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This report is being filed to provide additional information in h.6 and h.11.Investigation: an investigation was conducted for a journal article that references terumo bct product.Journal article, titled ¿extracorporeal photopheresis in pediatric and adult patients with graft-versus-host disease¿ by ionete et al was reviewed with primary purpose of screening for allegations of terumo bct device causing or contributing to death/injury or device malfunctions.Summary of terumo bct product in relation to the journal article: 2.3.Ecp treatment in this study, the ¿off-line¿ technique was used, which involves two distinct steps [25]: (i) collection of mononuclear cells (mncs, buffy-coat) using continuous flow cell separators.This procedure was initially performed using the cobe spectra (terumo bct) until 2017.Then, the optia spectra (terumo bct) was used under the cmnc protocol.Mnc apheresis was performed using a central venous catheter (cvc) with anticoagulant citrate dextrose solution a (acd-a) as the anticoagulant, at a ratio of 1:12 to 1:13, treating a total blood volume (tbv) between 1.5 to 2 times the patient¿s tbv.For children weighing less than 25 kg, a custom prime with 300 ml irradiated erythrocyte mass was used for apheresis.(ii) ex vivo treatment.The apheresis-harvested buffy-coat was incubated ex-vivo with 8-mop (at a final concentration of 200 ng/ml) and then exposed to uva irradiation (2 j/cm2).This step was initially performed using the mts uva pit device (pit medical systems gmbh) until february 2022 and subsequently performed using the lumi-light (pelham) device starting on january 2023.The final product was reinfused into the patient on the same day.The initiation and frequency of ecp sessions varied widely, with a median of 11 sessions and a range of 2 to 43 sessions.3.Results 3.1.Patient characteristics a retrospective medical evaluation was performed utilizing anonymized patient-level data extracted from the electronic medical records of 30 individuals who received ecp treatment for acute (n = 20) or chronic gvhd (n = 9) and one individual with overlap syndrome at the department of bone marrow transplantation unit and stem cell bank.The overlap case was included in the analysis as chronic gvhd because the patient presented cgvhd characteristics.At the initiation point of ecp treatment, all patients had previously received systemic corticosteroids and other immunosuppressive therapies for gvhd.Out of the total, 29 patients received peripheral blood stem cell grafts for conditions such as acute myeloid leukemia (aml), acute lymphoblastic leukemia (all), aplastic anemia (aa), hodgkin lymphoma (hl), non-hodgkin lymphoma (nhl), multiple myeloma (mm) and myelodysplastic syndrome (mds), except for one patient who received a bone marrow graft.One patient received a bone marrow graft from a mismatched unrelated donor (9/10).On day +22, the patient developed acute gvhd with skin involvement.Ecp sessions were initiated 10 days after the onset of gvhd, leading to complete resolution of the acute skin gvhd.However, the patient later passed away from other causes.The other patients received either a matched unrelated donor (mud, 50%) or a matched sibling donor (msd, 26.67%), and 23.33% had a haploidentical donor (haplo).The median time from agvhd onset to ecp was 11.5 days (range: 3 days¿9 months), while for cgvhd, the median time was 90 days (range: 2 days¿9 months).The median age of the pediatric patient cohort was 8 years, with a gender distribution of 45.45% females (5 patients) and 54.55% males (6 patients).In contrast, the adult patient cohort had a median age of 37 years, with a significant gender imbalance of 68.42% females (13 patients) versus 31.58% males (6 patients).In our study, the cell collection efficiency yielded an average of 38.1 × 109/l white blood cell (wbcs) using the ¿offline¿ system.The total average procedure time was 159 min [126.7¿199.3], with an average buffy coat volume of 125 ml [57¿222].Agvhd was graded ii for two patients (10%), iii for six (30%), and iv for twelve patients (60%).The distribution of cgvhd cases is relatively balanced across the staging categories.The moderate stage has the highest occurrence at 40%.Both mild and severe stages each represent 30% of the total cases.3.2.Adverse events after ecp wbc counts decreased during the ecp treatment, dropping from a median of 4.4 × 109/l (range: 1.7¿9 × 109/l) before treatment to 3.95 × 109 g/dl (range: 1.1¿8.8 × 109/l) after treatment (p = 0.0251).Hemoglobin levels also decreased from a median of 9 g/dl (range: 7.6¿15.2) before treatment to a median of 8.6 (range: 6.8¿16.4) after treatment (not statistically significant, ns).Hematocrit levels remained stable, with a median of 26.1% (range: 21.1¿43.6) before treatment, dropping to 24.2% (range: 19.6¿39.6) after treatment (p = <0.0001).Thrombocyte counts decreased from a median of 69.65 × 109/l (range: 12¿409.6) before treatment to a median of 52.7 × 109/l (range: 10¿327.5 × 109/l) after treatment (p = <0.0001).Previous research has revealed comparable findings on blood parameters [26].While ecp can have an impact on the levels of hemoglobin, hematocrit, leukocytes, lymphocytes, and thrombocytes, not all changes are clinically significant or solely attributable to ecp.However, it is important to note that there is a substantial risk of anemia (maximum grade 3 using ctcae grading) and thrombocytopenia emerging over time in patients receiving ecp treatment, emphasizing the need for consistent monitoring of blood parameters.Despite these occurrences, the adverse events were managed effectively, and no grade 4 or higher hematologic toxicities were reported.One non-hematological adverse effect observed during extracorporeal photopheresis (ecp) was hypocalcemia, which was classified as grade 2 according to ctcae.For moderate to severe hypocalcemia, intravenous calcium gluconate was commonly administered.3.3.Clinical response of agvhd after ecp treatment ecp treatment for agvhd showed an overall response rate (orr) of 60%, including either a complete (cr) or partial response (pr), and an overall survival rate (os) of approximately 40% (with three patients dying from causes unrelated to ecp).Notably, the use of ecp as a second-line therapy was associated with better responses in agvhd patients.The majority of patients had skin involvement (66.7%).Regarding agvhd, 20% of patients had grade i-ii (n = 4), grade iii 15% (n = 3), or grade iv 20% (n = 4) involvement, with an orr of 81.8%.All patients with grades i-iii of agvhd achieved a cr.Among those with grade iv agvhd, two patients obtained an orr.This suggests that while ecp can still be beneficial for severe cases, it may not be as effective as it is for less severe cases.The six-month os for patients with skin agvhd was 72%, with the one-year survival rate dropping to 40%.It is important to note that three patients passed away due to causes unrelated to gvhd had responded to ecp therapy.Next in frequency were cases of agvhd with 33.3% gastrointestinal involvement (gi).Of these, 15% of patients had grade iii involvement (n = 3) with two achieving a cr while 30% had grade iv involvement (n = 6).At these higher severity levels, ecp¿s effectiveness was lower, with only one patient achieving a partial response (pr).3.4.Clinical response of cgvhd after ecp treatment for cgvhd, 70% of patients had an orr to treatment, with a higher os of 60% (with one patient dying from other causes).In the case of skin cgvhd, 20% of patients had mild (n = 2), moderate 40% (n = 4), or severe 30% (n = 3) involvement.Additionally, among cgvhd patients with skin involvement, 13.3% experienced ocular involvement, 13.3% mucous membrane, 13.3% gastrointestinal, 6.7% connective tissue, and 3.3% genital involvement.In total, 50% (n = 5) of patients with moderate and severe skin cgvhd achieved a cr with an orr of 77.7%.The os at six months was 100%, while the one-year survival rate was 78%, with one patient who responded to ecp treatment passing away due to causes unrelated to gvhd.Only one cgvhd patient initially presented with moderate lung involvement (3.3%), while two others developed pulmonary gvhd during the course of their disease.All these patients did not survive.Among all patients with gi involvement, 50% had a clostridium difficile infection (which constitutes 16.7% of the total patient cohort).All patients with this infection did not survive.Eleven patients were treated with second-line ecp therapy (nine with agvhd, two with cgvhd), eleven with third-line therapy (seven with agvhd, four with cgvhd), and eight with fourth-line therapy (four with agvhd, four with cgvhd) (table 3).Patients with agvhd or cgvhd who started ecp treatment within two weeks of gvhd onset responded in 50% of cases.In contrast, patients who began ecp treatment later than two weeks achieved a 75% orr.For those who started ecp treatment earlier, the transition from a femoral central venous catheter (cvc) to a ¿long life¿ cvc typically resulted in a longer pause in ecp sessions.This interruption could be a possible explanation for the lower response rates observed in patients who initiated treatment within two weeks of gvhd onset.Patients who achieved a cr to ecp treatment began therapy an average of 19.11 days after gvhd onset.Those with a pr started treatment an average of 92.89 days after gvhd onset, which is significantly later compared to the complete responders.Patients who did not respond to ecp started treatment an average of 44.67 days after gvhd onset.Despite these differences, statistical analysis using the bonferroni test revealed no significant variations in response based on the timing of ecp initiation (p > 0.05 for all comparisons).These findings suggest that the timing of ecp initiation relative to gvhd onset does not significantly impact the treatment response.However, larger studies are needed to confirm these results and to investigate other factors that might affect ecp treatment outcomes.The clinical responses following ecp were not correlated with the baseline gvhd or with the age patients in the pediatric and adult groups.Furthermore, there was no correlation observed between clinical responses and sex and hla match.On may 24, 2019, the fda approved ruxolitinib for sr-agvhd; in september 2021, it was approved for sr-cgvhd in adult and pediatric patients 12 years and older [27,28].In our cohort, 23% (n = 8) of patients were treated with ruxolitinib as a third- or fourth-line therapy after initiation of ecp treatment.For seven patients, ecp and ruxolitinib were administered simultaneously.In total, 50% of these patients (n = 4) achieved an orr to the treatment.For one patient, ruxolitinib replaced ecp.He developed conjunctival and cutaneous gvhd and initially responded completely after 43 sessions of ecp.However, the skin response was not maintained after discontinuing ecp.The cutaneous gvhd completely remitted after the introduction of ruxolitinib.4.Discussion lung involvement did not respond to ecp therapy, which is consistent with the literature reports [31].In our group, three patients had pulmonary gvhd, none of whom survived.This included one patient with isolated pulmonary gvhd and two others who developed pulmonary gvhd during the course of their disease, initially starting ecp for skin involvement.One patient died from a relapse of the underlying leukemia rather than from gvhd, highlighting that gvhd is not always accompanied by the graft-versus leukemia (gvl) effect.[32].Although the peripheral venous access is preferred for apheresis, all of our patients required central venous catheter in order to perform apheresis procedures for ecp.Often, for many patients, a central venous catheter was placed in the femoral vein at the beginning of the apheresis sessions.During the apheresis, we faced two types of problems: catheter-related problems (insufficient flow rate up to blockage in some cases) and citrate related problems (hypocalcemia, solved by increasing the flow rate of prophylactic calcium gluconate infusion).Another issue linked to central venous access is the elevated risk of bacteremia due to potential transmission of skin microbiota into the bloodstream, thereby increasing the risk of clostridium difficile infection, especially in patients with gastrointestinal involvement, which was correlated with high mortality in our cohort.Clostridium difficile infections are a frequent complication in these patients due to the numerous antibiotic regimens they receive during the course of their disease.Managing clostridium difficile infections in daily practice proved to be quite challenging.During apheresis, the back-up device was transported to the patient¿s ward and remained there until the ecp sessions concluded.This procedure required both a doctor and a nurse to perform the treatment in the isolation room, which was a logistical challenge for our small team.Simultaneously, medical personnel needed to be present in the dedicated room to manage other apheresis procedures.Therefore, it is essential to investigate whether clostridium difficile is the trigger for the intestinal inflammation that subsequently activates lymphocytes.To address microbiota imbalances and treat gvhd triggered by this inflammation, we are exploring the use of fecal transplantation for these patients.Conclusion: despite limitations, such as heterogeneity, small numbers in the patient cohort, and the concomitant use of other immunosuppressive medications or ruxolitinib, ecp demonstrated better response rates with extended treatment durations and no detectable complications over a 38-week period.As for skin agvhd, progress is seen from one session to the next.In addition, this type of gvhd determines the most favorable response to ecp therapy.However, the absence of standardization in the application of ecp, including methods such as ¿online¿ vs.¿offline¿ systems, initiation timing, treatment schedules, and dose reduction protocols, remain a significant obstacle.Despite these uncertainties, ecp¿s favorable safety profile makes it a promising alternative to other immunosuppressive therapies.Consequently, clinical trials are essential to determine the optimal use of ecp in allo-hsct, including its prophylactic use in haploidentical transplants and its use as part of initial combination therapy.Further well-designed studies are necessary to better understand the mechanism of ecp, optimize treatment timing, and identify biomarkers to determine patient benefit.Since this was a journal publication to evaluate the efficacy and safety of extracorporeal photopheresis in pediatric and adult patients with graft-versus-host disease performed from may 2015 to december 2023, the lot numbers were not requested; therefore, a disposable lot history search could not be conducted.Since this was a journal publication to evaluate the efficacy and safety of extracorporeal photopheresis in pediatric and adult patients with graft-versus-host disease performed from may 2015 to december 2023, 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.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 was performed for the catheter-related problems (insufficient flow rate up to blockage in some cases).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: * flow rates were set too high relative to the size of the catheter.* obstructions in the catheter.* misplacement of the catheter.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.
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