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1.
Impact of antimicrobial drug-drug interactions on acute kidney injury after allogeneic hematopoietic cell transplantation
Wada, F., Arai, Y., Jo, T., Mizumoto, C., Kanda, J., Kitawaki, T., Nishikori, M., Yamashita, K., Takaori-Kondo, A.
Transplantation and cellular therapy. 2023
Abstract
Acute kidney injury (AKI) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Use of multiple antimicrobials is one of the major causes of post-transplant AKI, due the potential nephrotoxicity of each agent and drug-drug interactions (DDI). No satisfactory reports on DDI have appeared in the field of allo-HSCT, and we performed a retrospective analysis to compare the incidence of AKI within 100 days. In total, 465 transplant cases (416 patients) were included, and cumulative incidence of AKI was 40.0%. Incidence of AKI significantly reduced overall survival (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.95-3.55, p<0.01) and increased transplant-related mortality (HR 4.77, 95%CI 2.90-7.88, p<0.01). A higher incidence of AKI was significantly associated with the use of ciprofloxacin, cefepime, tazobactam/piperacillin, meropenem, vancomycin, liposomal amphotericin B, ganciclovir, and foscarnet. Among them, combinations with vancomycin plus tazobactam/piperacillin (HR 2.23. p=0.09 for interaction), ganciclovir plus cefepime (HR 5.93, p=0.04), and ganciclovir plus meropenem (HR 2.63, p=0.12) synergistically increased the risk of AKI, whereas combinations involving teicoplanin did not. This is the first report dealing with DDIs after allo-HSCT, and such combinations should be avoided so as to preserve renal function and to reduce AKI-related morbidity and mortality.
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2.
Protective effect of cryotherapy against oral mucositis among allogeneic hematopoietic stem cell transplant recipients using melphalan-based conditioning
Oku, S., Futatsuki, T., Imamura, Y., Hikita, H., Inada, A., Mizutani, S., Mori, Y., Kashiwazaki, H.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2023;31(9):521
Abstract
PURPOSE Oral cryotherapy is an effective method to prevent oral mucositis (OM) induced by chemotherapeutic agents, such as melphalan (Mel). However, there is limited data about cryotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients; thus, the current study aimed to examine the efficacy of cryotherapy among allo-HSCT recipients treated with Mel-containing regimens. METHODS Medical records of 78 consecutive allo-HSCT recipients were retrospectively analyzed. Baseline characteristics and clinical courses between the patients who received cryotherapy (cryotherapy group, n = 42) and those who did not (control group, n = 36) were compared, especially focusing on methotrexate (MTX) use as a part of graft-versus-host disease (GVHD) prophylaxis. RESULTS Binary logistic regression analysis revealed that a higher dose of Mel (OR, 3.82; 95%CI, 1.085-13.46; P = 0.037) or MTX use (OR, 7.61; 95% CI, 2.41-23.97; P < 0.001) was associated with the incidence of OM. MTX use was also significantly associated with the duration of OM (β = 0.515; 95% CI, 9.712-21.636; P < 0.001). Among 31 patients without MTX use, cryotherapy was associated with a significant reduction of OM development (0% in the cryotherapy group vs 35% in the control group, P = 0.021). We did not find such an association in 47 patients with MTX use. CONCLUSION Cryotherapy was useful to prevent the incidence of OM in allo-HSCT recipients in the cases without MTX for GVHD prophylaxis.
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Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation
Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., et al
Transplantation and cellular therapy. 2022;28(4):196-202
Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
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4.
The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation
Nakagaki, M., Kennedy, G. A., Gavin, N. C., Clavarino, A., Whitfield, K.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2022;:1-9
Abstract
PURPOSE Oral mucositis is a common complication during haematopoietic stem cell transplantation (HSCT). This study aimed to assess the incidence of severe mucositis in patients undergoing different HSCT regimens. METHODS This single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected. RESULTS Grade 3-4 oral mucositis was common in myeloablative total body irradiation (TBI)-based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced-intensity fludarabine/melphalan (FluMel) (43%) and carmustine/etoposide/cytarabine/melphalan (BEAM) autologous HSCT (41%). In contrast, grade 3-4 oral mucositis was less common in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%), all non-myeloablative regimens (0-9%) and high-dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity. CONCLUSIONS Severe oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.
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Effect of Keratinocyte Growth Factor on Hospital Readmission and Regimen-Related Toxicities after Autologous Hematopoietic Cell Transplantation for Lymphoma
El Jurdi, N., Fair, C., Rogosheske, J., Shanley, R., Arora, M., Bachanova, V., Betts, B., He, F., Holtan, S., Janakiram, M., et al
Transplantation and cellular therapy. 2021;27(2):179.e1-179.e4
Abstract
Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n?=?35) with historical controls (n?=?38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P?=?.04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P?=?.05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization.
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6.
Veno-occlusive disease risk in pediatric patients with acute myeloid leukemia treated with gemtuzumab ozogamicin before allogeneic hematopoietic cell transplantation
Duncan, C., St Martin, A., Pérez, W. S., Steinert, P., Zhang, M. J., Chirnomas, D., Hoang, C. J., Loberiza, F. R., Jr., Saber, W.
Pediatric blood & cancer. 2021;:e29067
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Abstract
BACKGROUND Gemtuzumab ozogamicin (GO) administered before allogeneic hematopoietic cell transplantation (alloHCT) has been linked to an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). PROCEDURE This retrospective analysis examined VOD/SOS risk and clinical outcomes in pediatric patients with acute myeloid leukemia who received myeloablative alloHCT in 2008-2011 with (n = 148) and without (n = 348; controls) prior GO exposure and were reported to the Center for International Blood and Marrow Transplant Research. RESULTS Cumulative incidences (95% confidence interval [CI]) of VOD/SOS and severe VOD/SOS, respectively, at 100 days were 16% (11-23%) and 8% (4-13%) for GO-exposed patients and 10% (7-13%) and 3% (2-5%) for controls. With a median follow-up of approximately 7 years, the 5-year adjusted overall survival probability (95% CI) after alloHCT was 51% (43-58%) and 55% (50-60%) for GO-exposed patients and controls, respectively; three (4%) and one (<1%) deaths were attributed to VOD/SOS. In multivariate analyses, GO exposure was observed to be associated with an increased risk of VOD/SOS at 100 days, but was not associated with overall survival, disease-free survival, relapse, or nonrelapse mortality. CONCLUSIONS Results suggest that GO treatment prior to alloHCT in pediatric patients may increase the risk of VOD/SOS but not death.
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Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation
Wysocka-Slowik, A., Gil, L., Slebioda, Z., Kregielczak, A., Dorocka-Bobkowska, B.
Annals of hematology. 2021
Abstract
This study was designed to investigate the frequency and severity of oral mucositis in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups based on the conditioning regimen used before transplantation. The intensity of oral inflammatory lesions induced by chemotherapy (oral mucositis) was evaluated according to a 5-point scale recommended by World Health Organization. Oral mucosa was investigated in all patients before the transplantation and during two subsequent stages of the post-transplantation procedure in relation to the conditioning regimen used. Mucositis in the oral cavity was observed in the majority of patients (66%) in the first week after transplantation, whereas the largest percentage of patients suffering oral lesions (74%) occurred in the second week after transplantation. A significantly higher percentage of patients with mucositis was observed in the group which underwent myeloablation therapy (74% of MAC and 50% of RIC patients in the first week; 83% of MAC and 53% of RIC patients in the second examination).The severity of mucositis after transplantation was higher in the MAC patients compared to the RIC patients. The highest mean value of the mucositis index was recorded in the second week in the MAC group (1.59). In AML sufferers receiving allo-HSCT, oral mucositis is a significant complication of the transplantation. This condition is more frequent and more severe in patients after treatment with myeloablation therapy.
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Post-Irradiation Hyperamylasemia Is a Prognostic Marker for Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Pediatric Population: A Retrospective Single-Centre Cohort Analysis
Baldo, F., Simeone, R., Marcuzzi, A., Grasso, A. G., Vidimari, R., Ciriello, F., Zanon, D., Maestro, A., Barbi, E., Maximova, N.
Journal of clinical medicine. 2021;10(17)
Abstract
BACKGROUND Total body irradiation (TBI) is a mandatory step for patients with acute lymphoblastic leukemia (ALL), undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the past, amylases have been reported to be a possible sign of TBI toxicity. We investigated the relationship between total amylases (TA) and transplant-related outcomes in pediatric recipients. METHODS We retrospectively analyzed the medical records of all the patients who underwent allogeneic HSCT between January 2000 and November 2019. The inclusion criteria were the following: recipient's age between 2 and 18, diagnosis of ALL, no previous transplantation, and use of TBI-based conditioning. The serum total amylase and pancreatic amylase were evaluated before, during, and after transplantation. Cytokines and chemokines assays were retrospectively performed. RESULTS 78 patients fulfilled the inclusion criteria. Fifty-seven patients were treated with fractionated TBI, and 21 with a single-dose regimen. The overall survival (OS) was 62.8%. Elevated values of TA were detected in 71 patients (91%). The TA were excellent in predicting the OS (AUC = 0.773; 95% CI = 0.66-0.86; p < 0.001). TA values below 374 U/L were correlated with a higher OS. The highest mean TA values (673 U/L) were associated with a high disease-progression mortality rate. The TA showed a high predictive performance for disease progression-related death (AUC = 0.865; 95% CI = 0.77-0.93; p < 0.0001). Elevated TA values were also connected with significantly higher levels of proinflammatory cytokines, such as TNF-a, IL-6, and RANTES (p < 0.001). CONCLUSIONS this study shows that TA is a valuable predictor of post-transplant OS and increased risk of leukemia relapse.
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Outpatient haploidentical hematopoietic stem cell transplant using post-transplant cyclophosphamide and incidence of hemorrhagic cystitis
Gutiérrez-Aguirre, C. H., Esparza-Sandoval, A. C., Palomares-Leal, A., Jaime-Pérez, J. C., Gómez-Almaguer, D., Cantú-Rodríguez, O. G.
Hematology, transfusion and cell therapy. 2020
Abstract
INTRODUCTION Hemorrhagic cystitis (HC) is a common complication of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), characterized by irritative symptoms of the urinary tract and a higher morbidity and mortality rate. The worldwide incidence is reported between 10% and 70%. The use of alkylating agents and BK viral infection are the most frequent etiologies. The aim of this study was to report the HC incidence in an outpatient haplo-HCST program with a reduced intensity-conditioning (RIC) regimen, cataloguing risk factors, complications and final outcomes. METHODS The medical database of patients who received a haplo-HSCT between January 2012 and November 2017 was retrospectively analyzed. Demographic variables, general characteristics and HC incidence were included. RESULTS One hundred and eleven patients were included, 30 (27%) of whom developed HC, most of them (70%) being grade II, with a 30-day (7-149) median time of post-transplant HC onset. The BK virus was detected in 71% of the urine samples analyzed. All HC patients responded to treatment, except two (6.6%), who died due to HC complications. CONCLUSIONS There was no difference in the HC incidence or severity, compared to that reported when performing haplo-HSCT in hospitalized patients, although the donor-recipient sex mismatch did relate to a higher HC incidence.
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Reduced risk of sinusoidal obstruction syndrome of the liver after Busulfan-Cyclophosphamide conditioning prior to allogeneic hematopoietic stem cell transplantation
El-Serafi, I., Remberger, M., Ringden, O., Torlen, J., Sundin, M., Bjorklund, A., Winiarski, J., Mattsson, J.
Clinical and translational science. 2019
Abstract
The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of busulfan was initiated in 2000 and the use of liver supportive drugs, such as ursodeoxycholic acid (UDCA) and N-acetyl-L-cysteine (NAC), were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-99 (16.2%) compared to 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46% and 27% at 100 days, 1 year and 5 years after HSCT respectively compared to 92%, 77% and 66% for those who did not develop SOS (P<0.001). In conclusion; the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and hence, improve the clinical outcome.