Marrow Dose Research Articles

Bone marrow toxicity in patients with locally advanced cervical cancer undergoing multimodal treatment with VMAT/IMRT: are there dosimetric predictors for toxicity?

PurposeFor women with locoregionally advanced cervical cancer, the standard of care treatment is the curatively intended chemoradiation therapy (CRT). A relationship between bone marrow (BM) dose–volume histograms (DVHs) and acute hematological toxicity (HT) has been debated recently. Aim of this study was the evaluation of BM dose constraints and HT in a contemporary patient cohort.MethodsRadiation treatment plans of 31 patients with cervical cancer (FIGO stage IIB–IVB) treated with intensity-modulated radiotherapy and simultaneous chemotherapy were explored retrospective. Pelvic bones (PB) and femoral heads (FH) were contoured and DVHs were correlated with white blood cells (WBC), hemoglobin levels and platelets.ResultsComparing the absolute blood levels with the dose volumes of both FH and PB the data showed a significant correlation between WBC and the median dose of the FH and the median dose, V30Gy, V40Gy and V50Gy of the PB. A correlation between the toxicity grade of anemia and mean dose, maximum dose and V5Gy of the PB was found. Counting the highest grade of HT of all three blood levels of each patient, significant correlations were found for the mean and median dose, V30Gy, V40Gy and V50Gy of the PB.ConclusionThe results show that blood levels may correlate with distinct dosimetric subvolumes of critical bone marrow compartments with a potential impact on therapeutic outcome and treatment-related toxicity. The data presented are in line with the previous findings on the relevance of dosimetric exposure of pelvic bony subvolumes.

Leukaemia, lymphoma, and multiple myeloma mortality after low-level exposure to ionising radiation in nuclear workers (INWORKS): updated findings from an international cohort study

A major update to the International Nuclear Workers Study (INWORKS) was undertaken to strengthen understanding of associations between low-dose exposure to penetrating forms of ionising radiation and mortality. Here, we report on associations between radiation dose and mortality due to haematological malignancies. We assembled a cohort of 309 932 radiation-monitored workers (269 487 [87%] males and 40 445 [13%] females) employed for at least 1 year by a nuclear facility in France (60 697 workers), the UK (147 872 workers), and the USA (101 363 workers). Workers were individually monitored for external radiation exposure and followed-up from Jan 1, 1944, to Dec 31, 2016, accruing 10·72 million person-years of follow-up. Radiation-mortality associations were quantified in terms of the excess relative rate (ERR) per Gy of radiation dose to red bone marrow for leukaemia excluding chronic lymphocytic leukaemia (CLL), as well as subtypes of leukaemia, myelodysplastic syndromes, non-Hodgkin and Hodgkin lymphomas, and multiple myeloma. Estimates of association were obtained using Poisson regression methods. The association between cumulative dose to red bone marrow, lagged 2 years, and leukaemia (excluding CLL) mortality was well described by a linear model (ERR per Gy 2·68, 90% CI 1·13 to 4·55, n=771) and was not modified by neutron exposure, internal contamination monitoring status, or period of hire. Positive associations were also observed for chronic myeloid leukaemia (9·57, 4·00 to 17·91, n=122) and myelodysplastic syndromes alone (3·19, 0·35 to 7·33, n=163) or combined with acute myeloid leukaemia (1·55, 0·05 to 3·42, n=598). No significant association was observed for acute lymphoblastic leukaemia (4·25, -4·19 to 19·32, n=49) or CLL (0·20, -1·81 to 2·21, n=242). A positive association was observed between radiation dose and multiple myeloma (1·62, 0·06 to 3·64, n=527) whereas minimal evidence of association was observed between radiation dose and non-Hodgkin lymphoma (0·27, -0·61 to 1·39, n=1146) or Hodgkin lymphoma (0·60, -3·64 to 4·83, n=122) mortality. This study reports a positive association between protracted low dose exposure to ionising radiation and mortality due to some haematological malignancies. Given the relatively low doses typically accrued by workers in this study (16 mGy average cumulative red bone marrow dose) the radiation attributable absolute risk of leukaemia mortality in this population is low (one excess death in 10 000 workers over a 35-year period). These results can inform radiation protection standards and will provide input for discussions on the radiation protection system. National Cancer Institute, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Institut de Radioprotection et de Sûreté Nucléaire, Orano, Electricité de France, UK Health Security Agency. For the French translation of the abstract see Supplementary Materials section.

Conversion from the frequency of chromosome translocations in T-lymphocytes to the bone marrow dose in the long-term period after internal 89,90 Sr exposure

Cytogenetic Fluorescence In Situ Hybridization studies, that allow assessing the frequency of stable chromosome aberrations in circulating T lymphocytes, are commonly used in retrospective dosimetry in cases of uniform whole-body exposure. In the event of 89,90Sr exposure, interpretation of cytogenetic data is challenging, especially if blood sampling occurs long after the start of exposure. The weighted average dose to T-lymphocytes at the time of donor blood sampling in the long-term period after exposure to 89,90Sr does not coincide with the red bone marrow dose. Previously, we developed a model that allows us to estimate the weighted average doses to T-lymphocytes upon 89,90Sr ingress into the body of people belonging to various age groups. In this study, the modeling results were used to estimate the conversion factors from the frequency of translocations to the red bone marrow dose, which is important for assessing radiobiological effects associated with hematological diseases. The objective of our study is to estimate numerically the conversion factors (Brbm) from the dose to lymphocytes to the dose to red bone marrow for various scenarios of 89,90Sr ingestion depending on age, sex, and time after the start of exposure. The following scenarios are considered: single, uniform chronic for six months, uniform chronic for 1-5 years, non-uniform intake for 5 years (simulates the dynamics of intake in the Techa riverside settlements in 1950-1954). As a result, it has been found that the Brbm values significantly depend on the age at the time of 89,90Sr intake. The older the person is at the start of exposure, the more the cytogenetic dose differs (it is significantly lower) from the dose to the red bone marrow. We can say that the cytogenetic dose corresponds to the red bone marrow dose only in newborns and infants. This is due to the age-related dynamics of T-cell populations. Sex does not have a significant effect on Brbm. The effect of the 89,90Sr intake duration on Brbm is the most pronounced for 15-year-old adolescents. For them, the difference in Brbm values for a single and chronic 5-year ingress reaches 13%. Non-uniform intake of 90Sr over several years does not have a significant effect on Brbm and can be modelled by a uniform intake of the same duration.

Dosimetry of 131I in remnant ablation and metastasis of differentiated thyroid cancer treated with high radioactivities and rhTSH

Purpose: Ruling out that healthy organs receive doses higher than those allowed in treatments with Iodo-131 (131I) for ablation of thyroid remnant is crucial for the radiological protection of the patient who also received the recombinant human thyroid-stimulating hormone (rhTSH). So, the investigation aimed to determine the changes in energy imparted by 131I in multiple organs due to the rhTSH in thyroid remnants and metastases of patients treated with high 131I activities (≥ 5,550 MBq). Materials and methods: Nine patients were divided into three groups (three per group); Group I included thyroid hormone withdrawal (THW) patients, while patients in groups II and III were stimulated with rhTSH. The activity and absorbed dose in regions of interest (ROIs) was quantified using the conjugated views method using gamma camera images. Results and discussion: Dosimetric variations of 131I produced by using rhTSH in the remnant thyroid (groups II and III) were observed, absorbed doses were minor for groups treated with rhTSH. Conclusion: The application of the high activities > 5,500 MBq administered together with the application of rhTSH is safe in dosimetric terms, also for 9250 MBq do not exceed established limits of absorbed dose in the bone marrow. Furthermore, these high activities provide more than three times the radiation dose to remaining thyroid tissue and approximately 1.5 times to metastases.

Association of effective dose to immune cells and vertebral marrow dose with hematologic toxicity during neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma

BackgroundTo explore the correlation between effective dose to immune cells (EDIC) and vertebral bone marrow dose and hematologic toxicity (HT) for esophageal squamous cell carcinoma (ESCC) during neoadjuvant chemoradiotherapy (nCRT).MethodsThe study included 106 ESCC patients treated with nCRT. We collected dosimetric parameters, including vertebral body volumes receiving 10–40 Gy (V10, V20, V30, V40) and EDIC and complete blood counts. Associations of the cell nadir and dosimetric parameters were examined by linear and logistic regression analysis. The receiver operating characteristic (ROC) curves were used to determine the cutoff values for the dosimetric parameters.ResultsDuring nCRT, the incidence of grade 3–4 lymphopenia, leukopenia, and neutropenia was 76.4%, 37.3%, and 37.3%, respectively. Patients with EDIC ≤ 4.63 Gy plus V10 ≤ 140.3 ml were strongly associated with lower risk of grade 3–4 lymphopenia (OR, 0.050; P < 0.001), and patients with EDIC ≤ 4.53 Gy plus V10 ≤ 100.9 ml were strongly associated with lower risk of grade 3–4 leukopenia (OR, 0.177; P = 0.011), and patients with EDIC ≤ 5.79 Gy were strongly associated with lower risk of grade 3–4 neutropenia (OR, 0.401; P = 0.031). Kaplan-Meier analysis showed that there was a significant difference among all groups for grade 3–4 lymphopenia, leukopenia, and neutropenia (P < 0.05).ConclusionThe dose of vertebral bone marrow irradiation and EDIC were significantly correlated with grade 3–4 leukopenia and lymphopenia, and EDIC was significantly correlated with grade 3–4 neutropenia. Reducing vertebral bone marrow irradiation and EDIC effectively reduce the incidence of HT.

Genotoxic effects of ablative treatment with I-131 determined through the analysis of dicentric chromosomes in peripheral blood lymphocytes. Can it influence the clinical management of patients with differentiated thyroid carcinoma?

Study including 61 differentiated thyroid cancer (DTC) patients who received ablative doses of I-131 after total thyroidectomy. Biodosimetry was performed by dicentric chromosomes analysis before and after treatment, determining dicentric yield and blood absorbed dose. An increased yield of dicentrics after treatment was demonstrated. With an average administered activity of 4.32 ± 0.879 GBq, the absorbed dose in bone marrow was 0.28 Gy (0.25–0.30 95% CI). These data were compared with the administered I-131 activity and body mass index. Increased genotoxic effects were observed, with a slightly higher dicentric yield rising along I-131 activity. No correlation was found between administered activity and BMI. No significant risk of myelotoxicity due to dose regimens of I-131 intended for ablative purposes in “de novo” treated patients was found among the ranges of activities used in clinical practice. Biodosimetric data was included in patients’ Clinical History, which translates into a more detailed dosimetric report. With this information, physicians can take a more patient-specific approach. Personalized administration would be of special consideration in the event of re-treatments, be it due to recurrent disease or I-131 refractory DTC patients.

Model of age-dependent dynamics and biokinetics of T-cells as natural biodosimeters.

Circulating T-lymphocytes are used as "natural biodosimeters" for estimating radiation doses, since the frequency of chromosomal aberrations induced in them is proportional to the accumulated dose. Moreover, stable chromosomal aberrations (translocations) are detected years and decades after exposure. Internal incorporation of radionuclides often leads to non-uniform exposure, which resulted in difficulties in the application of retrospective biodosimetry using T-lymphocytes. Some properties of T-lymphocytes complicate retrospective biodosimetry in this case: (1) the thymic production of T-cells depends significantly on age, the maximum is observed in early childhood; (2) the "lymphocyte-dosimeter" accumulates changes (translocations) while circulating through the body. The objective of this paper is to describe the technical characteristics of the model of age dynamics and T-cell biokinetics and approaches to assessing the dose to circulating lymphocytes under various exposure scenarios. The model allows to quantify the fractions of T-lymphocytes that were formed before and after exposure. The model takes into account the time fractions that circulating lymphocytes spend in various lymphoid organs. Age-related thymic involution was also considered. The model predicts that after internal exposure to 90Sr, the doses to T-lymphocytes can differ significantly from the doses to the bone marrow and other tissues. For uniform external γ-exposure, and for internal exposure due to non-bone -seeking radionuclides (for example, 144Ce), predicted doses to T-lymphocytes are very close to bone marrow doses. The model allows to quantify the correction factors for FISH-based doses to obtain doses to organs and tissues.

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies.

In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately. To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients. The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach. The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8cm (mean) with 0.5cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7Gy (mean) with 1.0Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2Gy (mean) with 10.8Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4Gy (mean) with 0.4Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient). We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90-95%, V20 < 65-86.6% and V40 < 22.8-40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

2976: CT- VS MRI-based Bone Marrow Dose in CCRT for Cervix cancer: A Pooled Data from 2 Prospective Trials

2976: CT- VS MRI-based Bone Marrow Dose in CCRT for Cervix cancer: A Pooled Data from 2 Prospective Trials

Impact of different models based on blood samples and images for bone marrow dosimetry after 177Lu-labeled somatostatin-receptor therapy

BackgroundPeptide receptor radionuclide therapy with 177Lu-DOTATATE is a recognized option for treating neuroendocrine tumors and has few toxicities, except for the kidneys and bone marrow. The bone marrow dose is generally derived from a SPECT/CT image-based method with four timepoints or from a blood-based method with up to 9 timepoints, but there is still no reference method. This retrospective single-center study on the same cohort of patients compared the calculated bone marrow dose administered with both methods using mono, bi- or tri-exponential models. For the image-based method, the dose was estimated using Planetdose© software. Pearson correlation coefficients were calculated. We also studied the impact of late timepoints for both methods.ResultsThe bone marrow dose was calculated for 131 treatments with the blood-based method and for 17 with the image-based method. In the former, the median absorbed dose was 15.3, 20.5 and 28.3 mGy/GBq with the mono-, bi- and tri-exponential model, respectively. With the image-based method, the median absorbed dose was 63.9, 41.9 and 60.8 with the mono-, bi- and tri-exponential model, respectively. Blood samples after 24h post-injection did not evidence any change in the absorbed bone marrow dose with the bi-exponential model. On the contrary, the 6-day post-injection timepoint was more informative with the image-based model.ConclusionThis study confirms that the estimated bone marrow dose is significantly lower with the blood-based method than with the image-based method. The blood-based method with a bi-exponential model proved particularly useful, without the need for blood samples after 24h post-injection. Nevertheless, this blood-based method is based on an assumption that needs to be more validated. The important difference between the two methods does not allow to determine the optimal one to estimate the true absorbed dose and further studies are necessary to compare with biological effects.

Low-dose radiation therapy for COVID-19 pneumonia: Comparison of dosimetry and life-time attributable risk of cancer with conventional AP-PA fields and bone marrow sparing VMAT.

Low-dose radiation therapy (LDRT) to lungs did show encouraging results in COVID-19 patients in some clinical trials. However, there has been some concern regarding the long-term risk of radiation-induced cancer (RIC). Compared to the conventional AP-PA field technique, volumetric modulated arc therapy (VMAT) can potentially reduce the dose to the marrow and other organs at risk (OARs) and thus minimize the risk of cancer. We designed a dosimetry study to study if VMAT can reduce the exposure to the marrow and other OAR doses and curtail the estimated life-time attributable risk (LAR) of cancer. We retrieved the computed tomography scan data of 10 patients (aged 40-60 years, median 48 years) who have been already treated for any malignancy in the region of the thorax. A dose of 1.0 Gy in single fraction was prescribed to both lungs. All the organs were delineated as per the established guidelines. The dosimetry achieved by the two plans was compared to find the difference. Mean OAR doses were used to estimate the LAR for both plans and compared. Planning target volume coverage parameters like conformity index and homogeneity index were significantly better with VMAT (P value < 0.05 for all). The mean dose to most OARs was significantly lower with VMAT (P value < 0.05 for all). The mean dose to the marrow was significantly lower with VMAT (59.05 vs 81.9 cGy with P value < 0.05). The overall LAR was significantly lower with VMAT as compared to the conventional plan (0.357% vs 0.398%, P value < 0.05). Compared to the conventional technique, VMAT provides better OAR dosimetry for lung irradiation (a prescription dose of 1.0 Gy or more) in COVID-19 pneumonia. VMAT significantly reduces the risk of RIC. We therefore suggest if lung LDRT is used for COVID-19 patients, VMAT is the preferred technique for a prescription dose of ≥1.0 Gy.

Investigation on Individual Variation of Organ Doses for Photon External Exposures: A Monte Carlo Simulation Study

Background: The reference dose coefficients (DCs) of the International Commission on Radiological Protection (ICRP) have been widely used to estimate organ doses of individuals for risk assessments. This approach has been well accepted because individual anatomy data are usually unavailable, although dosimetric uncertainty exists due to the anatomical difference between the reference phantoms and the individuals. We attempted to quantify the individual variation of organ doses for photon external exposures by calculating and comparing organ DCs for 30 individuals against the ICRP reference DCs.Materials and Methods: We acquired computed tomography images from 30 patients in which eight organs (brain, breasts, liver, lungs, skeleton, skin, stomach, and urinary bladder) were segmented using the ImageJ software to create voxel phantoms. The phantoms were implemented into the Monte Carlo N-Particle 6 (MCNP6) code and then irradiated by broad parallel photon beams (10 keV to 10 MeV) at four directions (antero-posterior, postero-anterior, left-lateral, right-lateral) to calculate organ DCsResults and Discussion: There was significant variation in organ doses due to the difference in anatomy among the individuals, especially in the kilovoltage region (e.g., &lt;100 keV). For example, the red bone marrow doses at 0.01 MeV varied from 3 to 7 orders of the magnitude depending on the irradiation geometry. In contrast, in the megavoltage region (1–10 MeV), the individual variation of the organ doses was found to be negligibly small (differences &lt;10%). It was also interesting to observe that the organ doses of the ICRP reference phantoms showed good agreement with the mean values of the organ doses among the patients in many casesConclusion: The results of this study would be informative to improve insights in individualspecific dosimetry. It should be extended to further studies in terms of many different aspects (e.g., other particles such as neutrons, other exposures such as internal exposures, and a larger number of individuals/patients) in the future.

Evaluation of 188Re- IBA as a novel radiopharmaceutical for bone marrow ablation

In this study, Ibandronate as a third generation of bisphosphonates was labeled with rhenium-188 radionuclide. Production and quality control of 188Re-IBA radiopharmaceutical was investigated. The radiation absorbed dose of this radiopharmaceutical was evaluated for adult male based on biodistribution data in mice using the RADAR and Sparks and Aydogan methodologies. The 188Re-IBA was produced with more than 96% radiochemical purity. The highest value of %ID/g was related to bone with 7.11% at 12 h post-injection. About 48% of injected activity was cumulated on the surface of bone tissue 48 h post-injection. The imaging studies confirmed the biodistribution pattern. Radiation absorbed doses of red bone marrow and osteogenic cells were estimated to about 0.39 and 0.71 mGy MBq-1, respectively. The maximum administrated activity was obtained 73.1 MBq kg-1 (2.0 mCi kg-1) of body weight. Effective dose was evaluated about 0.09 mSv MBq-1. The results were compared with other clinically used bone pain palliation radiopharmaceuticals. It was concluded that the 188Re-IBA radiopharmaceutical has a great tendency to be absorbed in bone tissue and it can provide sufficient care for bone marrow ablation with low undesired dose to other normal organs.

Dosimetric impact of bone marrow sparing for robustly optimized IMPT for locally advanced cervical cancer

Background and purposeTo investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC). Materials and methodsTwenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated. ResultsA total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7–21.6] GyRBE , which reduced to 12.0 [10.0–14.0] GyRBE with maximum BMS. The mean OAR dose [range] increased modestly for 1 GyRBE BMS: 0.2 [0.0 – 0.6] GyRBE for bladder, 0.3 [-0.2 – 0.7] GyRBE for rectum, 0.4 [0.1 – 0.8] GyRBE for small bowel, and 0.2 [-0.2 – 0.4] GyRBE for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 – 6.7] GyRBE for bladder, 5.8 [1.8 – 12.4] GyRBE for rectum, 3.9 [1.6 – 5.9] GyRBE for small bowel, and 2.7 [0.6 – 5.9] GyRBE for sigmoid. ConclusionAchieving 1 GyRBE BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks.

Risk of treatment-altering haematological toxicity and its dependence on bone marrow doses in peptide receptor radionuclide therapy

BackgroundPeptide receptor radionuclide therapy is effective in treating neuroendocrine tumours, but treatment may be limited by kidney and bone marrow toxicity. In this work, the absorbed dose burden to the bone marrow was estimated using image-based dosimetry and its potential use for predicting treatment-altering toxicity was studied. Peripheral blood samples taken before and after 229 treatments with 177Lu-DOTATATE in 59 patients were studied. In connection to the treatments, a total of 940 blood sample occasions provided data on white blood cell, neutrophil granulocyte, platelet, erythrocyte and haemoglobin concentrations. SPECT/CT image data were collected at two or three time points after each treatment. Absorbed doses to bone marrow were calculated from the activity concentration in a metastasis-free lumbar vertebra. The rate of delayed and aborted treatments was analysed based on medical records.ResultsThe average absorbed dose to the bone marrow was 0.42 Gy (median 0.33 Gy, SD 0.27 Gy) per treatment. Dose–response relationships between white blood cells, neutrophil granulocytes and haemoglobin concentrations were observed, most prominently at 31–45 days after each treatment. The correlations were stronger in patients with skeletal metastases. The rates of haematological toxicity-related delays and aborted treatments were 6% and 12%, respectively. None of the studied bone marrow dosimetric parameters could clearly predict treatment-related toxicity. However, patients with skeletal metastases had higher risk of treatment-altering toxicity (odds ratio = 6.0).ConclusionsTreatment-altering haematological toxicity in peptide receptor radionuclide therapy is relatively rare and appears difficult to fully predict from post-therapeutic image-based dosimetry. However, for patients with skeletal metastases, the haematological dose–response relationships are stronger. Future studies may focus on this patient group, to further investigate the usefulness of dosimetry in predicting decreases in blood values.

Rapid predictive dosimetry for Second Strike prescription based on whole body radioiodine kinetics in differentiated thyroid cancer.

In systemic radionuclide therapy such as radioiodine (I-131) for differentiated thyroid cancer, post-therapy dosimetry is essential to verify pre-therapy predictions, which in turn informs the next treatment. However, post-therapy multi-time point dosimetry is resource intensive and unfeasible in many institutions. We devised a schema of rapid predictive dosimetry by circumventing post-First Strike multi-time point dosimetry with carefully assigned gestalt values of predicted kinetics to personalise the Second Strike prescription. Verification is performed after the First Strike. Patient-specific time-activity curve is plotted from serial measurements of whole body exposure rates to obtain its decay constant; its inverse is the whole body Time Integrated Activity Coefficient (TIAC). The percentage of whole body TIAC attributed to blood is carefully assigned by gestalt based on population kinetics tabulated in Part 1, adjusted by any metastasis on I-131 whole body scintigraphy. Marrow absorbed dose is calculated by EANM formularism. Lung safety threshold at 48h post-therapy is linearly scaled by height, where the patient's risk of lung radiotoxicity is revealed from the whole body time-activity curve value at 48h. Predictive prescription for the second I-131 fraction (Second Strike) is by careful gestalt assessment based on predicted kinetics, remaining marrow and lung tolerance, marrow dose rate constraint per fraction (0.265 Gy/h), local regulatory and facility requirements in relation to radiation protection. Tumour dosimetry is obviated under the assumption of severe tumour absorbed dose heterogeneity. The final prescription for the Second Strike is usually the lowest I-131 activity amongst all clinical, dosimetric and regulatory constraints. This schema is incorporated into a Predictive Calculator spreadsheet for rapid predictive dosimetry, and is freely available. Calculations may be completed within minutes to generate personalised predictive prescriptions, making it feasible for routine clinical implementation. Our innovative schema of rapid verification and predictive dosimetry bridges the technological gap between empiric vs theranostic prescription to help institutions modernise. Its expeditious design makes this schema feasible to be integrated into the routine clinical workflow. Its predictive estimates provide invaluable dosimetric insight to inform the next I-131 fraction, allowing every prescription to be scientifically rationalised and personalised according to individual circumstances.

DHODH Inhibitor Therapy for the Treatment of T-ALL Spares the Developing Thymus

Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in children and young adults. When compared to B-ALL, T-ALL has a higher rate of induction failure as well as relapse, with very poor overall survival in both scenarios. Furthermore, T-ALL has not benefitted from immune-mediated therapies and continues to pose an ongoing treatment challenge with an unmet therapeutic need. DHODH has been highlighted as a potential therapeutic target in many hematologic and solid tumor malignancies including AML, neuroblastoma, glioblastoma, pancreatic cancer, and breast cancer. DHODH inhibition has a robust anti-leukemia effect in both in vitro and in vivo models of T-ALL. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T-ALL, including an aggressive NOTCH driven model in syngeneic recipients and two human patient derived xenografts. Given the goal of making DHODHi therapy available to young children with relapsed/refractory T-ALL, we wished to understand the ramifications of nucleotide starvation on normal T-cells and other hematopoietic progenitors. To specifically address this, we turned our attention to the effects of DHODH inhibition on the developing thymus. This compartment would be of particular interest in pediatric patients, whose thymi have not yet finished developing. We studied juvenile mice (3 weeks) whose thymi are just reaching their peak size and growth rate. These mice were treated with the small molecule DHODHi brequinar (BRQ) 50 mg/kg every 72 hours, and were paired with age and gender-matched controls at each time point of analysis. A subset of mice were analyzed following two doses of BRQ, and thymus, bone marrow, spleen, and peripheral blood were analyzed for T-cell populations, both relative and absolute numbers. Another cohort was allowed to “recover” for 2 weeks following treatment before analysis, and a third cohort was allowed a four week recovery period. We discovered that initial treatment with brequinar significantly impacts T-cells across all stages of development ( Figure 1). This is expected, as developing T-cells are rapidly proliferative (often dividing as quickly as every 6 hours) and therefore highly dependent on their supply of nucleotides for DNA replication as well as transcription. However, after the two-week and the four-week recovery periods, these differences are no longer detectable, demonstrating the resilience of the developing thymus, and demonstrating that the effects of nucleotide starvation are temporary and reversible. These data are encouraging, as this may also suggest that the developing human thymus which is similarly rapidly proliferative in nature would also recover once nucleotide starvation was removed. Based on these data, we were interested in understanding the differential sensitivity of normal thymocytes as compared to malignant T-lymphoblasts to DHODHi. The resilience shown by normal thymocytes following treatment with BRQ may be due to their ability to tolerate periods of inhibition of de novo pyrimidine synthesis by preferentially relying on extracellular nucleotide salvage, whereas the sensitivity of malignant T-cells to DHODH may be due to their lack of ability to utilize the salvage pathway. We performed experiments to understand how cells balance de novo synthesis vs extracellular salvage. First, we performed metabolite flux tracing in Jurkat cells to directly measure nucleotide salvage. Here, we followed incorporation of isotopically labeled glutamine ( 15N) and uridine ( 13C) to determine the relative contributions of synthesis vs salvage, as de novo pyrimidine synthesis initiates from glutamine and aspartate while a cell can also use membrane nucleoside transporters (SLC28A and SLC29A family of proteins) to salvage extracellular uridine. These experiments were performed in the presence and absence of BRQ. Once BRQ is added and the cell's ability to synthesize pyrimidines is shut down, the cell must rely more on extracellular salvage as shown in Figure 2. A defective or less efficient process of extracellular salvage could help to explain this cell line's unusual dependence on de novo nucleotide synthesis. Overall, we hope that these findings will pave the way for additional preclinical studies and eventually clinical trials for pediatric patients with T-cell disease.

High-Dose Targeted Radiation with 131I-Apamistamab Prior to HCT Demonstrated a Dose-Response for Durable Complete Remission in Patients with R/R AML

Background: Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can provide these pts with access to alloHCT. Methods: SIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of 131I-apamistamab led induction and conditioning versus physician's choice of conventional care (CC) in pts ≥55 years of age with active, R/R AML. Pts were randomized (1:1, n=153) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Primary endpoint was durable complete remission (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Pts not achieving CR in CC could crossover (CO) to receive 131I-apamistamab. Treatment with 131I-apamistamab was prescribed as an individualized dose for each pt following a dosimetric infusion and biodistribution analysis, with the prescribed activity of 131I set to deliver a maximum estimated radiation dose to the liver as the dose limiting organ of 24 Gy (determined as the maximum tolerable dose (MTD)) in earlier studies), thereby providing the highest dose to the diseased bone marrow and circulating leukemic cells without exceeding individual organ radiation dose tolerances. Here, we performed an analysis to determine whether a radiation dose-response relationship could be established based on either 1) administered radiation dose to liver and the rate of achieving the primary endpoint of dCR (with 95% binomial confidence intervals) or 2) dCR rate and the ratio of bone marrow/liver absorbed radiation dose as an indicator of favorable biodistribution between target/risk organ. Results: All pts receiving the therapeutic dose of 131I-apamistamab (n=66) were able to receive an alloHCT, and the primary endpoint (dCR) was achieved in 13 pts receiving 131I-apamistamab vs 0 pts in CC (p&amp;lt;0.0001). The median absorbed liver dose was 21.6 Gy (IQR: 21.0 - 22.8 Gy), median absorbed dose to bone marrow was 16.0 Gy (IQR: 11.5 - 22.3 Gy), and median ratio between marrow/liver dose was 0.79 (IQR: 0.52 - 1.02). Table 1 shows the distribution and rate of dCR for pts who received above or below 22 Gy administered dose to liver (24 Gy to liver was the established MTD from earlier studies, in which doses were escalated in 2 Gy increment and thus, 22 Gy represented MTD-1), and for pts stratified by marrow/liver dose ratio (higher ratio representing more favorable biodistribution). Pts with ≤22 Gy liver dose had a dCR rate of 13.5% vs. 27.6% for pts with &amp;gt;22 Gy liver dose, and pts with &amp;lt;median dose to bone marrow had a dCR rate of 12.1% vs. 27.3% for pts with ≥median estimated marrow dose. Importantly, pts with increasingly favorable biodistribution had nominally higher dCR rates of 10.0%, 20.0% and 26.9% for a marrow/liver ratio &amp;lt;0.6, 0.6-0.9 and &amp;gt;0.9, respectively, as illustrated in Figure 1. Taken together this demonstrates a radiation dose-response for the primary endpoint in this study. Overall, safety was similar across doses to the liver. Conclusion: 131I-apamistamab led induction and conditioning followed by alloHCT resulted in statistically significant improvement in dCR at 6 mos vs conventional care. A dose-response was demonstrated for pts receiving 131I-apamistamab with those receiving a liver dose closer to the MTD of 24 Gy having about twice the dCR rate compared to pts 22 Gy (MTD-1) or less. We also found pts with higher marrow/liver ratio experienced considerably higher rates of dCR which highlights the importance of maximizing the dose to target tissues, within the limits of established risk organ dose tolerances.

Effect of Chronic Radiation Exposure on Human microRNA Expression

Relative expression of mature microRNA assessed in peripheral blood cells in persons chronically exposed to low-dose radiation in the long-term period. The study included people exposed in the 1950s on the Techa River (Southern Urals, Russia). The cumulative red bone marrow doses (RBM) of the persons in the main study group (33 persons) ranged from 77.7 to 2869.8 mGy (mean value – 698.5 mGy). The comparison group consisted of 30 people with RBM dose not exceeding 70 mGy over their lifetime. Reverse transcription of RNA samples was performed using specific stem-loop primers (“stem-loop”). Changes in the relative content of microRNA were assessed by real-time PCR on the CFX96 detection system (BioRad, USA). Statistical analysis of the results was performed using Mann–Whitney U-criterion. A significant increase in hsa-miR-125b, hsa-miR-181a, and hsa-miR-16-5p content was detected in exposed people after 60 years, and their expression was found to depend on the RBM dose.