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1.
Incidence of subsequent malignancies after total body irradiation-based allogeneic HSCT in children with ALL - long-term follow-up from the prospective ALL-SCT 2003 trial
Eichinger, A., Poetschger, U., Glogova, E., Bader, P., Basu, O., Beier, R., Burkhardt, B., Classen, C. F., Claviez, A., Corbacioglu, S., et al
Leukemia. 2022
Abstract
Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children ≤2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 ± 0.01 and 0.13 ± 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7-13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0-9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.
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2.
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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3.
Risk of subsequent malignant neoplasms following hematopoietic stem cell transplantation with total body irradiation or total marrow irradiation: insights from early follow-up
Ladbury, C., Armenian, S., Bosworth, A., He, T., Wong, F. L., Dandapani, S., Han, C., Liu, A., Al Malki, M., Rosenthal, J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Total marrow irradiation (TMI) is an alternative to total body irradiation (TBI) as a component of the conditioning regimen for hematopoietic cell transplantation (HCT), offering the ability to deliver more targeted dose and facilitating organ sparing. The organ-sparing effect of TMI is theorized to decrease risk of complications associated with radiation, including subsequent malignant neoplasms (SMN), while allowing for dose escalation to improve oncologic outcomes. OBJECTIVE(S): The purpose of this study was to compare SMNs rates among patients treated with TBI or TMI-based conditioning regimens. We hypothesized that TMI would yield comparable, if not lower rates of SMNs compared to TBI. STUDY DESIGN Retrospective matched pair analysis of patients who underwent allogeneic HCT and received either TBI or TMI-based conditioning regimens to a total dose of 12-20 Gy was performed. Overall, there were 171 patients who were treated with TMI and they were matched (1:1) to patients who received TBI-based conditioning on age, sex, diagnosis, and length of follow-up. SMNs were identified from an established long-term follow-up protocol, our institutional cancer registry, and the California Cancer Registry. RESULTS There were no significant differences in patient and clinical characteristics between the TMI and TBI cohorts except for clinical response status at transplant and radiation dose. As expected, patients who received TMI had a higher radiation dose (p<0.001, TMI median 16.0 Gy vs TBI median 13.2 Gy). Median follow up for both cohorts was 2.0 years (range: 0.5-12.3 years). There was no significant difference in the risk of developing SMNs between the TMI and TBI cohorts (p=0.81). A total of nine patients (5.3%) treated with TBI and ten patients (5.8%) treated with TMI developed SMNs at a median of 3.3 years and 1.7 years following HCT, respectively. Excluding non-melanoma skin cancers and non-invasive neoplasms, two patients treated with TBI developed SMNs (both melanoma) and one patient treated with TMI developed an SMN (colon cancer). No patients developed subsequent hematologic malignancies. CONCLUSION(S): TMI-based conditioning is not associated with a significant difference in risk of developing SMNs compared to TBI-based conditioning during early post-HCT follow-up. Future studies with longer follow-up may be needed to further characterize risk of SMNs associated with undergoing TMI compared to TBI-based regimens.
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4.
Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies
Sieker, K., Fleischmann, M., Trommel, M., Ramm, U., Licher, J., Bug, G., Martin, H., Serve, H., Rödel, C., Balermpas, P.
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. 2022
Abstract
PURPOSE Total body irradiation (TBI) is a common part of the myelo- and immuno-ablative conditioning regimen prior to an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to concerns regarding acute and long-term complications, there is currently a decline in otherwise successfully established TBI-based conditioning regimens. Here we present an analysis of patient and treatment data with focus on survival and long-term toxicity. METHODS Patients with hematologic diseases who received TBI as part of their conditioning regimen prior to allo-HSCT at Frankfurt University Hospital between 1997 and 2015 were identified and retrospectively analyzed. RESULTS In all, 285 patients with a median age of 45 years were identified. Median radiotherapy dose applied was 10.5 Gy. Overall survival at 1, 2, 5, and 10 years was 72.6, 64.6, 54.4, and 51.6%, respectively. Median follow-up of patients alive was 102 months. The cumulative incidence of secondary malignancies was 12.3% (n = 35), with hematologic malignancies and skin cancer predominating. A TBI dose ≥ 8 Gy resulted in significantly improved event-free (p = 0.030) and overall survival (p = 0.025), whereas a total dose ≤ 8 Gy and acute myeloid leukemia (AML) diagnosis were associated with significantly increased rates of secondary malignancies (p = 0.003, p = 0.048) in univariate analysis. No significant correlation was observed between impaired renal or pulmonary function and TBI dose. CONCLUSION TBI remains an effective and well-established treatment, associated with distinct late-toxicity. However, in the present study we cannot confirm a dose-response relationship in intermediate dose ranges. Survival, occurrence of secondary malignancies, and late toxicities appear to be subject to substantial confounding in this context.
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5.
To Lighten the Burden of Cure: Thyroid Disease in Long-Term Survivors After TBI Conditioning for Paediatric ALL
Zubarovskaya, N., Bauer, D., Ronceray, L., Poetschger, U., Kurzmann, P., Lender, C., Kuzmina, Z., Lawitschka, A.
Frontiers in pediatrics. 2021;9:798974
Abstract
Thyroid disorders are well-studied after allogeneic haematopoietic stem cell transplantation (HSCT) following total body irradiation (TBI)-based conditioning, occurring in 15-30% of paediatric survivors. The toxic effect of TBI is known but data on the role of immunological dysregulation (ID) and chronic graft-versus-host-disease (cGvHD) are scarce. We studied functional and structural thyroid disorders in 97 paediatric ALL patients after TBI-based HSCT, assessing their correlation with patient/transplant characteristics including cGvHD, prolonged immunosuppression and ID. The 10- and 15-year cumulative incidence (CI) of functional disorders was 50 and 60%. Univariate analysis revealed TBI in 6 vs. 8 fractions (p = 0.01), an interval between ALL diagnosis and HSCT <1 year (p = 0.038), and the application of ATG (p = 0.044) as risk factors. The 10- and 15-year CI of structural disorders was 60 and 80%. No correlation between patient/transplant characteristics and structural disorders was observed. cGvHD, prolonged immunosuppression and additional radiotherapy were not associated with any thyroid disease. We observed a significant correlation between ID and the development of thyroid dysfunction in patients with structural changes (10-year CI: 77% for patients with ID vs. 56% without ID, p = 0.02). The impact of our results on thyroid follow-up evaluations and the significance of hormonal replacement therapy are discussed.
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6.
Cumulative incidence of subsequent malignancy after allo-HCT conditioned with or without low-dose total body irradiation
Nunez, L., Abedin, T., Naqvi, S. A., Shen, H., Chaudhry, A., Bellerby, S. M., Savoie, L., Daly, A., Shafey, M., Duggan, P., et al
Blood advances. 2021
Abstract
Subsequent malignancies (SM) present a significant burden of morbidity and are a common cause of late mortality in survivors of allogeneic HCT (hematopoietic cell transplant). Previous studies have described total body irradiation (TBI) as a risk factor for the development of SM in allo-HCT survivors. However, most studies of the association between TBI and SM have examined high dose TBI regimes (typically ≥600cGy) and thus little is known about the association between low dose TBI regimens and risk of SM. Thus, we set out to compare the cumulative incidence of SM in Albertan patients who received busulfan/fludarabine alone versus busulfan/fludarabine plus 400 cGy TBI. Of 674 included patients, 49 patients developed a total of 56 malignancies at a median of 5.9 years post-transplant. The cumulative incidence of SM at 15 years post-HCT in the entire cohort was 11.5% (95% CI 8.5-15.6%): 13.4% (95% CI 9.1-19.3%) in the no-TBI group and 10.8% (95% CI 6.6-17.4%) in the TBI group. In the multivariable model, TBI was not associated with SM, while number of pre-HCT cycles of chemotherapy was. The standardized incidence ratio for the entire cohort, as compared to the age, sex and calendar-year matched general population was 1.74. Allo-HCT conditioning that includes low dose TBI does not appear to increase risk of SM as compared to chemotherapy-alone conditioning.
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7.
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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8.
The Burden of Survivorship on Hematological Patients-Long-Term Analysis of Toxicities after Total Body Irradiation and Allogeneic Stem Cell Transplantation
Oertel, M., Martel, J., Mikesch, J. H., Scobioala, S., Reicherts, C., Kröger, K., Lenz, G., Stelljes, M., Eich, H. T.
Cancers. 2021;13(22)
Abstract
Total body irradiation is an effective conditioning modality before autologous or allogeneic stem cell transplantation. With the whole body being the radiation target volume, a diverse spectrum of toxicities has been reported. This fact prompted us to investigate the long-term sequelae of this treatment concept in a large patient cohort. Overall, 322 patients with acute leukemia or myelodysplastic syndrome with a minimum follow-up of one year were included (the median follow-up in this study was 68 months). Pulmonary, cardiac, ocular, neurological and renal toxicities were observed in 23.9%, 14.0%, 23.6%, 23.9% and 20.2% of all patients, respectively. The majority of these side effects were grades 1 and 2 (64.9-89.2% of all toxicities in the respective categories). The use of 12 Gray total body irradiation resulted in a significant increase in ocular toxicities (p = 0.013) and severe mucositis (p < 0.001). Renal toxicities were influenced by the age at transplantation (relative risk: 1.06, p < 0.001) and disease entity. In summary, total body irradiation triggers a multifaceted, but manageable, toxicity profile. Except for ocular toxicities and mucositis, a 12 Gray regimen did not lead to an increase in long-term side effects.
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9.
Dosimetric evaluation of ovaries and pelvic bones associated with clinical outcomes in patients receiving total body irradiation with ovarian shielding
Akahane, K., Shirai, K., Wakatsuki, M., Suzuki, M., Hatanaka, S., Takahashi, Y., Kawahara, M., Ogawa, K., Takahashi, S., Oyama-Manabe, N., et al
Journal of radiation research. 2021
Abstract
Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients' ovaries were shielded with cylinder-type lead blocks. The dose-volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose-volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.
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10.
Metabolic syndrome in male survivors of pediatric allogeneic hematopoietic stem cell transplantation: impact of total body irradiation, low-grade inflammation, and hypogonadism
Muhic, E., Mathiesen, S., Nielsen, M. M., Suominen, A., Sørensen, K., Ifversen, M., Nolsöe, R. L., Pedersen, K. M., Lähteenmäki, P., Nordestgaard, B. G., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. OBJECTIVES To determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and investigate predisposing factors including low-grade inflammation, altered fat distribution, and low testosterone levels. STUDY DESIGN We included 98 survivors aged 19-47 years at follow-up, median 18 (range 8-35) years after pediatric HSCT. MetS was defined according to the NCEP ATP III criteria. The prevalence and clinical manifestations of MetS were compared to a control group of males from the background population (n=4767). Fat distribution was assessed by android/gynoid (AG) ratio from a whole-body DXA scan. Systemic inflammation was evaluated by interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. RESULTS The prevalence of MetS was 30%, corresponding to the prevalence in the 50-80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared to age-matched controls (76% vs. 20%, p<0.001), whereas hypertension was more dominant in the control group (69% vs. 93%, p=0.01). In addition, normal or reduced BMI was more commonly observed among HSCT survivors with MetS compared with age-matched controls (41% vs. 11%, p=0.002). MetS was associated with total body irradiation (TBI) compared to chemotherapy regimens (OR=4.3 95% CI [1.2-24.4], p=0.02); lower testosterone levels (OR=5.4 95% CI [1.3-23.6], p=0.02); higher levels of IL-6 (OR=1.8 95% CI [1.2-2.8], p=0.004) and hsCRP (OR=1.8 95% CI [1.3-2.6], p<0.001) (estimates per two-fold increase). In addition, an increased AG ratio was strongly associated with MetS (OR=2.1 95% CI [1.5-2.9], p<0.001), despite only 7% of patients fulfilled the criteria for increased abdominal circumference. CONCLUSION Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestation differed from age-matched controls indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardio-metabolic risk-profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared to the background population.