or partial response: OS (p &lt;0.01); PFS (p &lt;0.02)]. Conclusion Our match-control study continues to support the results of our Phase III study showing that the infusion of A-ALC is a prognostic factor for survival of DLBCL patients undergoing APBHSCT. Our studies support the practice of not only collecting enough stem cells (i.e., CD34) for hematologic engraftment, but also enough immune effector cells (i.e., A-ALC) to improve clinical outcomes in DLBCL patients post-APBHSCT. Figure 1 Disclosures Ansell: Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding.

Background Trans-acting programmed death-ligand 1 (PD-L1) derives from malignant cells in three known forms. High levels of secreted splice variant PD-L1 (sPD-L1), ADAM10/ADAM17-shed sPD-L1, and PD-L1-positive extracellular vesicles (evPD-L1) each predict poor prognosis and limited response to PD-(L)1 checkpoint inhibitors in cancer. To our knowledge, no clinical intervention has reduced any of these circulating forms of extracellular PD-L1. Here, we explore therapeutic plasma exchange (TPE) as a treatment to reduce circulating extracellular PD-L1. Results In patients with melanoma, sPD-L1 levels above 0.277 ng/mL predicted inferior overall survival. In patients undergoing TPE for non-malignant indications, each TPE session removed a mean 70.8% sPD-L1 and 73.1% evPD-L1 detectable in plasma. TPE also reduced total and ADAM10-positive extracellular vesicles. Conclusion Here, we report the first known clinical intervention to remove either sPD-L1 or evPD-L1 from plasma in vivo. TPE reduces plasma sPD-L1 and evPD-L1 in vivo and may have a role in treatment with immunotherapy. TPE may also prove useful in patients with other extracellular vesicle-related conditions.

AbstractBackgroundA new protocol has been developed on the Amicus Separator that enables the device to perform online extracorporeal photopheresis (ECP) procedures when used in conjunction with the Phelix photoactivation device and associated disposable kit. The objective of this study was to evaluate the safety and performance of the Amicus ECP System in adult subjects with steroid‐refractory or dependent chronic graft vs host disease (cGVHD).Study Design and MethodsEight subjects with mild to severe cGVHD underwent 31 procedures. Subject safety evaluations were performed pre and post procedure and adverse events (AEs) were recorded during treatment and 24 hours after the last procedure. In vitro evaluations of the treated cells included hematology counts and lymphocyte apoptosis, viability and proliferation as measures for ECP procedure validation.ResultsFor n = 23 evaluable procedures, median (range) procedure time was 88 (78‐110) minutes, during which 2.9 (0.6‐4.7) × 109 TNCs (approximately 90% MNCs) were treated and reinfused to the subjects. All subject safety evaluations (vitals, cell counts, plasma hemoglobin and bacterial and endotoxin testing) were within expected ranges. All device or procedure related AEs were mild in nature. After 24 hours in culture, 86 (52‐98)% of treated lymphocytes were apoptotic compared to 27 (15‐51)% in controls. Inhibition of lymphocyte proliferation was >91% in all procedures.ConclusionECP procedures were safely completed in adult subjects with SR‐cGVHD treated using the new online Amicus ECP system.

Abstract Introduction: Peripheral blood hematopoietic progenitor cell collection is a more popular source of stem cells for transplantation than bone marrow harvest. A number of automated cell separators exist which can be used to perform mononuclear cell collections. These separators collect varying amounts of other cells during the collection process, including them in the mononuclear cell product. Because of this, collection of mononuclear cells can result in significant reductions in platelet count and loss of red blood cells during the procedure. In order to minimize platelet transfusion support, we developed an algorithm to optimize mononuclear cell collections while minimizing platelet losses using the Gambro COBE Spectra and the Baxter Amicus Methods: Previously, patients were assigned randomly to any available apheresis machine. Starting August 2nd 2002, patients with a WBC count higher than 35×10 (9)/L were preferably assigned to Amicus for 5 hour collection with processing 1000 ml/cycle or as second choice Spectra for 5 hours run with maximum draw rate 65 ml/Min., for both instruments. If the WBC was lower than 35×10 (9)/L, the preferred machine would be Amicus for 5 hours run at 1400 ml/cycle with maximum draw rate 90ml/Min. or Spectra for 5 hours run with maximum draw 100 ml/Min. We reviewed the difference of pre and post procedure platelet counts of non Hodgkin’s Lymphoma patients undergoing stem cells collection for 6 months before and after the implementation of the above protocol from February 2002 till February 2003. All CBC were performed on the same Coulter analyzer. Results: 14 patients (2 on Amicus and 12 on Spectra) underwent stem cells collection before August 2nd, 2002. 13 patients (8 on Amicus and 5 on Spectra) were collected after this date. The Fisher’s exact test was used for this study. The median and mean differences in the first group were 141.5 ×10(9)/L and 135 ×10 (9)/L respectively (95% CI, p 0.0183). The second group had a median and mean of 45 ×10 (9)/L and 51 × 10(9)/L (95% I, p 0.0183). The minimum and maximum differences were 36 × 10(9)/L and 200 × 10(9)/L respectively in the first group and −19 ×10(9)/L and 121×10(9)/L for the second group. There was no difference in the numbers of the collections days in both groups in regard to the type of automated cell collector. Discussion: The implemented algorithm showed a net advantage. Even though none of the patients required blood transfusions, there was lesser drop of platelets counts with the new settings.

PurposeTerumo BCT Spectra Optia (O) and Fenwal Amicus (A) can perform therapeutic plasma exchange (TPE). We compared these systems in a prospective, randomized, crossover study of 81 paired procedures. Primary objective was to determine if there was a difference in platelet loss between the instruments. Secondary objectives were to determine differences in procedure time (PT), plasma removal efficiency (PRE 1), plasma removal rate (PRR), and fluid balance (FB).MethodsFifty‐seven adults undergoing 162 procedures were included. Diagnoses included neurologic, nephrologic, and hematologic diseases. Replacement fluids included 5% normal serum albumin and/or fresh frozen plasma. The first instrument (randomized) established the inlet flow rate for the second with a maximum inlet rate of 120 ml/min. Spun HCT was used to program the procedure. One plasma volume was exchanged, for both instruments. Multivariable general estimating equations were used to assess the relationship between the outcome variables with machine after adjusting for covariates, with P values <.05 significant.ResultsMedian total blood volume (4,775 mL‐A, 4,775 mL‐O) and preprocedure spun HCT (33%‐A, 34%‐O) were not statistically different. The plasma removed (3196 mL‐A, 3120 mL‐O), PLT in waste plasma (0.62 × 1011‐A, 0.33 × 1011‐O), PLT decline (8.5%‐A, 6.5%‐O), and PRR (48.1 mL/min‐A, 49.2 mL/min‐O) were not statistically different. There were statistically significant, but clinically irrelevant, differences in PLT CE1 (6.2%‐A, 3.6%‐O), PRE 1 (85.3%‐A, 83.9%‐O), FB (+2 mL‐A,+15 mL‐O), and PT (71 min‐A, 71 min‐O).ConclusionsStatistical differences were seen but none were of a magnitude to be clinically relevant, indicating comparable TPE performance.

AbstractThyroid storm or severe thyrotoxicosis results from extreme thyroid hormone elevation. Therapy includes medical management to prevent hormone production, release, recycling, and peripheral conversion while stabilizing adrenergic tone. Thyroid dysfunction is the usual cause but it can be due to excessive thyroid hormone ingestion. Therapeutic plasma exchange (TPE) has been used to rapidly remove protein‐bound thyroid hormone. American Society for Apheresis guidelines make a weak recommendation to perform TPE in selected patients in the treatment of thyrotoxicosis based on low quality evidence. We present a case of excessive thyroid replacement hormone ingestion treated by TPE. The patient presented with the clinical picture of thyroid storm, including cardiovascular compromise and massively elevated total and free T3 (525 ng/dL, nl 80–200 ng/dL and 28 pg/mL, nl 2.0–3.5 11 pg/mL), which failed medical therapy. A single, one plasma volume TPE was performed. Both total and free T3 demonstrated substantial declines immediately after TPE with the patient's mental status returning to near‐normal. Thyroid hormone extraction efficiency and collection efficacy were calculated as 37.1% and 40.8%, respectively. Prior to discharge on day 6, the patient's compounding pharmacy indicated that a “bad batch” of bovine thyroid gland derived replacement hormone had been produced. TPE appears to be effective in removing protein bound thyroid hormone in extreme iatrogenic thyrotoxicosis.