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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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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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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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4.
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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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.
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Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Imus, P. H., Tsai, H. L., DeZern, A. E., Jerde, K., Swinnen, L. J., Bolaños-Meade, J., Luznik, L., Fuchs, E. J., Wagner-Johnston, N., Huff, C. A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.
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Azithromycin may increase hematologic relapse rates in matched unrelated donor hematopoietic cell transplant recipients who receive anti-thymocyte globulin, but not in most other recipients
Sheshadri, A., Saliba, R., Patel, B., Ahmed, T., Bueno, L. C., Arain, M. H., Mehta, R. S., Popat, U. R., Hosing, C. M., Rondon, G., et al
Bone marrow transplantation. 2020
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Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide
Arango, M., Combariza, J. F.
Hematology/oncology & stem cell therapy. 2017;10(2):79-84
Abstract
OBJECTIVE/BACKGROUND Noninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients. METHODS A retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out. RESULTS Thirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5h (range, 9.5-100h) and median peak temperature was 39.0degreeC (range, 38.1-40.5degreeC). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96h of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion. CONCLUSION Fever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis.
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A Time-to-Event Model for Acute Kidney Injury after Reduced-Intensity Conditioning Stem Cell Transplantation Using a Tacrolimus- and Sirolimus-based Graft-versus-Host Disease Prophylaxis
Pinana, J. L., Perez-Pitarch, A., Garcia-Cadenas, I., Barba, P., Hernandez-Boluda, J. C., Esquirol, A., Fox, M. L., Terol, M. J., Queralto, J. M., Vima, J., et al
Biology of Blood & Marrow Transplantation. 2017;23(7):1177-1185
Abstract
There is a paucity of data evaluating acute kidney injury (AKI) incidence and its relationship with the tacrolimus-sirolimus (Tac-Sir) concentrations in the setting of reduced-intensity conditioning (RIC) after allogeneic stem cell transplantation (allo-HSCT). This multicenter retrospective study evaluated risk factors of AKI defined by 2 classification systems, Kidney Disease Improving Global Outcome (KDIGO) score and "Grade 0-3 staging," in 186 consecutive RIC allo-HSCT recipients with Tac-Sir as graft-versus-host disease prophylaxis. Conditioning regimens consisted of fludarabine and busulfan (n=53); melphalan (n=83); or a combination of thiotepa, fludarabine, and busulfan (n=50). A parametric model, with detailed Tac-Sir consecutive blood levels, describing time to AKI was developed using the NONMEM software version 7.4. Overall, 81 of 186 (44%) RIC allo-HSCT recipients developed AKI with a cumulative incidence of 42% at a median follow-up of 25 months. Time to AKI was best described using a piecewise function. AKI-predicting factors were melphalan-based conditioning regimen (HR,1.96; P<.01), unrelated donor (HR, 1.79; P=.04), and tacrolimus concentration: The risk of AKI increased 2.3% per each 1-ng/mL increase in tacrolimus whole blood concentration (P<.01). In multivariate analysis, AKI grades 2 and 3 according to KDIGO staging were independent risk factors for 2-year nonrelapse mortality (HR, 2.8; P=.05; and HR, 6.6; P<.0001, respectively). According to the KDIGO score, overall survival decreased with the increase in severity of AKI: 78% for patients without AKI versus 68%, 50%, and 30% for grades 1, 2, and 3, respectively (P<.0001). In conclusion, AKI is frequent after Tac-Sir-based RIC allo-HSCT and has a negative impact on outcome. This study presents the first predictive model describing time to AKI as a function of tacrolimus drug concentration. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.