Dose Total Body Irradiation Research Articles

Non-myeloablative allogeneic blood or marrow transplantation (AlloBMT) with post-transplant cyclophosphamide (PTCy) for peripheral T-cell lymphoma (PTCL): Improved outcomes with peripheral blood (PB) allografts and increased total body irradiation (TBI) to 400 cGV.

7047 Background: The use of PTCy for graft-versus host-disease (GVHD) prophylaxis has revolutionized alloBMT, but there is limited published experience in PTCL. Methods: All patients with PTCL who received a non-myeloablative alloBMT using PTCy-based GVHD prophylaxis between January 2004 and December 2020 at Johns Hopkins Hospital were analyzed. Standard population statistics were used. Results: Sixty-five patients were identified. The median age was 59 years (range, 24-75 years). Lymphoma histology included PTCL-not otherwise specified (n=24), ALK-negative anaplastic large cell lymphoma (n=14), angioimmunoblastic T-cell lymphoma (n=7), enteropathy-associated T-cell lymphoma (n=6), hepatosplenic T-cell lymphoma (n=4), and other (n=10). Eleven patients were in first complete remission (CR1, 17%). The remaining patients were in first partial remission (PR1) or underwent salvage therapy to at least PR prior to transplant. Forty-eight patients received an alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (mMUD, 11%). All patients received non-myeloablative conditioning with fludarabine, cyclophosphamide, and TBI. The graft source was bone marrow (BM) in the first 46 patients (71%). Because of relatively high relapse rates, in 2018 we began using PB and increased TBI from 200 to 400 cGy; the remaining 19 patients (29%) received this regimen. GVHD prophylaxis was PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow up of 2.8 years, the 3-year progression-free survival (PFS) for the entire cohort was 39% (95% confidence interval [CI] 28-54%), and the 3-year overall survival (OS) was 43% (95% CI 31-58%). The cumulative incidence (CuI) of relapse and non-relapse mortality (NRM) at 1 year was 25% (95% CI 14-35%) and 12% (95% CI 4-20%), respectively. Among 29 cases of GVHD (45%), 2 were grade 3-4 acute GVHD (3%) and 3 were severe chronic GVHD (5%). Univariate analysis including age, histology, mMUD, PB/400cGy, and CR1 revealed only PB/400 cGy TBI as a significant predictor of survival, relapse, or NRM. Outcomes by source. Conclusions: AlloBMT with non-myeloablative conditioning and PTCy is safe and well-tolerated in patients with PTCL. Our preliminary data suggest increasing TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings. [Table: see text]

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children

Background and purposeMyeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. Material and methodsThe European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. ResultsMyeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3–4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III–IV evidence. Preferential TBI dose in children is 12–14.4 Gy in 1.6–2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. ConclusionsThese ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Amomum subulatum mitigates total body irradiation-induced oxidative stress and its associated inflammatory response by enhancing the antioxidant status and regulating the pro-inflammatory cytokines

Free radical-induced oxidative damage and associated inflammatory responses play a crucial role in cancer radiotherapy (RT) mediated normal tissue toxicities. Supplementation of antioxidants or inflammation modulators may alleviate RT toxicity, thereby improving clinical outcomes. Amomum subulatum is a dietary spice rich in biologically active phytochemicals. The present study investigates radiation dose-modifying factor (DMF) and radioprotective efficacy of methanolic extract of Amomum subulatum dry fruits (MEAS) in mice exposed to different doses of total body irradiation (TBI). Administration of MEAS resulted in a DMF of 1.25 Gy, ascertaining its radioprotective efficacy. MEAS reversed X-ray-induced redox imbalance by enhancing antioxidant defense mechanisms. MEAS prevented TBI-induced hematopoietic damages by significantly (P<.01) enhancing bone marrow cellularity, total white blood cell count, and hemoglobin level. MEAS prevented p53-mediated apoptotic death of intestinal cells and increased the expression of cytoprotective genes Nrf2 (nuclear factor-erythroid factor 2-related factor 2) and HO-1 (heme oxygenase-1). Expression of apoptosis regulating genes revealed that MEAS reduced radiation-induced apoptotic death of intestinal cells. Treatment with MEAS also reduced inflammatory responses via reversing TBI-induced elevation in serum pro-inflammatory cytokine (TNF-α, IL-1β, IL-6) levels. Tissue histopathology further confirmed the protective effect of MEAS against TBI-induced inflammatory responses, suggesting the potential of MEAS in modulating inflammation. These effects might perhaps be attributed to the synergistic effect of biologically active polyphenols with antioxidant, anti-inflammatory, and Nrf2 activating potential in MEAS. Our findings demonstrated the radioprotective efficacy of MEAS, suggesting the possible nutraceutical application of Amomum subulatum in modulating oxidative stress and inflammation.

Combining CD34+ stem cell selection with prophylactic pathogen and leukemia directed T-cell immunotherapy to simultaneously reduce graft versus host disease, infection, and leukemia recurrence after allogeneic stem cell transplant.

We designed a trial to simultaneously address the problems of graft versus host disease (GVHD), infection, and recurrence of malignancy after allogeneic stem cell transplantation. CD34+ stem cell isolation was used to minimize the development of acute and chronic GVHD. Two prophylactic infusions, one combining donor-derived cytomegalovirus, Epstein-Barr virus, and Aspergillus fumigatus specific T-cells and the other comprising donor-derived CD19 directed chimeric antigen receptor (CAR) bearing T-cells, were given 21-28 days after transplant. Two patients were transplanted for acute lymphoblastic leukemia from HLA identical siblings using standard doses of cyclophosphamide and total body irradiation without antilymphocyte globulin. Patients received no post-transplant immune suppression and were given no pre-CAR T-cell lymphodepletion. Neutrophil and platelet engraftment was prompt. Following adoptive T-cell infusions, there was rapid appearance of antigen-experienced CD8+ and to a lesser extent CD4+ T-cells. Tetramer-positive T-cells targeting CMV and EBV appeared rapidly after T-cell infusion and persisted for at least 1 year. CAR T-cell expansion occurred and persisted for up to 3months. T-cell receptor tracking confirmed the presence of product-derived T-cell clones in blood targeting all three pathogens. Both patients are alive over 3 years post-transplant without evidence of GVHD or disease recurrence. Combining robust donor T-cell depletion with directed T-cell adoptive immunotherapy targeting infectious and malignant antigens permits independent modulation of GVHD, infection, and disease recurrence. The combination may separate GVHD from the graft versus tumor effect, accelerate immune reconstitution, and improve transplant tolerability.

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)

The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source. Single administration of doses ranging from 0.3 to 1 mg/kg, given 4, 8, 12 or 24 h post-TBI (LD70 dose) increased survival by 30–90% as compared to saline control treatment. At the conclusion of the 30-day study, significant increases in bone marrow colony forming units and megakaryocytes were observed in animals administered JNJ-26366821 compared to those administered saline. In addition, enhanced recovery of FLT3-L levels was observed in JNJ-26366821-treated animals. Probit analysis of survival in the JNJ-26366821- and saline-treated cohorts revealed a dose reduction factor of 1.113 and significant increases in survival for up to 6 months following irradiation. These results support the potential use of JNJ-26366821 as a medical countermeasure for treatment of acute TBI exposure in case of a radiological/nuclear event when administered from 4 to 24 h post-TBI.

308 - Switching to IV Melphalan with or without Low Dose Total Body Irradiation Reduces Primary Graft Failure Rates in Children with Malignancies When Busulfan Monitorization Is Unavailable

308 - Switching to IV Melphalan with or without Low Dose Total Body Irradiation Reduces Primary Graft Failure Rates in Children with Malignancies When Busulfan Monitorization Is Unavailable

Comparison of Proteomic Expression Profiles after Radiation Exposure across Four Different Species.

There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan® proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery.

Impact of lung block shape on cardiac dose for total body irradiation.

Evaluating cardiac dose during total body irradiation (TBI) is of increasing interest. A three-dimensional beam model for TBI was commissioned and lung shielding was simulated in a treatment planning system with the cardiac silhouette partially blocked and unblocked. When blocked, the median heart dose decreased by 6% (IQR=6%) and the median cardiac V12Gy decreased by 27% (IQR=17%). The median left anterior descending artery dose decreased 20% (IQR=12%) for blocked cases. Because using partial heart shielding may result in considerable changes in dose to cardiac structures, TBI protocols should explicitly consider lung block design parameters and their potential effects.

Evaluation of Surface Dose and Commissioning of Compensator-Based Total Body Irradiation.

Purpose:The aim of the current study is to commission compensator-based total body irradiation (TBI) and to compare surface dose using percentage depth dose (PDD) while varying the distance between beam spoiler and phantom surface.Materials and Methods:TBI commissioning was performed on Elekta Synergy® Platform linear accelerator for bilateral extended source to surface distance treatment technique. The PDD was measured by varying the distance (10 cm, 20 cm, 30 cm, and 40 cm) between the beam spoiler and the phantom surface. Beam profile and half-value layer (HVL) measurement were carried out using the FC65 ion-chamber. Quality assurance (QA) was performed using an in-house rice-flour phantom (RFP). In-vivo diodes (IVD) were placed on the RFP at various regions to measure the delivered dose, and it was compared to the calculated dose.Results:An increase in Dmax and surface dose was observed when beam spoiler was moved away from the phantom surface. The flatness and symmetry of the beam profile were calculated. The HVL of Perspex and aluminum is 17 cm and 8 cm, respectively. The calculated dose of each region was compared to the measured dose on the RFP with IVD, and the findings showed that the variation was <4.7% for both Perspex and Aluminum compensators.Conclusion:The commissioning of the compensator-based TBI technique was performed and its QA measurements were carried out. The Mayneord factor corrected PDD and measured PDD values were compared. The results are well within the clinical tolerance limit. This study concludes that 10 cm −20 cm is the optimal distance from the beam spoiler to phantom surface to achieve prescribed dose to the skin.

Yiqi Jiedu herbal decoction attenuates the 2 Gy 60Co γ ray induced spleen injury by inhibiting apoptosis and modulating the immune balance

Ethnopharmacological RelevanceIrradiation-induced immunosuppression often occurs during radiotherapy in patients, which would increase the risk of opportunistic infections. Many Chinese herbal prescriptions or natural extracts have recently attracted increased radiation protection and therapy attention due to their low toxicity. Aim of the studyThe present study aimed to investigate the protective effects of Yiqi Jiedu (YQJD) decoction on spleen injury induced by 2 Gy 60Co γ ray in mice. Materials and methodsA total of 180 Balb/c mice were randomly divided into five groups: blank control (Ctrl), model (IR), positive drug (IRA), low-dose YQJD decoction (IRL), and high-dose YQJD decoction (IRH). After a ten-day intervention, mice were exposed to a single dose of total body irradiation (2 Gy) and sacrificed on the 1st, 3rd, and 7th day after irradiation. The indicators include general observations and body weight, changes in peripheral hemogram, index and histopathology examination of the spleen, distribution of lymphocyte subsets, cytokine levels, and apoptosis in the spleen. ResultsIn comparison to the Ctrl group, the body weight, spleen index, peripheral blood cell, and splenocyte quantities decreased significantly after exposure, accompanied by a notable increase of apoptosis in spleen cells. Moreover, ionizing radiation also broke the balance of CD4+/CD8+, Th1/Th2, and Th17/Treg, triggering immune imbalance and immunosuppression. The above injuries occurred on the 1st day after exposure, worsened on the 3rd, and were relieved on the 7th day. However, the pretreatment of YQJD decoction increased the spleen index, improved the spleen structure, and inhibited radiation-induced apoptosis after exposure. Additionally, YQJD decoction has shown its ability to promote immunological balance recovery following exposure by regulating CD4+/CD8+, Th1/Th2, and Th17/Treg ratios, which may minimize the risk of infection. In addition, the high-dose of YQJD decoction showed a better protective effect than the low-dose group. ConclusionThe protective effects of YQJD decoction on 2 Gy 60Coγray induced spleen injury were confirmed in this study. This mechanism may be related to inhibiting apoptosis and modulating immune balance. This exploration might provide new insights into the use of Chinese herbs on radioprotection of the immune system.

Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Reduced Intensity Hematopoietic Cell Transplantation Improves Cerebral Hemodynamics in Children with Sickle Cell Disease

IntroductionAllogeneic hematopoietic cell transplantation (HCT) is increasingly being utilized in patients with sickle cell disease (SCD) to prevent progressive organ dysfunction, including for primary or secondary stroke prevention. However, outcomes after HCT have mostly been evaluated using broad measures such as overall survival and event free survival with limited direct physiologic evidence of improved cerebral hemodynamics. Cerebral blood flow (CBF; mL blood/100 g tissue/min) is increased in SCD to compensate for chronic anemia, reduced oxygen carrying capacity and to maintain adequate oxygen delivery to the brain tissue. In SCD patients, CBF is inversely associated with intelligence quotient (Strouse JJ, et al. Blood. 2006;108(1):379-381.) and working memory (Prussien KV, et al. Stroke. 2021;52(5):1830-1834.) and has been shown to improve with blood transfusions (Guilliams KP, et al. Blood. 2018;131(9):1012-1021.). Assessment of CBF may help predict long-term neurocognitive outcomes in patients with SCD and assess therapeutic responses to therapies. Additionally, the high metabolic demand of the brain potentially makes assessment of CBF a sensitive predictor of future multiorgan damage in patients with SCD and hence may be useful to help determine eligibility of patients for curative therapies.MethodsWe performed anatomical and hemodynamic magnetic resonance imaging (MRI) of the brain prior to, and at 6 months after HCT in children with SCD undergoing a reduced intensity conditioning based HCT on a clinical study (NCT04362293). All patients received pretransplant conditioning with hydroxyurea, azathioprine, alemtuzumab, thiotepa and low dose total body irradiation (200-400 cGy). All patients received an unmanipulated mobilized peripheral blood derived hematopoietic stem and progenitor cell graft. One patient who received the graft from a haploidentical (HAPLO) donor also received post-transplant cyclophosphamide. Graft versus host disease prophylaxis comprised of sirolimus. A 3-dimensional (3D) T1 sequence was used for gray/white matter segmentation. 3D-pulsed arterial spin labeling (ASL) perfusion imaging (3 mm isotropic) was acquired to measure resting CBF. Mean CBF values were calculated from gray matter. Mean ± standard deviation and median values for various variables are presented.ResultsFour consecutive patients had 2 serial MRIs performed (one before HCT and another 6 months after HCT). Median age at HCT was 14.5 years. Indications for HCT, donor type and whether patients were receiving chronic transfusion therapy (CTT) prior to HCT are indicated in the Table. No patient had prior evidence of overt stroke. All patients engrafted and had >99% donor myeloid chimerism at the time of the post-HCT imaging. Mean pre-HCT hemoglobin was 8.7 ± 0.8 g/dL (median 8.6 g/dL) and it increased to 12.5 ± 2.1 g/dL (median 12.4 g/dL) at 6 months after HCT. All patients exhibited elevated resting CBF values prior to HCT (123.8 ± 32.2 mL blood/100 g tissue/min, median 112.8 mL blood/100 g tissue/min), that decreased following HCT (71.1 ± 32.1 mL blood/100 g tissue/min, median 72.8 mL blood/100 g tissue/min) (Table and Figure). None of the patients had any clinical neurological complications or imaging evidence of new infarcts or anatomical abnormalities in the follow up period.ConclusionOur preliminary results indicate that it is feasible to quantify CBF in patients with SCD before and after HCT using MRI. We demonstrate that cerebral hemodynamics improve after HCT in children with SCD, indicated by a decrease in CBF to near normal values (normal CBF ~80 mL blood/100 g tissue/min). The more substantial changes (-50% and -78%) are seen in children who were not receiving CTT, suggesting that CTT might partially mitigate CBF elevation prior to HCT. Nevertheless, 2 patients receiving CTT prior to HCT also had a further modest decrease in CBF after HCT (-5% and -18%). We plan to follow these changes at serial time points annually after HCT and correlate them with changes in neurocognitive functioning and other functional MRI measures. Improved CBF is expected to reduce stroke risk and may also preserve or improve neurocognitive functioning, and prospective monitoring of these outcomes are underway.Data on all the study participants who have undergone an HCT and had 2 serial MRIs performed by the ASH annual meeting will be presented. [Display omitted] DisclosuresSharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Vindico Medical Education: Honoraria. Triplett: Miltenyi: Other: Travel, meeting registration. Hankins: Vindico Medical Education: Consultancy; UpToDate: Consultancy; Global Blood Therapeutics: Consultancy; Bluebird Bio: Consultancy.

Allogeneic Stem Cell Transplantation Conditioned with Myeloablative Regimens Containing Total Body Irradiation in Adolescent and Young Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Who Were Treated with Pediatric-Type Chemotherapy

Allogeneic Stem Cell Transplantation Conditioned with Myeloablative Regimens Containing Total Body Irradiation in Adolescent and Young Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia Who Were Treated with Pediatric-Type Chemotherapy

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> 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. <h3>Materials/Methods</h3> 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/m²) (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. <h3>Results</h3> 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%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 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, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 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, <i>P</i> = 0.76). <h3>Conclusion</h3> 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.

Renal Dysfunction in Pediatric Acute Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation with Total Body Irradiation-Containing Conditioning Regimen

<h3>Purpose/Objective(s)</h3> Renal dysfunction after hematopoietic cell transplantation (HCT) is a multi-factorial disorder. Studies have linked dose and fractionation with the incidence of late renal dysfunction in patients who underwent total body irradiation (TBI)-based myeloablative conditioning, but the effect of dose rate remains under studied. We conducted a single-institution retrospective study to elucidate the effect of TBI parameters and peri-HCT factors on late renal dysfunction among pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) after allogeneic HCT. <h3>Materials/Methods</h3> 123 patients (age 1-22) with acute leukemia (38 AML, 85 ALL) underwent HCT using a TBI-based regimen at our institution from 2006-2019. HCT conditioning regimen included cyclophosphamide with or without fludarabine followed by TBI (13.2 Gy in 8 twice-daily fractions over 4 days). TBI dose rate was limited to < 20 cGy/min but ranged from 8.7-19.2 cGy/min depending on Linac availability. TBI parameters and peri-HCT factors were recorded and stratified by recipient of high-dose-rate (HDR; > 15 cGy/min; 35%) or low-dose-rate (LDR; ≤15 cGy/min; 65%) TBI. All patients received a calcineurin inhibitor to prevent graft-versus-host disease (GVHD). Serum creatinine (Cr) was recorded at baseline and trended post-HCT. Late renal dysfunction was defined as persistent increase of Cr > 1.2 mg/dL or ≥ 1.25 times the upper limit of age-dependent normal, onset ≥ 3 months after HCT. Using a statistical software, dichotomous variables were tested using Chi-square or Fisher's exact test; and continuous variables using Wilcoxon rank-sum test. Univariate and multivariate analyses were used to examine the association of these variables with late renal dysfunction. <h3>Results</h3> A total of 14 patients developed late renal dysfunction (11%): 6/38 patients in HDR group (14%) vs. 8/79 patients in LDR group (10%, <i>P</i> = 0.03). Comparison between HDR and LDR groups found no difference in age, sex, remission status, HCT comorbidity index (HCT-CI, predictive of late organ dysfunctions, factoring in baseline Cr) or baseline Cr. More patients in the HDR group were cord blood recipients taking cyclosporine/mycophenolate mofetil (37% vs. 19% in LDR, <i>P</i> < 0.01), and fewer were sibling recipients taking tacrolimus/methotrexate (0% vs. 10%, <i>P</i> < 0.01). More patients in HDR group developed acute GVHD (35% vs. 27%, <i>P</i> = 0.05). In univariate analysis, incidence of late renal dysfunction was associated with patient's age ≤12 at HCT (22% vs. 5% > 12), intermediate-high HCT-CI (22% vs. 6% low HCT-CI) and HDR (24% vs. 8% in LDR). On multivariate regression, late renal dysfunction remained associated with age, HCT-CI, and HDR (<i>P</i> = 0.01, 0.02, and < 0.01 respectively). <h3>Conclusion</h3> Patient's age ≤12 at HCT, intermediate-high HCT-CI, and HDR were associated with late renal dysfunction post-HCT. Since dose rate is the only modifiable factor, adoption of LDR TBI is recommended.

Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation.

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41years. The median total nucleated cell and total CD34+ cell doses in a UCB unit at cryopreservation were 2.5 × 107/kg and 0.7 × 105/kg, respectively. The median follow-up period for survivors was 47months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34+ cell dose in an UCB unit (≥ 0.7 × 105/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.

Practice Patterns of Pediatric Total Body Irradiation Techniques: A Children's Oncology Group Survey

The aim of this study was to examine current practice patterns in pediatric total body irradiation (TBI) techniques among COG member institutions. Between November 2019 and February 2020, a questionnaire containing 52 questions related to the technical aspects of TBI was sent to medical physicists at 152 COG institutions. The questions were designed to obtain technical information on commonly used TBI treatment techniques. Another set of 9 questions related to the clinical management of patients undergoing TBI was sent to 152 COG member radiation oncologists at the same institutions. Twelve institutions were excluded because TBI was not performed in their institutions. A total of 88 physicists from 88 institutions (63% response rate) and 96 radiation oncologists from 96 institutions (69% response rate) responded. The anterior-posterior/posterior-anterior (AP/PA) technique was the most common technique reported (49 institutions [56%]); 44 institutions (50%) used the lateral technique, and 14 (16%) used volumetric modulated arc therapy or tomotherapy. Midplane dose rates of 6 to 15 cGy/min were most commonly used. The most common specification for lung dose was the midlung dose for both AP/PA techniques (71%) and lateral techniques (63%). Almost all physician responders agreed with the need to refine current TBI techniques, and 79% supported the investigation of new TBI techniques to further lower the lung dose. There was no consistency in the practice patterns, methods for dose measurement, and reporting of TBI doses among COG institutions. The lack of standardization precludes meaningful correlation between TBI doses and clinical outcomes including disease control and normal tissue toxicity. The COG radiation oncology discipline is currently undertaking several steps to standardize the practice and dose reporting of pediatric TBI using detailed questionnaires and phantom-based credentialing for all COG centers.

Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P=.64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Evaluation of sodium orthovanadate as a radioprotective agent under total-body irradiation and partial-body irradiation conditions in mice

Purpose Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. Methods Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. Results TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. Conclusion Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.

Anti-CD45 Radioimmunotherapy Followed By Haploidentical Allogeneic Hematopoietic Cell Transplantation for Advanced Acute Leukemia or High-Risk MDS

Background: Although hematopoietic cell transplantation (HCT) may offer the best chance for cure for patients with relapsed/refractory hematologic malignancies, many of these patients will relapse after HCT. Escalating doses of total body irradiation (TBI) or chemotherapy prior to HCT can decrease relapse, but incurs higher toxicity, resulting in no survival benefit. Therefore, there is a need to reduce relapse without increasing the toxicity of the conditioning regimen prior to HCT. In addition, many potentially curable candidates for HCT do not have a fully human leukocyte antigen (HLA) matched donor. This is an especially challenging hurdle for many ethnic minority patients, yet nearly all patients have a related donor identical for one HLA haplotype (i.e., haploidentical). Radioiodinated anti-CD45 radioimmunotherapy (RIT) has been shown to deliver high-doses of radiation specifically to hematolymphoid organs, while sparing normal tissues. We report a phase I/II study using iodine-131 (131I)-anti-CD45 antibody (BC8) combined with pre- and post-transplant cyclophosphamide, and reduced intensity conditioning prior to haploidentical HCT.Methods and Patients: Eligible patients over the age of 18 had relapsed or refractory acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), or high-risk (>5% active marrow blasts) myelodysplastic syndrome (MDS). Patients received a 131I-anti-CD45 dosimetry dose, followed by serial gamma-camera imaging for organ dosimetry estimates. One to two weeks later a therapeutic dose delivering escalating doses (12 to 26 Gy) to the liver (the normal organ that received the highest dose) was administered, followed by fludarabine (FLU; 30 mg/m2 on day -6 to -2), cyclophosphamide (CY; 14.5 mg/m2 on day -6 and -5), 200 cGy TBI on day -1, and subsequent haploidentical marrow HCT on day 0. For GVHD prophylaxis, patients received CY (50 mg/kg) on day+3 plus standard tacrolimus and mycophenolate mofetil.Results: A total of 25 patients have been treated (21 with advanced AML, 3 with ALL and 1 with high-risk MDS). Ten patients were in florid refractory relapse with 6-20% abnormal marrow blasts while 9 were in remission with minimal residual disease (MRD) 0.03-5.4% by flow cytometry, and only 6 were in remission and MRD negative by flow cytometry. All 24 patients who had marrow aspiration on day 28 after HCT achieved a morphologic remission, with only two patients showing MRD by flow cytometry (0.002 -1.8% abnormal blasts). There were no graft failures, and all patients with chimerism studies (n=15) had 100% donor CD3+ and CD33+ cell engraftment at day 28 after haploidentical HCT. Median time to neutrophil engraftment (ANC>500/ml for 3 consecutive days) was 15 (range, 12-19) days. Median time to platelet engraftment (platelets >20,000/ml for 7 consecutive days without transfusion support) was 23 (19-44) days. The maximum tolerated dose was not determined and there were no unexpected adverse events, as the most frequent grade ≥3 adverse events were infections/neutropenic fevers (32), gastrointestinal (22), and laboratory abnormalities (cytopenias 18; metabolic 16). Five patients had grades 3-4 acute GVHD. Twelve patients relapsed with median time to relapse of 2.4 months. Most deaths have been from relapse (11), and infections (2). Eight (32%) patients were alive at a median follow up of 4 years after HCT (range 1 to 9 years). Overall survival at one and three year was 42% and 26%, and progression-free survival was 40% and 25%, respectively (Figure).Conclusions: Although patients with active disease are not traditionally referred for HCT, the use of 131I-anti-CD45 RIT prior to a haploidentical HCT may facilitate improved survival for these patients. Given these results, anti-CD45 RIT prior to HCT using haploidentical donors warrants further investigation for patients with advanced leukemia and high-risk MDS. [Display omitted] DisclosuresOrozco:Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Shadman:PLEXXIKON: Research Funding; AbbVie: Other: advisory board; Genentech: Consultancy, Research Funding; Emergent: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Pharmacyclics: Other: advisory board, Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding. Pagel:Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.