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.
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.