| Catalog Number 12320 |
| Device Problems
Adverse Event Without Identified Device or Use Problem (2993); Insufficient Information (3190)
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| Patient Problems
Anemia (1706); High Blood Pressure/ Hypertension (1908); Appropriate Clinical Signs, Symptoms, Conditions Term / Code Not Available (4581)
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| Event Date 07/13/2023 |
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Event Type
Injury
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Manufacturer Narrative
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Lot number and expiry information are not available at this time.Investigation is in process, a follow-up report will be provided.Citation: bastian, h., lounnas-mourey, n., heimendinger, p., hsu, b. l., schreeb, k. h., chapman, c., culme-seymour, e., atkinson, g. f., & cantarovich, d.(2023).Feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease. translational medicine communications, 8(1). https://doi.Org/10.1186/s41231-023-00150-y.
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Event Description
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Per journal article "feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease translational medicine communications") background gene-modified cell therapy with regulatory t cells (tregs) is a promising approach to prevent graft rejection and induce immunological tolerance in organ transplantation.We are developing a cell therapy comprising autologous naïve tregs that are isolated from leukapheresate, transduced with lentiviral vector encoding a chimeric antigen receptor (car) recognising human leukocyte antigen class i molecule a*02 (hla-a*02), and expanded ex vivo before cryopreservation as resultant drug product (tx200-tr101).In an ongoing first-in-human study (nct04817774), kidney transplant recipients will receive a single infusion of tx200-tr101 2¿3 months after transplantation.The phase 0 study described here evaluated the feasibility of manufacture of tx200-tr101 for the target population, i.E., endstage renal disease (esrd) necessitating kidney transplantation.Participants in this study did not receive an infusion of drug product.Methods four patients with esrd and hla-a*02 negative typing underwent leukapheresis to collect starting material for manufacture of tx200-tr101.Manufacturing success criteria were predefined as a batch of car-tregs with cell quantity in each batch = 104 cells/kg body weight, cell viability = 70%, transduction efficiency = 20% and hypomethylation of the foxp3 gene (treg-specific demethylated region [tsdr]) = 80%.Other manufacturing variables included treg identity and maturation by phenotyping, residual bead count, vector copy number, endotoxin level, sterility, and presence of mycoplasma.The characteristics of leukapheresate starting material and drug product from patients with esrd were compared with those from commercially purchased leukapheresate from 10 healthy donors.Results no safety issues were identified during leukapheresis collections.Batches of drug product were manufactured from all 4 patients with esrd and met the predefined success criteria.There was some variability in leukapheresate starting material in terms of volume of apheresis and total leukocyte counts between patients with esrd and healthy donors, but percentage differential white blood cell counts were comparable.The quality, quantity and functional activity of manufactured car-tregs were similar between esrd patients and healthy donors.Car-treg drug product from one patient with pre-existing lymphopenia had similar high quality but reduced cell quantity compared with batches from the other patients with esrd, although yield was still above the predefined target minimum number of cells.Conclusions manufacture of high-quality naïve car-tregs from patients with esrd is safe and feasible.No safety issues were identified during the leukapheresis procedure in any patient.No serious adverse event or abnormality of common terminology criteria for adverse events (ctcae) grade 3 or higher was reported.Twelve procedure-emergent adverse events were reported.Post-procedure haematological profiles were consistent with those anticipated with leukapheresis.Reported grade 2 events inlcuded hameoglobin decrease (1), asthemia (1), anemia (1) and hypertension (1).It is unknown if medical intervention was required for these event.Specific details, such as patient information and outcome, were not included in the article for these events, therefore this report is being provided as a summary of the events.The collection set is not available for return because it was discarded by the customer.
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Manufacturer Narrative
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This report is being filed to provide additional information in h.6 and h.10.Investigation: part evaluation is not feasible for this journal article investigation because there are many months between collection of data, to peer review, to final publication.This was a journal publication presenting data of feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease using leukapheresates collected from healthy hla-a*02-negative donors on spectra optia.A request for lot numbers is not feasible because there are many months between collection of data, to peer review, to final publication.Therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.According to therapeutic apheresis: a physician's handbook, with current centrifugal technology, reductions in platelet count are usually modest, and levels quickly return to baseline.In a severely thrombocytopenic patient, however, such a loss may mask the beginning of platelet recovery.Similarly, the small amount of red cells lost in the apheresis circuit may be more apparent in an anemic patient who has meager production capacity and who is receiving multiple procedures.Although generally well tolerated, the large-volume leukocytapheresis for stem cell collections in patients often results in a decline in hematocrit and platelet count, particularly because some red cells and platelets are incidentally removed with the stem cells.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.According to adverse events in apheresis: an update of the world apheresis association registry data (henriksson, et al), more aes occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively).Aes were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%).<5 moderate hypertension and <1 mild fatigue in 10,000 procedures may be expected to appear with cellapheresis.Investigation is in process, a follow-up report will be provided.Citation: bastian, h., lounnas-mourey, n., heimendinger, p., hsu, b. l., schreeb, k. h., chapman, c., culme-seymour, e., atkinson, g. f., & cantarovich, d.(2023).Feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease. translational medicine communications, 8(1). https://doi.Org/10.1186/s41231-023-00150-y.
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Event Description
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Per journal article "feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease translational medicine communications") background gene-modified cell therapy with regulatory t cells (tregs) is a promising approach to prevent graft rejection and induce immunological tolerance in organ transplantation.We are developing a cell therapy comprising autologous naïve tregs that are isolated from leukapheresate, transduced with lentiviral vector encoding a chimeric antigen receptor (car) recognising human leukocyte antigen class i molecule a*02 (hla-a*02), and expanded ex vivo before cryopreservation as resultant drug product (tx200-tr101).In an ongoing first-in-human study (nct04817774), kidney transplant recipients will receive a single infusion of tx200-tr101 2¿3 months after transplantation.The phase 0 study described here evaluated the feasibility of manufacture of tx200-tr101 for the target population, i.E., endstage renal disease (esrd) necessitating kidney transplantation.Participants in this study did not receive an infusion of drug product.Methods four patients with esrd and hla-a*02 negative typing underwent leukapheresis to collect starting material for manufacture of tx200-tr101.Manufacturing success criteria were predefined as a batch of car-tregs with cell quantity in each batch = 104 cells/kg body weight, cell viability = 70%, transduction efficiency = 20% and hypomethylation of the foxp3 gene (treg-specific demethylated region [tsdr]) = 80%.Other manufacturing variables included treg identity and maturation by phenotyping, residual bead count, vector copy number, endotoxin level, sterility, and presence of mycoplasma.The characteristics of leukapheresate starting material and drug product from patients with esrd were compared with those from commercially purchased leukapheresate from 10 healthy donors.Results no safety issues were identified during leukapheresis collections.Batches of drug product were manufactured from all 4 patients with esrd and met the predefined success criteria.There was some variability in leukapheresate starting material in terms of volume of apheresis and total leukocyte counts between patients with esrd and healthy donors, but percentage differential white blood cell counts were comparable.The quality, quantity and functional activity of manufactured car-tregs were similar between esrd patients and healthy donors.Car-treg drug product from one patient with pre-existing lymphopenia had similar high quality but reduced cell quantity compared with batches from the other patients with esrd, although yield was still above the predefined target minimum number of cells.Conclusions manufacture of high-quality naïve car-tregs from patients with esrd is safe and feasible.No safety issues were identified during the leukapheresis procedure in any patient.No serious adverse event or abnormality of common terminology criteria for adverse events (ctcae) grade 3 or higher was reported.Twelve procedure-emergent adverse events were reported.Post-procedure haematological profiles were consistent with those anticipated with leukapheresis.Reported grade 2 events inlcuded hameoglobin decrease (1), asthemia (1), anemia (1) and hypertension (1).It is unknown if medical intervention was required for these event.Specific details, such as patient information and outcome, were not included in the article for these events, therefore this report is being provided as a summary of the events.The collection set is not available for return because it was discarded by the customer.
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Event Description
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Per journal article "feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease translational medicine communications") background gene-modified cell therapy with regulatory t cells (tregs) is a promising approach to prevent graft rejection and induce immunological tolerance in organ transplantation.We are developing a cell therapy comprising autologous naïve tregs that are isolated from leukapheresate, transduced with lentiviral vector encoding a chimeric antigen receptor (car) recognising human leukocyte antigen class i molecule a*02 (hla-a*02), and expanded ex vivo before cryopreservation as resultant drug product (tx200-tr101).In an ongoing first-in-human study (nct04817774), kidney transplant recipients will receive a single infusion of tx200-tr101 2¿3 months after transplantation.The phase 0 study described here evaluated the feasibility of manufacture of tx200-tr101 for the target population, i.E., endstage renal disease (esrd) necessitating kidney transplantation.Participants in this study did not receive an infusion of drug product.Methods four patients with esrd and hla-a*02 negative typing underwent leukapheresis to collect starting material for manufacture of tx200-tr101.Manufacturing success criteria were predefined as a batch of car-tregs with cell quantity in each batch = 104 cells/kg body weight, cell viability = 70%, transduction efficiency = 20% and hypomethylation of the foxp3 gene (treg-specific demethylated region [tsdr]) = 80%.Other manufacturing variables included treg identity and maturation by phenotyping, residual bead count, vector copy number, endotoxin level, sterility, and presence of mycoplasma.The characteristics of leukapheresate starting material and drug product from patients with esrd were compared with those from commercially purchased leukapheresate from 10 healthy donors.Results no safety issues were identified during leukapheresis collections.Batches of drug product were manufactured from all 4 patients with esrd and met the predefined success criteria.There was some variability in leukapheresate starting material in terms of volume of apheresis and total leukocyte counts between patients with esrd and healthy donors, but percentage differential white blood cell counts were comparable.The quality, quantity and functional activity of manufactured car-tregs were similar between esrd patients and healthy donors.Car-treg drug product from one patient with pre-existing lymphopenia had similar high quality but reduced cell quantity compared with batches from the other patients with esrd, although yield was still above the predefined target minimum number of cells.Conclusions manufacture of high-quality naïve car-tregs from patients with esrd is safe and feasible.No safety issues were identified during the leukapheresis procedure in any patient.No serious adverse event or abnormality of common terminology criteria for adverse events (ctcae) grade 3 or higher was reported.Twelve procedure-emergent adverse events were reported.Post-procedure haematological profiles were consistent with those anticipated with leukapheresis.Reported grade 2 events inlcuded hameoglobin decrease (1), asthemia (1), anemia (1) and hypertension (1).It is unknown if medical intervention was required for these event.Specific details, such as patient information and outcome, were not included in the article for these events, therefore this report is being provided as a summary of the events.The collection set is not available for return because it was discarded by the customer.
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Manufacturer Narrative
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This report is being filed to provide additional information in h.6 and h.10.Investigation: part evaluation is not feasible for this journal article investigation because there are many months between collection of data, to peer review, to final publication.This was a journal publication presenting data of feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease using leukapheresates collected from healthy hla-a*02-negative donors on spectra optia.A request for lot numbers is not feasible because there are many months between collection of data, to peer review, to final publication.Therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.According to therapeutic apheresis: a physician's handbook, with current centrifugal technology, reductions in platelet count are usually modest, and levels quickly return to baseline.In a severely thrombocytopenic patient, however, such a loss may mask the beginning of platelet recovery.Similarly, the small amount of red cells lost in the apheresis circuit may be more apparent in an anemic patient who has meager production capacity and who is receiving multiple procedures.Although generally well tolerated, the large-volume leukocytapheresis for stem cell collections in patients often results in a decline in hematocrit and platelet count, particularly because some red cells and platelets are incidentally removed with the stem cells.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.According to adverse events in apheresis: an update of the world apheresis association registry data (henriksson, et al), more aes occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively).Aes were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%).<5 moderate hypertension and <1 mild fatigue in 10,000 procedures may be expected to appear with cellapheresis.No safety issues were identified during leukapheresis collections.Batches of drug product were manufactured from all 4 patients with esrd and met the predefined success criteria.There was some variability in leukapheresate starting material in terms of volume of apheresis and total leukocyte counts between patients with esrd and healthy donors, but percentage differential white blood cell counts were comparable.The quality, quantity and functional activity of manufactured car-tregs were similar between esrd patients and healthy donors.Car-treg drug product from one patient with pre-existing lymphopenia had similar high quality but reduced cell quantity compared with batches from the other patients with esrd, although yield was still above the predefined target minimum number of cells.Per the journal conclusion, manufacture of high-quality naive car-tregs from patients with esrd is safe and feasible.Root cause: a root cause assessment was performed for the reported hemoglobin decrease and anemia.Based on the available information a definitive root cause could not be determined but it is likely due to one or a combination of the possible causes listed below: * patient's underlying disease state * patient's blood physiology interferes with separation of cellular components and chamber triggering (i.E.Abnormal rbcs, hyperviscous plasma) * incorrect setting of collection preference * the presence of a small buffy coat which resulted in red cells getting collected along with the target cells.* inaccurate entry of the patient's hematocrit * inlet flow rate was too high to adequately separate red cells from buffy coat * rbc port height is too high * improper loading of the channel into the filler * hazy camera window which causes the light to diffuse around the collect port.This makes the collect port appear light, even when rbcs are flowing through the port.* lighting is too bright due to improperly calibrated diffuser plate.A root cause assessment was performed for the reported citrate reactions.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.A root cause assessment was performed for the hypertension, fatigue, asthenia.Based on the available information a definitive root cause could not be determined.Hypertension is a common side effect of therapeutic apheresis procedures.They are typically caused by the patient's disease state, the length of the procedure, the patient's sensitivity to the procedure and/or the hemodynamic stress of the procedure.Citation: bastian, h., lounnas-mourey, n., heimendinger, p., hsu, b. l., schreeb, k. h., chapman, c., culme-seymour, e., atkinson, g. f., & cantarovich, d.(2023).Feasibility of manufacture of chimeric antigen receptor-regulatory t cells from patients with end-stage renal disease. translational medicine communications, 8(1). https://doi.Org/10.1186/s41231-023-00150-y.
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Search Alerts/Recalls
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