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This report is being filed to provide additional information in h.6 and h.11.Investigation: autologous hematopoietic stem cell transplantation (asct) after high-dose chemotherapy has been shown to promote better outcomes compared with conventional treatment in certain scenarios for haematological malignancies, such as multiple myeloma (mm), amyloidosis and lymphomas.The success of asct relies on proper operations throughout the entire process including key stages of haematopoietic stem cell mobilization, harvesting, and re-infusion after chemotherapy.The number of co34+ cells infused has been regarded as the most important factor associated with haematopoietic reconstitution following myeloablative treatment.Therefore, the initial effective stem cell mobilization and harvesting are critical.Previous studies have reported mobilization failure in up to 40% of the cases.A number of factors were associated with the risk of mobilization failure, such as age, previous radiation therapy, extensive chemotherapy, prolonged use of lenalidomide or purine analogues and low pre-apheresis peripheral co34+ counts.However, prediction of mobilization failure has been challenging.Several strategies have been used to tackle issues in apheresis collection including increasing the number of stem cells in the bloodstream (e.G.Plerixafor) and developing prediction algorithms and large-volume processing leukapheresis to better capture the targeted cells.Based on the existing correlation between the pre-apheresis co34+ and the number of cells collected, several authors have developed prediction models to determine the blood volume to process during the apheresis to achieve the desired co34+ cell yield.These prediction models often use variables such as co34+ peripheral blood counts, co34+ collection efficiency, donor weight, and blood volume to be processed.Although these prediction models appeared to be useful in managing poor mobilizers there is no consensus on the best algorithm or prediction models just yet.Apheresis harvesting peripheral blood stem cells (pbsc) can be performed as a standard-volume procedure, with typical processing of 2 to 3 times the patient's blood volume or as a large volume leukapheresis (lvl) processing from 3 to 6 blood volumes.The latter can be especially useful to poor mobilizers, with some authors reporting significant higher stem cell yields in patients with a pre-apheresis peripheral blood cd34+ count 20 cells/l.However, lvl can be associated with an increased risk of hypocalcaemia, due to increased exposure to anticoagulant citrate dextrose solution a (acd-a).The traditional strategy based on a standard processed volume of 2 to 3 total blood volumes for every patient, will be referred as one size fits all approach (osfa).Several publications have shown that a different approach with determination of the volume processed being calculated according to the patient's pbsc collection target and cd34+ peripheral count, here called the custom-tailored approach (ct) could be beneficial.In this study, the authors evaluated the results of stem cell collection using the two strategies, including apheresis procedure effectiveness, safety and feasibility and aimed to assess what strategy would promote better stem cell collection outcomes.In this retrospective study, the authors assessed the effectiveness and safety of two different strategies for harvesting stem cells for autologous stem cell transplantation.Adults (18 years old) with haematological malignancies (lymphoma, multiple myeloma and amyloidosis) submitted to pbsc mobilization and harvesting from january 2021 to october 2023, at christchurch hospital, aotearoa new zealand, were included in the study.Pbsc were mobilized with granulocyte colony-stimulating fac tor (g-csf) with or without chemotherapy and plerixafor according to the nz national protocols.Leukapheresis was performed by trained nurses when the peripheral blood cd34 + count was over 10/l, using the continuous mononuclear cells collection program on the automated apheresis equipment (spectra optia, terumo bct, lakewood, co, usa).From january 2021 to april 2022, the one size fits all (osfa) approach was utilized.This strategy was based on a standard processed volume of 2 to 3 total blood volumes for every patient.Calcium supplements were given orally if a patient presented with symptoms of hypocalcemia.From may 2022 to october 2023, under the custom-tailored (ct) approach, the blood volume to be processed was calculated according to the patient's cd34+ collection target, cd34+ peripheral count, using the historical median collection efficiency (ce2) of 45% (0.45), obtained from the osfa approach procedures.For patients that were going to be submitted to lvl (processed volume 3 total blood volumes), prophylaxis of citrate toxicity with intravenous calcium infusion was recommended.Acd-a (baxter, lake zurich, ll) was the only anticoagulant used in the study period.Cd34+ cells enumeration and viability were assessed before product processing using multi-parameter flow cytometry according to the international society of hematotherapy and graft engineering (ishage) protocol.The pbsc harvest target was determined by the patient clinician who could contemplate one or two transplants.The minimum dose of cd34+ cells for transplant is established according to the diagnosis and the need for more than one transplant.The current international guidelines recommend a minimum threshold of 2 x 10 6 cd34+ cells/kg per autologous transplant (standard dose).To ensure that 2 x 10 6 cd34+ cells/kg are infused, some centers aim for a higher cell collection yield (e.G.3 x 106 cd34+ cells/ kg).However, in this study center, the minimal dose was 3 and 6 x 106 cd34+ cells/kg, for one or two asct, respectively (high dose protocol).Patient harvesting outcomes were classified according to the following criteria: 1."failure" when the minimum target wasn't achieved.2."optimal failure" when the minimum dose was achieved but not the total amount the cells requested (for example for 2 transplants); and 3."success" when the requested tar¿¿get cell dose was achieved.The harvesting outcomes were further analysed according to the standard and high-dose endpoints described above.A total of 263 collections from 144 patients were included in the study.The indications of patients for ascts were multiple myeloma (8 6.8%) non-hodgkin lymphoma (nhl) (20.1%), hodgkin lymphoma (4.8%), and amyloidosis (0.7%).Patients had a male preponderance (65.2%), with a median age of 59.4 years and on average 1.8 collections per patient.No significant differences in patient demographic characteristics were observed between the two strategy groups.The majority of the patients were mobilized with g-csf alone.Plerixafor was used similarly between the two groups, whereas the ct strategy patients used less g-csf with chemotherapy as the mobilization regimen than the counterpart (p = 0.007).In venous access for harvesting, the osfa patients were more often to use the central venous line (p = 0.03) and less often to use peripheral veins (p = 0.03) than the ct patients.A total of 20 procedures met the criteria for failure and the minimum target was not achieved.Considering the apheresis harvesting and collected products, significant differences were observed as expected between the two different strategies including blood volume processed (14.8 , 2.9 versus 16.6 , 3.4), the use of lvl (3.4% versus 49.3%), and duration of the procedures (269 , 41.1 versus 284 ,50 min) there were no significant differences between the two strategies in average number of procedures per patient, collection efficiency, and cd34 + cell counts in the pre-collection samples and the collected products.However, the ct strategy promoted a significantly higher cd34+ cell yield when the pre-collection cd34 was lower than 20/l (1.02 , 0.16 versus 1.36 , 0.23, p 0.001) the ct strategy also promoted a decrease in the proportion of mobilization cycles that needed 3 apheresis to achieve the desired collection target (31% versus 14%, p = 0.02) furthermore, the ct strategy promoted collection outcome defined as the achievement of the predefined cell count target, including higher rates of success and lower rates of optimal failure and failure in terms of the standard as well as high cell dose (p 0.01).Regarding terumo bct product, spectra optia, there were 52 (51 mild, 1 moderate) and 50 (49 mild, 1 moderate) adverse events reported from the osfa and ct strategy respectively, counting for 45.5% and 35% of the harvesting procedures for each group.The differences between the two groups were not significant.Most of the adverse events were classified as mild, and the occurrence of significant clinical events was low.No major bleeding, arrhythmias, or cardiac events were identified.Based on the risk of adverse events such as increased citrate toxicity rates, fluid overload, as well as prolonging the procedures and incurring in staff related costs and fatigue, many centers around the world, including some europeans and australasians, are cautious in using lvl as part of their arsenal.Here the authors have demonstrated that the implementation of measures providing patients with additional loads of calcium and /or association with different anticoagulants (e.G.Acd-a and heparin), the overall frequency of adverse events and citrate toxicity was minimized.Furthermore, the development of harvesting yield prediction models, made it possible to identify patients who would not be able to reach the planned stem cell target before the collection and adapt the apheresis strategy.The authors concluded that their report showed that tailoring the collection to the patient's targets, improved the outcome, by increasing the rates of success and decreasing the occurrence of optimal failure and complete mobilization failure.Intriguingly, although lvl has been reported to be associated with higher rates of adverse events, increase of adoption of lvl in the ct group (taking almost half of the apheresis) did not escalate adverse events at all, which might be explained by the adoption of prophylactic intravenous calcium infusion when more than 3 total blood volumes were predicted to be processed during the procedure.Since this was a journal publication outlining a retrospective study assessing the effectiveness and safety of two different strategies for harvesting stem cells for autologous stem cell transplantation from january 2021 to october 2023, at christchurch hospital, aotearoa new zealand; the disposable 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.A risk assessment was conducted for the adverse events outlined in this study.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension transient hypocalcemia associated with apheresis is usually well tolerated.Symptoms often show as paresthesia (tingling) but patients may also experience unusual taste, nausea, lightheadedness, shivering, and tremors.Severe hypocalcemia may also cause muscle contractions and can progress to tetany and seizures if hypocalcemia escalates and is not corrected.Root cause: a root cause assessment for the failed collection efficiency was performed for this complaint.Historically, lower than expected yields can occur due to access pressure issues such as the inlet flow rate being too high and/or inadequate patient access.Other possible causes include but are not limited to the patient's blood physiology interfering with separation of the cellular components, or from not processing enough blood to optimize the collection of targets cells.Platelet clumping can also interfere with the proper separation of cells in the connector and/or chamber.Disposable defects, sampling errors, lab errors and channel loading errors can all contribute to the yield collection being lower than expected.A root cause assessment for the adverse patient reactions was performed for this complaint.The authors implemented measures providing additional loads of calcium for patients that were going to be submitted to lvl (processed volume 3 total blood volumes).However, the authors alleged that there were 52 (51 mild, 1 moderate) and 50 (49 mild, 1 moderate) adverse events reported from the osfa and ct strategy respectively.The authors did not disclose if the hypocalcemia encountered was limited to the lvl group.Therefore, a root cause assessment was performed for the drop in ionized calcium.A decreased ionized calcium in circulation is a result of exogenous citrate administered during the apheresis procedure and are influenced by patient physiology, the patient's disease state, the rate of ac infusion, the citrate contents in the replacement fluid, and/or the length of the procedure.These symptoms may be treated with oral or intravenous calcium supplements or by adjusting the ac infusion rate.These reactions occur due to decreased ionized calcium in circulation as a result of exogenous citrate administered during the apheresis procedure and are influenced by patient physiology, the patient's disease state, the rate of ac infusion, the citrate contents in the replacement fluid, and/or the length of the procedure.These symptoms may be treated with oral or intravenous calcium supplements or by adjusting the ac infusion rate.The authors did not provide further information regarding the adverse events experienced.Therefore, the complications remain unknown, and due to the retrospective nature of this journal article, it is not feasible to request further information.Adverse events are common side effects of therapeutic apheresis procedures.They are typically caused by fluid shift, blood loss, length of the procedure, donor's sensitivity to the procedure and/or hemodynamic stress of the procedure.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension.De carvalho duarte, g., & wei, w.(2024).Personalized autologous stem cell harvesting improves patient collection outcomes.Transfusion clinique et biologique.Https://doi.Org/10.1016/j.Tracli.2024.06.004.
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