-
1.
Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review
Ehler, E. D., Turcotte, L. M., Skamene, S., Baker, K. S., Das, S. K., Constine, L. S., Yuan, J., Dusenbery, K. E.
International journal of radiation oncology, biology, physics. 2023
Abstract
PURPOSE Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS. METHODS AND MATERIALS A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data. RESULTS Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy(-1) (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process. CONCLUSIONS This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.
-
2.
Incidence and predictors of idiopathic pneumonia syndrome in hematopoietic stem cell transplant patients: a nationwide registry study
Liu, M. A., Lee, C. C., Phung, Q., Dao, Q. L., Tehrani, B., Yao, M., Li, C. C., Wu, K. H., Chen, T. C., Gau, J. P., et al
International journal of hematology. 2022
Abstract
Idiopathic pneumonia syndrome (IPS) is a rare but deadly complication of hematopoietic stem cell transplantation (HSCT). This study characterized the incidence and risk factors for IPS after HSCT in Taiwan. Data from January 2009 to February 2019 was collected from the Taiwan Society of BMT national registry. Forty-three (1.1%) of 3924 HSCT patients who developed IPS were identified. Incidence of IPS was lower in patients who received autologous HSCT than patients who received allogeneic HSCT (0.68% vs 1.44%, P = 0.022). Multivariate analysis showed that use of TBI and intravenous busulfan in the conditioning regimen were each independent predictor of IPS after HSCT. In addition, development of IPS was significantly associated with increased risk of death in the first 120 days post-HSCT (HR, 2.09; 95% CI, 1.08 to 4.05, P = 0.029) and 2 years post-HSCT (HR, 1.65; 95% CI, 1.07 to 2.542, P = 0.023), but not beyond 2 years post-HSCT. However, survival outcomes did not differ significantly between patients with IPS who received autologous versus allogeneic HSCT (P = 0.52). In conclusion, despite the relatively low incidence of post-HSCT IPS in Taiwan, mortality remains high. The results of this study will help to identify high-risk patients for early intervention and guide future therapeutic research.
-
3.
Risk factors and outcomes of definite or clinical idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation
Tamaki, M., Nakasone, H., Nakamura, Y., Kawamura, M., Kawamura, S., Takeshita, J., Yoshino, N., Misaki, Y., Yoshimura, K., Matsumi, S., et al
Leukemia & lymphoma. 2022;:1-9
Abstract
Idiopathic pneumonia syndrome (IPS) is a fatal pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HCT). However, it is often difficult to diagnose IPS, since a considerable number of IPS patients are critically ill, which makes it difficult for them to undergo bronchoscopy. In this study, we explored the risk factors of IPS based on two definitions. Definite IPS was diagnosed based on the results of bronchoscopy, whereas clinical IPS was diagnosed based on the clinical condition and bronchoscopy was not mandatory. Among 444 allo-HCT recipients at our center, 30 definite IPS and 54 clinical IPS were identified. In a multivariable analysis, a high ferritin level was associated with a higher incidence of definite IPS, whereas clinical IPS was frequently associated with older age, MAC, high ferritin level, low %DLCO and second allo-HCT due to graft failure. These risk factors may contribute to the accurate and early diagnosis of IPS.
-
4.
Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation
Sun, S. Y., DeFor, T. E., Ehler, E., Weisdorf, D. J., Macmillan, M., Terezakis, S. A., Dusenbery, K. E.
International journal of radiation oncology, biology, physics. 2021;111(3s):e177-e178
Abstract
PURPOSE/OBJECTIVE(S): To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. MATERIALS/METHODS Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n?=?33), single unrelated cord blood (sUCB; n?=?57), or double unrelated cord blood (dUCB; n?=?31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n?=?89) or without fludarabine (75 mg/m(2)) (n?=?32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was =3% higher than prescription dose (n?=?28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; =15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. RESULTS Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, P < 0.01), HDR TBI (35% vs 9% for LDR, P < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, P?=?0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, P?=?0.20) and lung compensator (HR 1.8, P?=?0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, P?=?0.76). CONCLUSION TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates =15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.
-
5.
Influence of total body irradiation dose rate on idiopathic pneumonia syndrome in acute leukemia patients undergoing allogeneic hematopoietic cell transplantation
Gao, R. W., Weisdorf, D. J., DeFor, T. E., Ehler, E., Dusenbery, K. E.
International journal of radiation oncology, biology, physics. 2018
Abstract
PURPOSE/OBJECTIVES To determine the relationship between dose rate and other factors with the development of idiopathic pneumonia syndrome (IPS) in acute lymphoblastic (ALL) and acute myeloid (AML) leukemia patients undergoing total body irradiation (TBI)-based myeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT). MATERIALS/METHODS From 2006 to 2016, 202 acute leukemia patients (111 ALL, 91 AML) ranging in age from 1 to 57 years (median: 25) underwent allogeneic HCT at XXX. Pre-transplantation conditioning included cyclophosphamide (120 mg/kg) with (68%) or without fludarabine (75 mg/m(2)) followed by 13.2 Gy TBI given in 8 twice daily fractions of 1.65 Gy over 4 days. Dose rate varied based on linac availability and ranged from 8.7-19.2 cGy/min. Patients were stratified by receipt of high (>15 cGy/min) (HDR) (56%) or low (≤15 cGy/min) dose rate (LDR) (44%) TBI for all 8 fractions. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, and/or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. RESULTS IPS developed in 42 (21%) patients between 4 and 73 days (median: 16) after transplantation. HDR TBI was associated with a higher rate of IPS compared to LDR TBI [29% versus 10%, P<.01]. On multiple regression analysis, HDR remained a significant predictor of IPS [HR: 2.6 (95% CI: 1.2-5.3), P=.01) and this led to inferior 1-year overall survival (60% versus 76%, P=.01) and increased 1-year non-relapse mortality (28% versus 15%, P=.02). CONCLUSIONS TBI dose rates ≤15 cGy/min reduce the risk of post-transplantation IPS and improve overall survival. LDR TBI should be strongly considered as an easily implemented parameter to improve the safety of pre-transplantation TBI-based conditioning.
-
6.
Factors associated with pulmonary toxicity after myeloablative conditioning using fractionated total body irradiation
Byun, H. K., Yoon, H. I., Cho, J., Kim, H. J., Min, Y. H., Lyu, C. J., Cheong, J. W., Kim, J. S., Kim, H. S., Kim, S. J., et al
Radiation Oncology Journal. 2017;35(3):257-267
Abstract
PURPOSE Pulmonary toxicities, including infectious pneumonia (IP) and idiopathic pneumonia syndrome (IPS), are serious side effects of total body irradiation (TBI) used for myeloablative conditioning. This study aimed to evaluate clinical factors associated with IP and IPS following TBI. MATERIALS AND METHODS Fifty-eight patients with hematologic malignancies who underwent TBI before allogeneic hematopoietic stem cell transplantation between 2005 and 2014 were reviewed. Most patients (91%) received 12 Gy in 1.5 Gy fractions twice a day. Pulmonary toxicities were diagnosed based on either radiographic evidence or reduced pulmonary function, and were subdivided into IP and IPS based on the presence or absence of concurrent infection. RESULTS Pulmonary toxicities developed in 36 patients (62%); 16 (28%) had IP and 20 (34%) had IPS. IP was significantly associated with increased treatment-related mortality (p = 0.028) and decreased survival (p = 0.039). Multivariate analysis revealed that the risk of developing IPS was significantly higher in patients who received stem cells from a matched unrelated donor than from a matched sibling donor (p = 0.021; hazard ratio [HR] = 12.67; 95% confidence interval [CI], 1.46-110.30). Combining other conditioning agents with cyclophosphamide produced a higher tendency to develop IP (p = 0.064; HR = 6.19; 95% CI, 0.90-42.56). CONCLUSION IP and IPS involve different risk factors and distinct pathogeneses that should be considered when planning treatments before and after TBI.
-
7.
The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type
Vande Vusse, L. K., Madtes, D. K., Bolgiano, D., Watkins, T. R.
Transfusion. 2016;56(2):489-96
-
-
Free full text
-
Abstract
BACKGROUND Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p=0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p=0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p=0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p=0.47). CONCLUSION The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS. Copyright © 2015 AABB.