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This report is being filed to provide additional information in h.6 and h.11, corrected information is provided in h.1 and d.4.Investigation: since this was a journal publication to assess non-cryopreserved peripheral blood stem cells as a safe and effective alternative for autologous transplantation in multiple myeloma between 2017 and 2021, the lot numbers were not requested; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Autologous hematopoietic stem cell transplantation is often used as therapy to treat many hematological diseases, especially for multiple myeloma (mm).They are regularly collected by apheresis (peripheral blood stem cells ¿ pbsc), and the product is infused after cryopreservation and storage.However, the fresh maintenance of pbsc is possible while the patient receives the conditioning regimen.Moreover, studies have shown that autologous transplantation with non-cryopreserved pbsc can be safe and present better outcomes, such as earlier neutrophilic grafting, fewer cases of infusion-related complications, early platelets engraftment, lower incidence of neutropenic fever, less mucositis, fewer days using antibiotic, and less requirement for parenteral nutrition and opioids.Besides the clinical advantages, non-cryopreserved transplants can reduce laboratory and hospital expenses.Many factors can contribute to the negative effects of cryopreserved cells, such as the clinical symptoms of dmso exposure (nausea, vomiting, abdominal cramps, headaches, hypo or hypertension, bradycardia, hemolysis, rashes, renal failure, pulmonary edema, bronchospasm, cardiac arrest, and neurological damage), cell debris, cell aggregation, red blood cell lysis products, electrolyte imbalance, and the requirement of adjustable cd34+ collection goals, considering the cellular losses due to the cryopreservation/thawing process.Because of the benefits of fresh infusion and the lack of studies comparing clinical outcomes of fresh and cryopreserved stem cells transplantation, we propose to compare the outcomes and adverse effects of transplanted patients under fresh and cryopreserved pbsc grafts.Apheresis was performed using an automated apheresis system (cobe spectra optia, terumo bct, usa).The anticoagulant used was acd-a, infused at a ratio of 1:13 during apheresis.After collection, pbsc was transported to the cellular processing laboratory and stored in the refrigerator at 4°c (± 2°c).Fresh pbsc were maintained in the refrigerator for three days in a concentration up to 300 x 103 tnc/¿l.For cryopreservation, pbsc were processed until 24 h.Pbsc were concentrated by plasma reduction after centrifugation (950 g/10 min/4°c) for a concentration of 600 x 103 tnc/ l.An equal volume of cryoprotective solution was added to the pbsc for a final concentration of 300 x 103 tnc/ l, 5% dmso, 6% hydroxyethyl starch, and 3% human albumin.After the cryoprotective solution was added, freezing bags were immediately cryopreserved in a mechanical freezer (-80°c, uncontrolled freezing rate).On the transplantation day, cryopreserved pbsc were thawed bedside in a 37°c¿40°c water bath and infused up to 15min/bag after thawing.Except for one patient, who was conditioned using busulfan, etoposide, cytarabine, and cyclophosphamide (beac), all others received melphalan 200 mg/m2 or 140 mg/m2 for two consecutive days.Pbsc were infused 24 h after the last dose.All patients received antihistamines and corticosteroids before infusion to avoid reactions.Secondary outcomes were antibiotics use, adverse events (aes) related to infusion, transfusion requirement posttransplant, and overall survival (os).Neutrophil engraftment (ne) was defined as the first of three consecutive days with neutrophil count of at least 500/ l after infusion day (d0).Platelet engraftment (pe) was defined as the first of seven consecutive days with platelet count of at least 20 x 103/ l without platelet transfusion.Reactions caused by infusion considered the occurrence of aes during the pbsc infusion and 24 h after.These events were graded according to the common terminology criteria for adverse events (ctcae) 5.0 (https://ctep.Cancer.Gov/protocoldevelopment/electronic_applications/ctc.Htm#ctc_50).Maximum grade was considered for transplant classification.Regarding terumo bct product, cobe spectra, the authors evaluated 45 autologous transplantations for mm (17 fresh and 28 cryopreserved transplanted grafts).Table 1 shows the clinical characteristics related to patients and treatment.The fresh storage time was 72 h for all patients.The cryopreserved autografts were stored in -80°c for 86.5 days (median, range 4¿483 days).Both groups were similar regarding patients and transplant-related characteristics (table 1), except for the time from diagnosis to transplantation.Table 2 shows the transplantation outcomes.The results showed a significantly less time to neutrophil engraftment in the fresh group.Although without significant difference, the fresh transplanted patients showed a smaller post-transplant hospital stay (table 2).Both types of transplants showed no incidence of graft failure.Table 2 shows that the occurrence of ae was significantly higher in patients who received cryopreserved pbsc (incidence ratio [ir] = 1.46, range 1.10¿1.93).Women, graft volume/kg, dose dmso/kg, and cnt/kg affected the infusions effects in the bivariate analysis.The authors observed 47 aes in the study (10 events in the fresh group vs.37 events in the cryopreserved group).Aes during the fresh infusion included: fever (2), vomiting (1), chills (1), hypotension (2), hypertension (1), paresthesia (1), and desaturation (2); whereas in the cryopreserved group the infusion-related events were: coughing (5), sore throat (5), nausea (5), vomiting (5), flushing (3), malaise (1), dizziness (1), hypertension (2), hypotension (1), desaturation (2), hypopnea (1), loss of consciousness (1), paresthesia (1), chest pain (1), tachycardia (1), and abdominal pain (2).Both groups showed no grade 4 or 5 adverse reaction in the nih categorization of adverse events.There was no difference between patients with events > grade 2 in both groups.However, we observed a moderate positive correlation between dose of dmso/kg and aes grade in the cryopreserved group (kendall's correlation 0.363, p = 0.016).We have also observed a moderate positive correlation between infusion volume/kg and aes grade (kendall's correlation 0.342, p = 0.003).Regarding transfusion support, the use of rbc and plasma were similar in both groups (p = 0.721 and p = 0.199 respectively).The cryopreserved group required more platelet transfusions (median 24 vs.16, p = 0.025).The platelet doses were primarily derived from apheresis.All rbc and platelet units were leukocyte reduced and irradiated to a minimum of 25 gy prior infusion.We did not use cryoprecipitated units in patients.The median follow-up time was 25 months.The overall survival was 93% for fresh pbscs and 88% for cryopreserved pbscs during this period.The overall survival was similar in both groups (p = 0.736) (figure 1).The fresh group showed significantly less adverse events despite occurring in both groups.Ae grades 4 or 5 were not reported in both groups, similar to other pbsc autotransplantation studies.Our study shows that higher amounts of dmso and volume/kg infused is also related to the increased frequency of aes.Moreover, higher amounts of dmso have also been previously related to the increased frequency of = grade 2 aes.Overall, authors concluded the infusion of fresh pbsc stored for up to three days at 4°c (± 2°c) is effective and safe for mm patients under autologous transplantation.We emphasize the importance of tnc/ l quantification up to 24 h, diluted when necessary, considering our previous laboratorial study.We only included grafts maintained cooled with total nucleated cells (tnc) up to 300.000/ l.More evidence is required to reinforce the practice of fresh autologous transplantation and to direct studies on transplants of other diseases and for other cellular therapy products.According to the aabb tech manual 20th edition, most allogeneic hpc(m) and hpc(a) products are infused fresh within 48 to 72 hours after collection.If the fresh products are not intended to be infused within that time, they are cryopreserved.Hpc(a) that are transported or stored for more than a few hours should be maintained at 2 to 8 c and, ideally, diluted to a cell concentration that minimizes metabolic stress.By comparison, hpc(m) products do not require dilution and may be stored and transported at room temperature for up to 48 to 72 hours without significant loss of cd34+ cell viability or numbers.Autologous hpc(a) products are concentrated and cryopreserved until the patient has undergone preconditioning therapy and is ready for transplantation.In selected circumstances, such as for patients with a documented severe dmso allergy, washing thawed hpc products may be the safer choice.Washing to remove dmso and other additives raises concerns over loss of hpcs due to additional manipulation and increased exposure time of cells to dmso.Various procedures have been developed to remove dmso through manual or automated methods, and some of these have been associated with reduced infusion related aes.Importantly, the cellular component of thawed hpc(a) products, particularly granulocytes, may also contribute to toxicities during or shortly after reinfusion.Separating out these cellular components and debris after thawing to mitigate toxicity is technically challenging; however, limiting the number of infused nucleated cells can reduce severe infusion-related complications.In most settings, it is safe to infuse the cryopreserved hpc(a) product directly into the patient after the thawing process is completed at the bedside.Cryopreserved hpc(a) or hpc(m) products are usually thawed at the time and place of the planned infusion¿typically at the bedside.This is done to minimize the amount of time cells are exposed to dmso in the liquid state after thawing and before infusion.Rapid thawing in a 37 c water bath followed by infusion as quickly and safely as possible is recommended to avoid dmso-mediated cytotoxicity.Infusion-related aes associated with hpc products may be similar to those that occur with transfusion of blood components.These include allergic, hemolytic, and febrile reactions, as well as fluid overload.Certain aes have been attributed specifically to dmso, including nausea, vomiting, headache, changes in blood pressure and pulse, and cough.The incidence of aes following infusion of cryopreserved hpc products ranges from 6% up to 70%, with variable degrees of severity.The variability probably reflects differences in processing, premedication, patient monitoring, and the classification of aes.Additional aes include facial flushing, skin rashes, nausea, vomiting, fever, chills, abdominal pain, hypotension, hypertension, bradycardia, and tachycardia.In one study of 1191 adult patients, hypoxia requiring oxygen was noted in 29% of infusions, chest tightness in 16.7%, and shortness of breath in 8.3%.Neurologic toxicities have also been reported, including amnesia, encephalopathy, seizures, and stroke.Fortunately, severe infusion related aes are uncommon.Many patients may receive premedication in an attempt to prevent allergic, dmso-related, and febrile nonhemolytic reactions, along with a combination of hydration, antihistamines, antipyretics, and anti-inflammatory agents.Intravenous hydration (eg, for 2-6 hours before and up to 6 hours after infusion) along with diuretics may be needed with dmso-containing hpcs.Patients¿ vital signs and oxygen saturation should be closely monitored during and up to several hours after infusion of cryopreserved hpc products.Product and infusion-related aes may be reduced by certain cell-processing techniques, such as red cell or plasma reduction, post thaw washing, or dilution.Some transplantation centers routinely wash cryopreserved products after thawing and before infusion in order to reduce the dmso content.112,115 dmso depletion has been shown to reduce the frequency of aes but could result in loss of cd34+ cells and introduction of bacterial contamination.For these reasons, most transplantation centers avoid post thaw washing or other manipulations.Root cause: based on the available information within the journal article, a definitive root cause could not be determined for the reported adverse events within the cryopreserved group, but as stated by the authors, ¿many factors can contribute to the negative effects of cryopreserved cells, such as the clinical symptoms of exposure (nausea, vomiting, abdominal cramps, headaches, hypo or hypertension, bradycardia, hemolysis, rashes, renal failure, pulmonary edema, bronchospasm, cardiac arrest, and neurological damage), cell debris, cell aggregation, red blood cell lysis products, electrolyte imbalance, and the requirement of adjustable cd34+ collection goals, considering the cellular losses due to the cryopreservation/thawing process.Our study shows that higher amounts of dmso and volume/kg infused is also related to the increased frequency of aes¿.Cause for the reported adverse events within the fresh infusion group could not be determined but may be related to the patient¿s underlying disease state, side effects of chemotherapy/conditioning regimen, medications patients received treatment or cellular debris in the transfused product.Article citation: araújo, a., et.Al.Non-cryopreserved peripheral blood stem cells as a safe and effective alternative for autologous transplantation in multiple myeloma.Transfusion.2022;1¿6.
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