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Comparison of pulmonary toxicity after total body irradiation- and busulfan-based myeloablative conditioning for allogeneic hematopoietic stem cell transplantation for pediatric patients
Liu, K. X., Poux, N., Shin, K. Y., Moore, N., Chen, Y. H., Margossian, S., Whangbo, J. S., Duncan, C. N., Lehmann, L. E., Marcus, K. J.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS) and the impact of different myeloablative conditioning remains incompletely described. OBJECTIVE To compare the acute and long-term incidence of pulmonary toxicity after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. STUDY DESIGN We conducted a retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana Farber Cancer Institute/Boston Children's Hospital between 2008-2018. Pulmonary toxicity was graded using Common Terminology Criteria for Adverse Events v5.0. The primary objective was to compare cumulative incidence of grade ≥3 and grade 5 pulmonary toxicity after TBI- and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors that associate with pulmonary toxicity and overall survival using competing risk analysis and Cox regression analyses, respectively. RESULTS Incidence of grade ≥3 pulmonary toxicity (29.2% vs. 34.7% at 2 years, p=0.26) or grade 5 pulmonary toxicity (6.2% vs. 6.1% at 2 years, p=0.47) did not differ between TBI (n=227) and busulfan (n=84) groups, respectively. Age (Hazard Ratio [HR]: 1.70, 95% Confidence Interval [CI]: 1.11-2.59, p= 0.01), grade ≥2 pulmonary toxicity prior to allo-HSCT or pre-existing pulmonary conditions (HR: 1.84, 95% CI: 1.24-2.72, p<0.01), acute graft versus host disease (GVHD) (HR: 2.50, 95% CI: 1.51-4.14, p<0.01), and chronic GVHD (HR: 2.61, 95% CI: 1.26-5.42, p=0.01) were associated with grade ≥3 pulmonary toxicity on multivariable analysis. Grade ≥3 pulmonary toxicity was associated with worse overall survival (81.1% vs. 61.5% at 2 years; p<0.01). CONCLUSION In pediatric allogeneic transplant recipients, rates of pulmonary toxicity were similar between TBI-based and busulfan-based myeloablative regimen. Age, the presence of pulmonary toxicity or pre-existing pulmonary conditions prior to transplant, and the development of either acute or chronic GVHD were associated with grade ≥3 pulmonary toxicity post-transplant. Furthermore, the occurrence of grade 3-4 pulmonary toxicity post-transplant was associated with inferior overall survival.
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High dose busulfan - fludarabin (Bu - Flu) conditioning and low alveolar volume as predictors of pulmonary complications after allo-PBSCT in children
Lee, H. J., Kim, S. K., Lee, J. W., Chung, N. G., Cho, B.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The purpose of this study was to the investigate risk factors and predictors of infectious and noninfectious pulmonary complications (PCs) after allogeneic hematopoietic stem cell transplantation in children. METHODS We conducted a retrospective analysis of the post-transplantation PCs of 240 patients who received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) between 2009 and 2018. Transplant related variables, pre-transplant baseline spirometry, body plethysmography, and diffusing capacity were analyzed for association with the development of infectious pulmonary complications (IPCs) and noninfectious pulmonary complications (NIPCs). RESULTS The PC group showed statistically significant lower overall survival (77.8% vs 50.6%, p < 0.001), higher disease related mortality (DRM, 26.6% vs 54.4%, p < 0.001), and higher non-relapse mortality (NRM, 5.9% vs 31.6%, p < 0.001) than the control group. The number of patients receiving high-dose busulfan 520 mg/m2 (Bu 520) and fludarabin 160 mg/m2 (Flu 160) conditioning was greater in both the IPC and NIPC groups. In the multivariate Cox hazard regression analysis, Bu 520 significantly increased the risk of NIPC (HR, 1.99; 95% CI, 1.13-3.49; p = 0.016), and Flu 160 was a predictor of IPC (HR, 1.99; 95% CI, 1.13-3.49; p = 0.016). The Bu 520 + Flu 160 regimen statistically significantly increased the risk of NIPC (HR, 1.92; 95% CI, 1.09-3.37; p = 0.023). In the multivariate analysis using baseline lung function before transplantation, alveolar volume (VA) grades 3 and 4 and lung function score (LFS) VA categories III and IV increased the risk for both IPC and NIPC. CONCLUSION In summary, we identified the high-dose Bu - Flu conditioning regimen as an independent risk factor for NIPC after transplantation. The impairment of diffusing capacity before transplantation, especially VA reduction, contributes to the risk of post-transplant pulmonary complications, and pre-transplant risk can be estimated by grading the degree of insufficiency of VA and LFS VA.
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Myeloablative TBI is associated with increased risk of pulmonary GVHD in patients undergoing allogeneic hematopoietic stem cell transplant
Baranwal, A., Byun, J., Ritz, E., Kadanagowd, A., Murphy, D., Marinovic, D. A., Wang, D., Okwuosa, T., Katz, D., Varma, A., et al
Bone marrow transplantation. 2022
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Pulmonary Toxicity after Total Body Irradiation-An Underrated Complication? Estimation of Risk via Normal Tissue Complication Probability Calculations and Correlation with Clinical Data
Oertel, M., Kittel, C., Martel, J., Mikesch, J. H., Glashoerster, M., Stelljes, M., Eich, H. T.
Cancers. 2021;13(12)
Abstract
Total body irradiation (TBI) is an essential part of various conditioning regimens prior to allogeneic stem cell transplantation, but is accompanied by relevant (long-term) toxicities. In the lungs, a complex mechanism induces initial inflammation (pneumonitis) followed by chronic fibrosis. The hereby presented analysis investigates the occurrence of pulmonary toxicity in a large patient collective and correlates it with data derived from normal tissue complication probability (NTCP) calculations. The clinical data of 335 hemato-oncological patients undergoing TBI were analyzed with a follow-up of 85 months. Overall, 24.8% of all patients displayed lung toxicities, predominantly pneumonia and pulmonary obstructions (13.4% and 6.0%, respectively). NTCP calculations estimated median risks to be 20.3%, 0.6% and 20.4% for overall pneumonitis (both radiological and clinical), symptomatic pneumonitis and lung fibrosis, respectively. These numbers are consistent with real-world data from the literature and further specify radiological and clinical apparent toxicity rates. Overall, the estimated risk for clinical apparent pneumonitis is very low, corresponding to the probability of non-infectious acute respiratory distress syndrome, although the underlying pathophysiology is not identical. Radiological pneumonitis and lung fibrosis are expected to be more common but require a more precise documentation by the transplantation team, radiologists and radiation oncologists.
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Impact of lung function on bronchiolitis obliterans syndrome and outcome after allogeneic hematopoietic cell transplantation with reduced intensity conditioning
Duque-Afonso, J., Ihorst, G., Waterhouse, M., Zeiser, R., Wasch, R., Bertz, H., Muller-Quernheim, J., Finke, J., Marks, R., Prasse, A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Lung function deterioration contributes to treatment-related morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Better understanding of impaired lung function including bronchiolitis obliterans syndrome (BOS) as chronic manifestation of Graft-versus-Host-Disease (GvHD) might improve outcomes of patients after allo-HCT. In order to detect early pulmonary function tests abnormalities associated with BOS incidence and outcome after allo-HCT, we performed a retrospective analysis of homogenous-treated 445 patients (median age 61.9 years, range 19-76) with a reduced intensity/toxicity conditioning protocol. The cumulative incidence of BOS was 4.1% (95% CI 2.6-6.4) at 1 year and 8.6% (95% CI 6.3-11.6) at 5 year after allo-HCT with a median follow-up of 43.2 months (range 3.3-209). In multivariate analysis, pre-existence of moderate small airway disease reflected by decreased mid-expiratory flows prior allo-HCT was associated with increased risk for BOS development. In addition, severe small airway disease prior allo-HCT and combined restrictive/obstructive lung disease at day +100 after allo-HCT were associated with higher risk for non-relapse mortality due mainly to pulmonary cause of death. In summary, we identified novel pulmonary function tests abnormalities prior and after allo-HCT associated with BOS development and non-relapse mortality. These findings might help to identify a risk population and result in personalized GvHD prophylaxis and preventive or early therapeutic interventions.
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Radiologic evaluation of pulmonary injury following carmustine- and cyclophosphamide-based preparative regimen for autologous peripheral blood stem cell transplantation in children
Kim, Y. J., Kim, W. S., Choi, Y. H., Cheon, J. E., Choi, J. Y., Kang, H. J., Park, J. E., Ryu, Y. J., Kim, I. O.
Pediatric radiology. 2018
Abstract
BACKGROUND Toxicity of carmustine and cyclophosphamide can cause pulmonary injury after hematopoietic stem cell transplantation. OBJECTIVE To evaluate the radiologic findings of pulmonary injuries following carmustine- and cyclophosphamide-based preparative regimens in children. MATERIALS AND METHODS From 2010 to 2014, 35 children received carmustine- and cyclophosphamide-based preparative regimens. Fourteen of 35 children presented with symptoms and radiologic abnormalities. Eight of 14 children had no evidence of infection, cardiogenic edema, or other explainable causes. We retrospectively analyzed their chest radiographs and CT scans for ground-glass opacity, consolidation, septal thickening and pleural effusion. RESULTS Major chest radiographic findings were bilateral diffuse ground-glass opacity (n=8) and septal thickening (n=7). CT findings were multifocal patchy (n=4) or inhomogeneously diffuse (n=4) ground-glass opacity, multifocal consolidations (n=7) and septal thickening (n=7). All of these lesions at CT were bilateral, but showed lower lobe predominance in 88, 100, and 63%, respectively. There was no central/peripheral or anterior/posterior predilection. Six children had small pleural effusions, which were bilateral in five children. CONCLUSION Bilateral ground-glass opacity with or without consolidation, septal thickening and pleural effusion were common radiologic findings in pulmonary injury following carmustine- and cyclophosphamide-based preparative regimens.
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Pulmonary function after hematopoietic stem cell transplantation is significantly better in pediatric recipients following reduced toxicity compared with myeloablative conditioning
Majzner, R., Sandoval, C., Dozor, A. J., Jin, Z., van de Ven, C., Dalal, R., Morris, E., Harrison, L., Wolownik, K., Fabricatore, S., et al
Bone Marrow Transplantation. 2016;51(11):1530-1532