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High risk of acute pulmonary toxicity with both myeloablative and non-myeloablative total body irradiation-based conditioning for allogeneic stem cell transplantation
Patel, P., Dillon, M., Niedzwiecki, D., Crowell, K. A., Horwitz, M. E., Wang, E., Kelsey, C. R.
Bone marrow transplantation. 2023
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2.
Clinical Features of AKI in the Early Post-Transplant Period Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation
Vergara-Cadavid, J., Johnson, P. C., Kim, H. T., Yi, A., Sise, M. E., Leaf, D. E., Hanna, P. E., Ho, V. T., Cutler, C. S., Antin, J. H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplant (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). Few studies have examined risk factors for AKI at engraftment, or its relationship with clinical outcomes. OBJECTIVE The objective of this study was to examine the incidence and risk factors for peri-engraftment AKI, as well as the association between AKI and overall survival and non-relapse mortality. METHODS We conducted a retrospective analysis of adult patients receiving reduced intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Peri-engraftment (day 0 to day 30) AKI incidence and severity was defined using modified Kidney Disease: Improving Global Outcomes criteria. Factors associated with peri-engraftment AKI risk were examined using Cox regression analysis. The impact of peri-engraftment AKI on overall survival and non-relapse mortality (defined as death without recurrent disease after HCT), was evaluated using Cox regression and Fine and Gray's competing risk model, respectively. Kidney recovery, defined as a return of serum creatinine within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 in relation to HCT. RESULTS Peri-engraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days [IQR 4-30] post-transplant. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (HR: 1.56, 95% CI: 1.20-2.03; p<0.001), fludarabine/melphalan conditioning (HR: 1.35, 95% CI: 1.01-1.81; p=0.05; compared to fludarabine/busulfan and fludarabine, cyclophosphamide, total body irradiation), HCT-Comorbidity Index ≥4 (HR: 1.43, 95% CI: 1.14-1.79; p=0.002), albumin <3.4 g/dl (HR: 2.04, 95% CI: 1.33-3.12; p=0.001), hemoglobin ≤12 (HR 1.96, 95% CI 1.38-2.78; p<0.001), supratherapeutic tacrolimus (HR 1.45, 95% CI 1.07 - 1.95; p=0.02), and baseline serum creatinine >1.1 mg/dl (HR: 1.87, 95% CI: 1.48-2.35; p<0.001). Peri-engraftment AKI was associated with worse overall survival (HR 1.40, 95% CI: 1.16-1.71; p<0.001) and non-relapse mortality (subdistribution HR 2.10, 95% CI: 1.52-2.89; p<0.001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, 2, and 3 AKI without KRT, respectively, and 4 of 16 (25%) patients were liberated from KRT. CONCLUSION Peri-engraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for peri-engraftment AKI. Peri-engraftment AKI is associated with worse overall survival and non-relapse morality, highlighting the importance of timely recognition and management of AKI.
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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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Post-transplant sinusoidal obstruction syndrome in adult patients with B-cell Acute Lymphoblastic Leukemia treated with pre-transplant Inotuzumab
Agrawal, V., Pourhassan, H., Tsai, N. C., Ngo, D., Koller, P., Malki, M. M. A., Salhotra, A., Ali, H., Aribi, A., Sandhu, K. S., et al
Transplantation and cellular therapy. 2023
Abstract
Sinusoidal obstruction syndrome (SOS) is potentially a life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), however, it is associated with increased risk of SOS among transplant recipients. Here, we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL that received inotuzumab and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low dose heparin was administered as well to patients receiving myeloablative conditioning. SOS occurred in 12 (26%) patients post-HCT, with a median onset of 11 days (range: 3-41). SOS was graded as very severe in 50% (n=6), severe in 25% (n=3), and mild in 25% (n=3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range: 3-34), with resolution of SOS in 67% (n=8) of patients. Mortality rate from SOS was 33% (n=4) and occurred with a median of 10 days from diagnosis (range: 3-31), and in patients graded as very severe (n=3) or severe (n=1). No significant difference in median duration between the last dose of inotuzumab and transplant (46 vs. 53 days, P=0.37), the use of myeloablative conditioning regimen (42% vs. 49%, P=0.75), number of lines of therapy prior to inotuzumab (P=0.79), the median number of administered cycles of inotuzumab (2 vs. 2, P=0.14), or receiving inotuzumab as the last therapy prior to HCT (67% vs. 66%, P=1.0) was observed between patients who did and did not develop SOS, respectively. Sirolimus-based graft versus host disease (GVHD) prophylaxis was utilized more frequently in the SOS group (75% vs. 29%, P<0.01), but there were no differences in the peak sirolimus level (P=0.81) or the median time to peak sirolimus level (7 vs. 3.5 days, P=0.39) between the two subgroups, respectively. In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with increased risk of SOS (HR=7.50 [95% CI:1.7-33.6, P<0.01]). In the SOS group, the 100-day mortality rate was 33% (n=4) and median overall survival (OS) post-HCT of 4.3 months (range: 0.2 - 57.2). In the group without SOS, the 100-day mortality rate was 14% (n=5) and the median OS post-HCT was 10.7 months (range: 0.52 - 39.6). Here, we showed that SOS is prevalent in transplant recipients who were treated with inotuzumab prior to transplant, and that sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients in our cohort.
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Interaction between High-Dose Intravenous Busulfan and Post-Transplant Cyclophosphamide on Hemorrhagic Cystitis after Allogeneic Hematopoietic Cell Transplantation
Carreira, A. S., Salas, M. Q., Remberger, M., Novitzky-Basso, I., Law, A. D., Lam, W., Pasic, I., Mazzulli, T., Cserti-Gazdewich, C., Kim, D. D. H., et al
Transplantation and cellular therapy. 2023
Abstract
This study investigates the incidence and predictors of hemorrhagic cystitis (HC) in 960 adults undergoing allo-HSCT. Two-hundred and fifty-two (26.5%) patients received MAC regimens, and 81.4% received high-dose IV busulfan (HD Bu). Six-hundred and ninety-five (72.4%) patients received PTCY-based prophylaxis, and 91.4% additionally received ATG and CsA (PTCY-ATG-CsA). 228 (23.8%) patients developed HC. The day +100 cumulative incidences of grades 2-4 and 3-4 HC were 11.1% and 4.9%. BK virus was isolated in 58.3% of urinary samples. Using HD BU myeloablative regimens increased the risk for grade 2-4 HC (HR 1.97, P=0.035), and HD BU combined with ATG-PTCY-CsA increased this four times (HR 4.06, HR<0.001) for grade 2-4 HC compared to patients who received neither of these drugs. A significant correlation was documented between grade II-IV aGVHD and grade 2-4 HC (HR 2.10, P<0.001). Moreover, patients with BK-POS grade 2-4 HC had lower 1-year OS (HR 1.51, P=0.009) and higher NRM (HR 2.31, P<0.001), and patients with BK-NEG grade 2-4 HC had comparable post-transplant outcomes. In conclusion, intravenous HD Bu was identified as a predictor for grade 2-4 HC. Moreover, when HD Bu was combined with PTCY-ATG-CsA, the risk increased four-fold. Based on the results provided by this study, preventing the onset of HC, especially in high-risk patients, is mandatory as its presence significantly increases the risk for mortality.
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Fludarabine-induced bradycardia in allogeneic hematopoietic stem cell transplantation: A retrospective study
Çelik, S., Güven, Z. T., Altınsoy, A., Tubay Ş, E., Keklik, M., Ünal, A.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231189868
Abstract
INTRODUCTION Fludarabine, a purine analog, is getting more attention with the increasing use of reduced intensive conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The side effect of bradycardia was observed in only a few cases reported in the literature. In clinical practice, bradycardia can be asymptomatic or cause syncope and cardiac arrest. This study aimed to evaluate the bradycardia side effect of fludarabine used in the conditioning regimen in allo-HSCT recipients and to increase awareness of this issue. METHODS This retrospective study included 73 patients who received fludarabine in the allo-HSCT conditioning regimen between January 2015 and January 2021. Patients with and without bradycardia were compared regarding demographic data, allo-HSCT characteristics, electrolyte values, fludarabine administration dose and duration, and survival. Univariate and multivariate analyzes were performed to evaluate independent predictors for fludarabine-induced bradycardia. RESULTS Fludarabine administration doses and days were higher in the bradycardia group, but no statistically significant difference was observed. In the multivariate analysis, age was the only independent predictor of fludarabine-induced bradycardia (odds ratio (OR) 0.93, 95% confidence interval (CI): 0.89-0.98, p = 0.007). The median age in the group with bradycardia was 19 years younger than those without bradycardia (34 (19-49) vs 53 (19-69), p = 0.005). In 11 (84.6%) of the patients who had bradycardia, bradycardia improved with the discontinuation of fludarabine alone, but atropine was administered in 2 (15.4%) patients. CONCLUSION Age was the only independent predictor of fludarabine-induced bradycardia; therefore, close heart rate monitoring is recommended during fludarabine administration, especially in younger patients.
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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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Cyclophosphamide-induced cardiotoxicity at conditioning for allogeneic hematopoietic stem cell transplantation would occur among the patients treated with 120 mg/kg or less
Marumo, A., Omori, I., Tara, S., Otsuka, Y., Konuma, R., Adachi, H., Wada, A., Kishida, Y., Konishi, T., Nagata, A., et al
Asia-Pacific journal of clinical oncology. 2022;18(5):e507-e514
Abstract
Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.
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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.