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Tocilizumab for Cytokine Release Syndrome Management after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis
Yao, J. M., Otoukesh, S., Kim, H., Yang, D., Mokhtari, S., Samara, Y., Blackmon, A., Arslan, S., Agrawal, V., Pourhassan, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplant (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. OBJECTIVES In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplant cyclophosphamide- (PTCy-) based graft-versus-host disease (GVHD) prophylaxis. STUDY DESIGN Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (MAC vs RIC/NMA), and CRS grading (1, 2 vs 3-4). Instead of 22 controls, we chose 21 patients because there was only one control matched with one TOCI treatment patient in one stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (HR=3.4 or higher) in transplant outcomes using a two-sided 0.05 test. The power would be reduced to about 20-30% if the difference was moderate (HR=2.0) using the same test. RESULTS No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range: 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% CI: 0.28-1.06, P=0.08). Median time to platelet engraftment was 34 days (range: 20-81) in TOCI and 28 days (range: 12-94) in NO-TOCI group (HR=0.56; 95% CI: 0.25-1.22, P= 0.19). Cumulative incidences of day +100 acute GVHD grades II-IV (P=0.97) and grades III-IV (P=0.47) were similar between the two groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% vs 24%; P=0.05). Rates of NRM (P=0.66), relapse (P=0.83), disease-free survival (P=0.86), and overall survival (P=0.73) were similar at 1-year post-HCT between the two groups. CONCLUSIONS Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore, using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.
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Mycophenolate mofetil increases the risk of diarrhea in allogeneic hematopoietic stem cell transplantation recipients
Lin, L., Hong, M., Fu, X.
The Journal of international medical research. 2023;51(10):3000605231206968
Abstract
OBJECTIVES Mycophenolate mofetil (MMF) was reported to be a main cause of diarrhea following organ transplantation. However, research on MMF-induced diarrhea following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently insufficient. This retrospective study examined the incidence of MMF-induced diarrhea among allo-HSCT recipients. METHODS Recipients were divided according to the receipt of MMF and the appearance of diarrhea. The differences in clinical information, MMF usage and trough concentrations, and the occurrence of diarrhea from the first day of conditioning treatment to 100 days after transplantation were analyzed. RESULTS In total, 32.9% of the recipients reported diarrhea. The incidence rate of diarrhea was higher in the MMF group than in the non-MMF group (40.0% vs. 16.7%). MMF-induced diarrhea usually occurred within 9 days of MMF initiation and persisted for 7.27 ± 3.54 days. The average body weight, MMF daily dose, and MMF trough concentration were higher in patients with diarrhea. CONCLUSION MMF increased the risk of diarrhea in allo-HSCT recipients, and the risk was related to the MMF dose and trough concentration. The difference in onset time could be a basis for identifying the cause of diarrhea in allo-HSCT recipients.
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Occurrence and influencing factors of cyclosporine A on the kidney injury following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis
Lu, R., Shi, Y., Yang, M., Yang, N., He, S., Xin, L., Qin, Y., Li, H., Zeng, L., Zou, K., et al
International immunopharmacology. 2023;122:110633
Abstract
OBJECTIVE Whether cyclosporine A (CsA) is a risk factor of kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been determined. We aim to comprehensively review the correlation and influencing factors between CsA and kidney injury in patients following allo-HSCT. METHODS We searched PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, VIP, Wanfang and CBM Database from inception to March 2022. Two researchers independently conducted literature screening, data extraction and quality assessment. Qualitative and quantitative methods were combined to analyze the data. RESULTS We included a total of 30 studies. Meta-analyses of total incidence of kidney injury related to CsA was 37.0% [95% CI (25.4%, 48.6%); n = 15]. The proportion of CsA-related acute kidney injury to total acute kidney injury following allo-HSCT was 59.7% [95% CI (49.1%, 70.3%); n = 9]. One study found that AKI had a significant association with CsA in multivariate analysis [RR = 6.173; 95% CI (4.032, 9.434)]. With respect to cyclosporine combination and nephrotoxicity, 6/9 studies demonstrated that the concomitant medications for CsA (especially aminoglycoside antibiotics and amphotericin B) had negative effect on kidney functions related to CsA in allo-HSCT patients. No consensus was reached for "dose of CsA", "duration of CsA use", "comorbidities" and "CsA levels" across studies. CONCLUSIONS CsA may be a risk factor for kidney injury in patients following allo-HSCT, especially the concomitant use of CsA and nephrotoxic medications.
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Feasibility of cyclosporine prophylaxis withdrawal in critically ill allogenic hematopoietic stem cell transplant patients admitted to the Intensive Care Unit with no GVHD
Saillard, C., Legal, P. H., Furst, S., Bisbal, M., Servan, L., Sannini, A., Gonzalez, F., Faucher, M., Vey, N., Blaise, D., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Twenty percent of allogenic hematopoietic stem cell transplantation (allo-HSCT) patients require intensive care unit (ICU) admission. Feasibility and long-term consequences of cyclosporine graft-versus-host disease (GVHD) prophylaxis withdrawal in the ICU are unknown. OBJECTIVES To assess the impact of cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients admitted to the ICU on GVHD incidence and to evaluate 6-months overall survival according to cyclosporine withdrawal and GVHD occurrence. STUDY DESIGN From 2010 to 2020, 101 critically ill allo-HSCT patients admitted to the ICU in our institution were included. All received cyclosporine as GVHD prophylaxis. None of them had GVHD at ICU admission. RESULTS Patients were admitted in the ICU after a median time of 11 days [5.5-18] after allo-HSCT. ICU, hospital mortality and 6-months mortality were 43.6%, 56.4% and 59.4% respectively. Cyclosporine was withdrawn for 52 and continued for 49 patients in the ICU. 38.6% (n=39) developed secondarily acute GVHD (aGVHD) after a median of 28 days (15-40) after cyclosporine stop. In 74.4% (n=29) of cases, patients developed aGVHD after ICU discharge, in hematology ward. Cyclosporine dosages were similar in both groups. Factors independently associated with aGVHD occurrence in multivariate analysis were cyclosporine withdrawal in the ICU (sHR=2.04, 95%CI=1.02-4.1, p=0.044), renal replacement therapy (RRT) (sHR=0.43, 95%CI=0.19-0.9, p=0.03) and fungal prophylaxis (sHR=2.62, 95%CI=1.35-5.07, p=0.004). Cyclosporine withdrawal in the ICU was associated with poorer 6-months overall survival (OS) (HR=1.96, 95%CI=1.16-3.33, p=0.012), but after adjusting on severity (SAPSII, vasopressors, mechanical ventilation and RRT requirement), 6-months OS did not differ (HR=1.35, 95%CI=0.76-2.42, p=0.3). GVHD occurrence after ICU stay was significantly associated with better 6-months OS in unadjusted (HR=0.53, 95%CI= 0.31-0.90, p= 0.02) and severity-adjusted analysis (HR=0.54, 95%CI=0.31-0.93, p=0.028). CONCLUSION Cyclosporine prophylaxis withdrawal in critically ill allo-HSCT patients in the ICU appears as feasible and did not impair long-term outcome.
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Impact of Defibrotide in the Prevention of Acute Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation
Tilmont, R., Yakoub-Agha, I., Ramdane, N., Srour, M., Coiteux, V., Magro, L., Odou, P., Simon, N., Beauvais, D.
The Annals of pharmacotherapy. 2022;:10600280211068177
Abstract
BACKGROUND Defibrotide is indicated for patients who develop severe sinusoidal obstructive syndrome following allogeneic hematopoietic cell transplantation (allo-HCT). Preclinical data suggested that defibrotide carries a prophylactic effect against acute graft-versus-host disease (aGVHD). OBJECTIVE The purpose of this study was to investigate the effect of defibrotide on the incidence and severity of aGVHD. METHODS This single-center retrospective study included all consecutive transplanted patients between January 2014 and December 2018. A propensity score based on 10 predefined confounders was used to estimate the effect of defibrotide on aGVHD via inverse probability of treatment weighting (IPTW). RESULTS Of the 482 included patients, 64 received defibrotide (defibrotide group) and 418 did not (control group). Regarding main patient characteristics and transplantation modalities, the two groups were comparable, except for a predominance of men in the defibrotide group. The median age was 55 years (interquartile range [IQR]: 40-62). Patients received allo-HCT from HLA-matched related donor (28.6%), HLA-matched unrelated donor (50.8%), haplo-identical donor (13.4%), or mismatched unrelated donor (7.0%). Stem cell source was either bone marrow (49.6%) or peripheral blood (50.4%). After using IPTW, exposure to defibrotide was not significantly associated with occurrence of aGVHD (HR = 0.97; 95% CI 0.62-1.52; P = .9) or occurrence of severe aGVHD (HR = 1.89, 95% CI: 0.98-3.66; P = .058). CONCLUSION AND RELEVANCE Defibrotide does not seem to have a protective effect on aGVHD in patients undergoing allo-HCT. Based on what has been reported to date and on these results, defibrotide should not be considered for the prevention of aGVHD outside clinical trials.
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Cytokine release syndrome during ATG/ATLG serotherapy for GVHD prophylaxis before allogeneic HSCT: incidence and early clinical impact according to ASTCT grading criteria
Knaus, H. A., Rottner, T., Baumann, C. K., Cserna, J., Mitterbauer, M., Schulenburg, A., Rabitsch, W., Wohlfarth, P.
Transplantation and cellular therapy. 2022
Abstract
Background Anti-thymocyte globulin (ATG)/Anti-T-lymphocyte globulin (ATLG) aids graft-versus-host disease (GVHD) prophylaxis in human leukocyte antigen-matched related and unrelated donor hematopoietic stem cell transplantation (HSCT). Its use is frequently accompanied by systemic infusion reactions attributable to cytokine release syndrome (CRS). However, detailed data on ATG/ATLG-induced CRS and its correlation with clinical outcome parameters are lacking. Objectives To analyze the incidence, characteristics, risk factors, and early clinical impact of CRS during ATG/ATLG administration before allogeneic HSCT according to the American Society of Transplantation and Cellular Therapy (ASTCT) CRS grading criteria. Study design We conducted a retrospective single-center analysis including consecutive recipients of allogeneic HSCT treated with ATG/ATLG as GVHD prophylaxis at the Medical University of Vienna, Austria, between January 1, 2014, and August 15, 2021. Multivariate regression models were used to explore risk factors of CRS and its association with clinical outcomes (acute GVHD II-IV, clinically significant cytomegalovirus infection, non-relapse mortality, overall survival) 6 months after HSCT. Results A total of 284 patients (median age: 54 [interquartile range: 45-61] years; f:m = 120:164) were included in the study. ATLG was used in 222 (78%) patients, ATG in 62 (22%) patients. 166 (58%) patients developed CRS grade ≥1 during ATG/ATLG administration. CRS was mostly mild, and 92% of the cases experienced CRS grades 1-2. Thirteen (5%) patients developed CRS grade 3, one patient CRS grade 4. No CRS-related death (grade 5) was observed. Patients with CRS showed a pronounced systemic inflammatory response as measured by inflammatory markers (i.e., C-reactive protein, interleukin-6, procalcitonin). In multivariate analysis, lymphoma as the underlying disease, high ATLG dose level of 60 mg/kg, and body weight were significantly associated with CRS. Patients with CRS grade ≥1 had a higher 6-month incidence of acute GVHD II-IV than non-CRS patients (24% vs. 14%, p=0.04). This effect remained statistically significant only for CRS grades 3-4 (subdistribution hazard ratio: 3.70 [95% confidence interval: 1.58-8.68]; p<0.01) after adjusting for relevant confounders. Other clinical outcome parameters were not affected by the occurrence of CRS. Conclusion In our cohort, CRS defined by ASTCT grading was a frequent but mostly mild complication following ATG/ATLG administration for GVHD prophylaxis. Our data suggest a possible interaction of (higher grade) CRS with increased risk for developing acute GVHD. Further studies to corroborate this finding are warranted, as it could inform the investigation of additional prophylactic interventions, such as interleukin-6 blockade, in this setting.
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Early Cardiac Toxicity Associated With Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation
Duléry, R., Mohty, R., Labopin, M., Sestili, S., Malard, F., Brissot, E., Battipaglia, G., Médiavilla, C., Banet, A., Van de Wyngaert, Z., et al
JACC. CardioOncology. 2021;3(2):250-259
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Editor's Choice
Abstract
BACKGROUND Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce. OBJECTIVES This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy. METHODS The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring. RESULTS The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no-PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival. CONCLUSIONS PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy.
PICO Summary
Population
Patients in a single centre in France undergoing allogeneic stem cell transplant for haematological malignancies (n=331)
Intervention
Patients who received post-transplant cyclophosphamide PT-Cy (n = 136)
Comparison
Patients who did not receive PT-Cy (n = 195)
Outcome
The cumulative incidence of early cardiac events (ECE) was 19% in the PT-Cy group and 6% in the no-PT-Cy group. The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival.
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Intrapatient variability in concentration/dose ratio of tacrolimus predicts transplant-associated thrombotic microangiopathy
Sagou, K., Fukushima, N., Ukai, S., Goto, M., Ozeki, K., Kohno, A.
International journal of hematology. 2020
Abstract
Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous. To clarify relationships between various parameters of TAC and early complications such as pre-engraftment immune reactions/engraftment syndrome, aGVHD, and transplant-associated thrombotic microangiopathy (TA-TMA), a total of 146 patients who underwent allo-HSCT were included. Intrapatient variabilities in the concentration and C/D ratio of TAC were estimated by intrapatient mean absolute deviation (iMAD). The mean concentration and C/D ratio of TAC were not significantly different between with and without complications. A strong association was observed between greater iMAD for TAC C/D ratio from days 15 to 21 and the development of TA-TMA. iMAD values for TAC C/D ratio of 11.4 or greater was a risk factor for TA-TMA and the cumulative incidence of nonrelapse mortality (NRM) was significantly higher in patients with iMAD values for TAC C/D ratio of 11.4 or greater. Intrapatient variability in the C/D ratio of TAC was associated with the incidence of TA-TMA and NRM and might be useful for predicting TA-TMA.
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Oral mucositis after tacrolimus/sirolimus or cyclosporine/methotrexate as graft-versus-host disease prophylaxis
Garming Legert, K., Ringdén, O., Remberger, M., Törlén, J., Mattsson, J., Dahllöf, G.
Oral diseases. 2020
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Abstract
OBJECTIVES To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following hematopoietic stem cell transplantation. SUBJECTS AND METHODS The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68, to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak, and duration of oral mucositis from the day -3 to day 24 post-transplant. RESULTS Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found. CONCLUSIONS The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in hematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate.
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The Pattern of Cyclosporine Nephrotoxicity and Urinary Kidney Injury Molecule 1 in Allogenic Hematopoietic Stem Cell Transplant Patients
Karimzadeh, I., Jafari, M., Davani-Davari, D., Ramzi, M.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2020
Abstract
OBJECTIVES The typical immunosuppressive regimen of hematopoietic stem cell transplant includes cyclosporine. However, cyclosporine nephrotoxicity is a concern. We studied cyclosporine nephrotoxicity epidemiology in hematopoietic stem cell transplant patients and compared the pattern and urinary levels of the KIM-1 kidney injury molecule versus serum and urine creatinine levels. MATERIALS AND METHODS The study covered 10 months at Namazi Hospital, Shiraz, Iran. All patients met the following criteria: > 15 years old, received allogenic hematopoietic stem cell transplant without history of acute or chronic kidney disease, and scheduled for at least 1 week of cyclosporine treatment. Urinary and serum levels of creatinine, urea, sodium, potassium, magnesium, and the KIM-1 kidney injury molecule were measured on days 0, 3, 5, 7, 10, and 14 of cyclosporine treatment. RESULTS Of 42 patients, one-third developed cyclosporine nephrotoxicity (30.95%), and median onset time was 15 days. Hypokalemia and hypomagnesemia were reported in 76.2% and 53.4% of the cohort, respectively. None of the demographic, clinical, and paraclinical parameters was significantly associated with cyclosporine nephrotoxicity. Median duration of hospital stay for patients with cyclosporine nephrotoxicity (41 days) was significantly higher (P < .001) than those without nephrotoxicity (29 days). Area under the curve for receiver operating characteristic showed that accuracy of serum creatinine (0.267; 95% CI, 0.11-0.43) at day 0 of cyclosporine treatment was significantly lower (P = .017) than the accuracy of urine creatinine (0.477; 95% CI, 0.28-0.67) and urine levels of the KIM-1 kidney injury molecule (0.594; 95% CI, 0.41-0.78). CONCLUSIONS Cyclosporine nephrotoxicity is a common adverse effect in the setting of hematopoietic stem cell transplant and occurs mostly within the first 2 weeks of cyclosporine treatment. Urine KIM-1 kidney injury molecule measurement had no overall superiority and no improved accuracy over serum or urine creatinine measurements for prediction or detection of cyclosporine nephrotoxicity.