Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation
International journal of radiation oncology, biology, physics. 2021;111(3s):e177-e178
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.
Post-Irradiation Hyperamylasemia Is a Prognostic Marker for Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Pediatric Population: A Retrospective Single-Centre Cohort Analysis
Journal of clinical medicine. 2021;10(17)
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.
Determining the incidence of interstitial pneumonitis and chronic kidney disease following full intensity haemopoetic stem cell transplant conditioned using a forward-planned intensity modulated total body irradiation technique
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2021
PURPOSE/OBJECTIVE Total body irradiation (TBI) remains a key component of conditioning for allogeneic haemopoietic stem cell transplant (HSCT), with interstitial pneumonitis (IP) and chronic kidney disease (CKD) important late sequelae. We undertook a retrospective service evaluation of TBI patients treated with a forward-planned intensity modulated radiotherapy technique (FP IMRT). MATERIAL/METHODS 74 adult patients were identified; all received step and shoot FP IMRT TBI, 14.4 Gy in 8 fractions over 4 days. Mean doses to the lungs and kidneys were 12- 12.5 Gy. Toxicities were defined as per CTCAE v4.0: IP as multilobar infiltrates on CT with symptoms of dyspnoea, and renal dysfunction as an Estimated Glomerular Filtration rate (eGFR) <60ml/min/1.73m(2) for >3 months. Secondary endpoints were overall survival (OS), progression free survival (PFS), cumulative incidence of non-relapse mortality (NRM), relapse risk and of acute and chronic GvHD. RESULTS Patients received treatment for the following diagnosis: ALL/LBL (n=37); AML (n=33), CML-BC (n=2) and High grade NHL (n=2). The rate of IP due to any cause was 30%; positive microbiological evidence in 73% (16 /22). Idiopathic IP was seen in 8%, with only 4% (n=3) having IP Grade = 3. Two (4%) of 52 long term survivors developed CKD, one with thrombotic microangiopathy. 4 year NRM was 16% (CI 11-32%); no treatment related deaths in matched sibling or umbilical cord blood HSCT. CONCLUSION FP IMRT TBI, reducing dose to the lungs and kidneys, has lower rates of idiopathic IP and CKD compared to the literature. This technique is safe and effective conditioning for full intensity HSCT.
Radiation Related Toxicities Using Organ Sparing Total Marrow Irradiation Transplant Conditioning Regimens
International journal of radiation oncology, biology, physics. 2019
PURPOSE Toxicities after organ sparing myeloablative total marrow irradiation (TMI) conditioning regimens have not been well characterized. The purpose of this study is to report pulmonary, renal, thyroid, and cataract toxicities from a prospective trial monitoring patients up to 8 years after TMI. METHODS A total of 142 patients with primarily multiple myeloma or acute leukemia undergoing hematopoietic cell transplantation (HCT) were evaluated. Follow-up included pulmonary function tests, serum creatinine, GFR, thyroid panel, and ophthalmologic exams performed at 100 days, 6 months, and annually. Median TMI dose was 14 Gy (10-19 Gy) delivered at 1.5-2.0 Gy twice a day at a dose-rate of 200 cGy/minute. RESULTS Median age was 52 years (range 9-70). Median follow-up (range) for all patients was 2 years (0-8) and for patients alive at the time of last follow-up (n=50) 5.5 years (0-8). Mean organ doses in Gy were lung 7.0, kidneys 7.1, thyroid 6.7 and lens 2.8. The crude incidence of radiation pneumonitis (RP) was 1/142 (0.7%). The cumulative incidence (CI) of infection and RP (I/RP) was 22.7% at 2 years post TMI. Mean lung dose (MLD) < 8 Gy predicted for significantly lower rates of I/RP (2-year CI 20.8% vs 31.8%, p=0.012). No radiation induced renal toxicity was noted. Hypothyroidism (HT) occurred in 6.0% and cataract formation (CF) in 7.0% of patients. CONCLUSION TMI delivered with IMRT results in lower organ doses and was associated with fewer toxicities compared to historical cohorts treated with conventional TBI. Keeping the mean lung dose to 8 Gy or less was associated with lower pulmonary complications. Further evaluation in clinical trials of IMRT to deliver TMI, TMLI and organ sparing conformal TBI is warranted.
Less mucositis toxicity after 6 versus 3 fractions of high-dose total body irradiation before allogeneic stem cell transplantation
Bone marrow transplantation. 2019
Influence of total body irradiation dose rate on idiopathic pneumonia syndrome in acute leukemia patients undergoing allogeneic hematopoietic cell transplantation
International journal of radiation oncology, biology, physics. 2018
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.
High Incidence of Veno-Occlusive Disease With Myeloablative Chemotherapy Following Craniospinal Irradiation in Children With Newly Diagnosed High-Risk CNS Embryonal Tumors: A Report From the Children's Oncology Group (CCG-99702)
Pediatric Blood & Cancer. 2016;63(9):1563-70
BACKGROUND The outcomes with high-risk central nervous system (CNS) embryonal tumors remain relatively poor despite aggressive treatment. The purposes of this study using postirradiation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (ASCR) were to document feasibility and describe toxicities of the regimen, establish the appropriate dose of thiotepa, and estimate the overall survival (OS) and event-free survival (EFS). PROCEDURE The Children's Cancer Group conducted this pilot study in children and adolescents with CNS embryonal tumors. The treatment consisted of induction chemotherapy to mobilize hematopoietic stem cells, chemoradiotherapy, and myeloablative consolidation chemotherapy with ASCR. RESULTS The study accrued 25 subjects in 40 months and was closed early due to toxicity, namely, veno-occlusive disease (VOD) of the liver, more recently termed sinusoidal obstructive syndrome (SOS). Of 24 eligible subjects, three of 11 (27%) receiving thiotepa Dose Level 1 (150 mg/m(2) /day x 3 days) and three of 12 (25%) receiving de-escalated Dose Level 0 (100 mg/m(2) /day x 3 days) experienced VOD/SOS. One additional subject experienced toxic death attributed to septic shock; postmortem examination revealed clinically undiagnosed VOD/SOS. The 2-year EFS and OS were 54 +/- 10% and 71 +/- 9%, respectively. The 5-year EFS and OS were 46 +/- 11% and 50 +/- 11%. CONCLUSIONS The treatment regimen was deemed to have an unacceptable rate of VOD/SOS. There was complete recovery in all six cases. The overall therapeutic strategy using a regimen less likely to cause VOD/SOS may merit further evaluation for the highest risk patients. Copyright © 2016 Wiley Periodicals, Inc.
CD34+ selection and the severity of oropharyngeal mucositis in total body irradiation-based allogeneic stem cell transplantation
Supportive Care in Cancer. 2016;24(2):815-22
OBJECTIVE The purpose of the present study was to evaluate the impact of ex vivo T cell depleted (TCD) by CD34+ selection on the incidence and severity of oropharyngeal mucositis (OM) after myeloablative allogeneic stem cell transplant (allo-SCT) with total body irradiation (TBI) conditioning. This approach has the advantage of avoiding methotrexate for graft versus host disease (GVHD) prophylaxis. PATIENTS AND METHODS We analyzed the incidence and severity of OM in a cohort of 105 consecutive patients who underwent CD34+ selected (peripheral blood stem cells (PBSCs) from human leukocyte antigen (HLA)-identical siblings) allo-SCT with total body irradiation (TBI) conditioning. OM was graded by the World Health organization (WHO) and the Bearman regimen-related toxicity (RRT) scales. RESULTS The incidence of WHO grade 3-4 OM was 34.3 %. There were no cases of grade 3-4 OM by the RRT scale. Significant correlation was found between the severity of OM and the use of intravenous (IV) narcotic medications (r (2)=0.15, p=0.004), total parenteral nutrition (TPN; r (2)=0.68, p<0.001), and hospital length of stay (LOS) (r (2)=0.12, p=0.01). DISCUSSION TBI-induced OM can inflict significant morbidity in the early transplant period, and the incidence of WHO grade 3-4 OM can exceed 50 % when methotrexate is used for GVHD prophylaxis. In the CD34+ selected setting, methotrexate is avoided and the incidence of WHO grade 3-4 OM, use of TPN, and need for narcotic analgesia appear to be lower than historic evidence from standard T-replete allogeneic transplantation. CONCLUSION We conclude that toxicity from OM is tolerable in CD34+ selected allo-SCT and should be prospectively measured in randomized trials comparing CD34+ selection versus T-replete transplantation.