Total Marrow And Lymphoid Irradiation Research Articles

Assessment of lymph node area coverage with total marrow irradiation and implementation of total marrow and lymphoid irradiation using automated deep learning-based segmentation.

Total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) have the advantages. However, delineating target lesions according to TMI and TMLI plans is labor-intensive and time-consuming. In addition, although the delineation of target lesions between TMI and TMLI differs, the clinical distinction is not clear, and the lymph node (LN) area coverage during TMI remains uncertain. Accordingly, this study calculates the LN area coverage according to the TMI plan. Further, a deep learning-based model for delineating LN areas is trained and evaluated. Whole-body regional LN areas were manually contoured in patients treated according to a TMI plan. The dose coverage of the delineated LN areas in the TMI plan was estimated. To train the deep learning model for automatic segmentation, additional whole-body computed tomography data were obtained from other patients. The patients and data were divided into training/validation and test groups and models were developed using the "nnU-NET" framework. The trained models were evaluated using Dice similarity coefficient (DSC), precision, recall, and Hausdorff distance 95 (HD95). The time required to contour and trim predicted results manually using the deep learning model was measured and compared. The dose coverage for LN areas by TMI plan had V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% median values of 46.0%, 62.1%, and 73.5%, respectively. The lowest V100% values were identified in the inguinal (14.7%), external iliac (21.8%), and para-aortic (42.8%) LNs. The median values of DSC, precision, recall, and HD95 of the trained model were 0.79, 0.83, 0.76, and 2.63, respectively. The time for manual contouring and simply modified predicted contouring were statistically significantly different. The dose coverage in the inguinal, external iliac, and para-aortic LN areas was suboptimal when treatment is administered according to the TMI plan. This research demonstrates that the automatic delineation of LN areas using deep learning can facilitate the implementation of TMLI.

Deep learning and atlas-based models to streamline the segmentation workflow of total marrow and lymphoid irradiation.

To improve the workflow of total marrow and lymphoid irradiation (TMLI) by enhancing the delineation of organs at risk (OARs) and clinical target volume (CTV) using deep learning (DL) and atlas-based (AB) segmentation models. Ninety-five TMLI plans optimized in our institute were analyzed. Two commercial DL software were tested for segmenting 18 OARs. An AB model for lymph node CTV (CTV_LN) delineation was built using 20 TMLI patients. The AB model was evaluated on 20 independent patients, and a semiautomatic approach was tested by correcting the automatic contours. The generated OARs and CTV_LN contours were compared to manual contours in terms of topological agreement, dose statistics, and time workload. A clinical decision tree was developed to define a specific contouring strategy for each OAR. The two DL models achieved a median [interquartile range] dice similarity coefficient (DSC) of 0.84 [0.71;0.93] and 0.85 [0.70;0.93] across the OARs. The absolute median Dmean difference between manual and the two DL models was 2.0 [0.7;6.6]% and 2.4 [0.9;7.1]%. The AB model achieved a median DSC of 0.70 [0.66;0.74] for CTV_LN delineation, increasing to 0.94 [0.94;0.95] after manual revision, with minimal Dmean differences. Since September 2022, our institution has implemented DL and AB models for all TMLI patients, reducing from 5 to 2h the time required to complete the entire segmentation process. DL models can streamline the TMLI contouring process of OARs. Manual revision is still necessary for lymph node delineation using AB models.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Total Marrow and Lymphoid Irradiation (TMLI) -Based Conditioning Regimen in Patients with Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplant with Measurable Residual Disease

Relapse of primary hematologic malignancy remains the leading cause of treatment failure afterallogeneic Hematopoietic cell transplantation (allo-HCT). Multiple studies have shown that presence of measurable residual disease (MRD), at the time of HCT, irrespective of the detection method, is associated with lower overall survival (OS) and relapse-free survival (RFS). In a recent meta-analysis of 11,151 patients with AML, Short et al., reported 5-year disease-free survival (DFS) of 25% for patients who have detectable MRD pre -HCT, compared to 64% for those without MRD. The 5-year OS was 34% and 68% for patients with or without MRD at HCT (JAMA Oncology 2020). In AML patients with genomic evidence of MRD before allo-HCT, myeloablative conditioning (MAC) regimens result in improved survival when compared to reduced intensity conditioning (RIC); (Hourigan et al, JCO 2020). Our center has pioneered and developed Total marrow and lymphoid irradiation (TMLI) that allows for delivery of higher dose of radiation to the sites with high disease burden (bone marrow and lymphoid organs), while sparing healthy tissues. In an ongoing Phase 2 trial (NCT02094794), we delivered TMLI (20Gy) with high dose chemotherapy to patients with high-risk leukemias (ALL or AML) undergoing allo-HCT from an HLA matched or mismatched donor. Here, we report on the results of our prospective analysis on a subset of patients of NCT02094794 who underwent allo-HCT with morphologic remission but had detectable MRD status in their pre HCT bone marrow biopsy (n=30). Conditioning regimen comprised of TMLI on days -9 to -5 (total of 20Gy), etoposide (60 mg/kg) on day -4, and cyclophosphamide (100mg/kg) on day -2. Unmanipulated peripheral blood stem cells (PBSC) graft from 10/10 HLA matched related or unrelated donor was infused on day 0 and graft-versus-host disease (GVHD) prophylaxis was tacrolimus and sirolimus-based. TMLI was delivered by intensity modulated radiation therapy (IMRT). MRD assay was done by either University of Washington flow cytometry with 0.01% - 0.1 % sensitivity, FISH/conventional cytogenetics, or NGS-based assays. Patient and HCT characteristics are summarized in Table 1. Briefly, the median age at the time of HCT was 36 years (range: 16-59) with the majority of patients receiving PBSC grafts (87%). Donors were match related (67%) or match unrelated (33%). The underlying diagnosis was AML (n=22; 73%), ALL (n=7; 23%), or CML-BC (n=1; 3%). Karnofsky performance status was 80-100 in 90% of patients and HCT-CI ≥3 was seen in 35% of patients. Pre-HCT MRD + status was documented by Flow cytometry MRD assay in 17 patients [AML (n=14) and ALL (n=3)], with mean MRD positivity of 2.9 % (range: 0.02-5.6%) for AML and 0.4% (range: 0.003-1.7%) for ALL patients. Thirteen additional patients had MRD positive status confirmed by FISH/cytogenetics (n=6 patients) or NGS (n=7). With a median duration follow up of 22.3 months (range: 6.0-81.1), the 1 and 2-year OS were 68% (95% CI: 0.47-0.82) and 59% (95% CI: 0.38-0.75), respectively. The 1 and 2- year disease-free survival (DFS) were 55% (95% CI: 0.34-0.71) and 45% (95% CI: 0.26-0.63), while the cumulative incidence (CI) of relapse at 1 and 2 years were 28% (95% CI: 0.13-0.46) and 33% (95% CI: 0.16-0.51), respectively. At day 100 post-HCT, the CI of NRM was 7%, grade 2-4 acute GVHD was 40% and Grade 3-4 acute GVHD was 13%. The CI of NIH moderate- severe chronic GVHD at 1- year was 35% (95% CI: 0.17-0.52). No difference in outcomes were noted in patients who were MRD positive by UWFC vs FISH/NGS testing. In conclusion, TMLI based conditioning regimen in patients undergoing allo-HCT with MRD+ disease from matched donors is associated with improvement in 2-year RFS/OS and is associated with low NRM compared to historic controls. The current phase 2 study is enrolling patients at our center.

Total marrow lymphoid irradiation IMRT treatment using a novel CT-linac

BackgroundA novel CT-linac (kilovolt fan-beam CT-linac) has been introduced into total marrow and lymphoid irradiation (TMLI) treatment. Its integrated kilovolt fan-beam CT (kV FBCT) can be used not only for image guidance (IGRT) but also to re-calculate the dose.PurposeThis study reported our clinical routine on performing TMIL treatment on the CT-linac, as well as dose distribution comparison between planned and re-calculated based on IGRT FBCT image sets.Methods11 sets of data from 5 male and 6 female patients who had underwent the TMLI treatment with uRT-linac 506c were selected for this study. The planning target volumes consist of all skeletal bones exclusion of the mandible and lymphatic sanctuary sites. A planned dose of 10 Gy was prescribed to all skeletal bones exclusion of the mandible in two fractions and 12 Gy in two fractions was prescribed to lymphatic sanctuary sites. Each TMLI plan contained two sub-plans, one dynamic IMRT for the upper body and the other VMAT for the lower extremity. Two attempts were made to obtain homogeneous dose in the overlapping region, i.e., applying two plans with different isocenters for the treatment of two fractions, and using a dose gradient matching scheme. The CT scans, including planning CT and IGRT FBCT, were stitched to a whole body CT scan for dose distribution evaluation.ResultsThe average beam-on time of Planupper is 30.6 min, ranging from 24.9 to 37.5 min, and the average beam-on time of Planlower is 6.3 min, ranging from 5.7 to 8.2 min. For the planned dose distribution, the 94.79% of the PTVbone is covered by the prescription dose of 10 Gy (V10), and the 94.68% of the PTVlymph is covered by the prescription dose of 12 Gy (V12). For the re-calculated dose distribution, the 92.17% of the PTVbone is covered by the prescription dose of 10 Gy (V10), and the 90.07% of the PTVlymph is covered by the prescription dose of 12 Gy (V12). The results showed that there is a significant difference (p < 0.05) between planning V10, V12 and delivery V10, V12. There is no significant difference (p > 0.05) between planned dose and re-calculated dose on selected organs, except for right lens (p < 0.05, Dmax). The actual delivered maximum dose of right lens is apparently larger than the planned dose of it.ConclusionTMLI treatment can be performed on the CT-linac with clinical acceptable quality and high efficiency. Evaluation of the recalculated dose on IGRT FBCT suggests the treatment was delivered with adequate target coverage.

Whole Regional Lymph Node Area Delineation with Deep Learning Model for Total Marrow and Lymphoid Irradiation.

Total body irradiation (TBI) has been performed for conditioning before hematopoietic stem cell transplantation. However, TBI can be related to diverse adverse events including radiation pneumonitis and cataract. Efforts to reduce these events include the total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI). Compared to TMI, TMLI requires more target delineations with lymph nodes which can be labor-intensive and time-consuming. However, with the TMI plans, the coverage to lymph node might be lower than TMLI and its clinical significance is unknown. In the current study, we aimed to develop a deep learning model for automatic delineation of whole regional lymph nodes area and assess the dose coverage of lymph nodes with TMI plans. Whole regional lymph nodes (cervical, axillary, mediastinal, para-aortic, common iliac, external iliac, internal iliac, obturator, presacral, inguinal lymph nodes) were manually contoured by 3 radiation oncologists in 26 patients having whole body computed tomography (CT) images. Twenty patients were designated as the training/validation set and 6 patients as the testing set, and model was developed using the 'nnUNET' framework. The trained model was evaluated with dice coefficient score (DCS), precision, and recall. In addition, dose coverage of the automatically or manually delineated lymph nodes in TMI plans was calculated. The mean value of DCS, precision, and recall of the trained model was 0.76, 0.81, and 0.74, respectively. Dose parameters for manually delineated lymph nodes in previously treated TMI plans showed the mean value of V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% to be 46.50%, 62.12%, and 73.68%, respectively. The highest V90% was observed in presacral (93.61%), axillary (90.40%), obturator (88.78%), and internal iliac lymph nodes (84.67%). In contrast, the lowest V90% was identified in inguinal (47.95%), cervical (61.69%), and para-aortic (65.75%) and external iliac lymph nodes (68.97%). For automatically delineated lymph nodes, the mean value of V100%, V95%, and V90% of TMI plan was 38.35%, 55.06%, and 67.84%, respectively. The difference with dose coverage of lymph node between delineated manually and automatically was not statistically significant. Automatic delineation of lymph node using deep learning showed the potential to reduce the labor-intensive process of TMLI. When treated with TMI, the coverage of inguinal, cervical, para-aortic and external iliac lymph nodes was lower than expected.

First-in-Human Phase I Trial Combining Biologically Guided Radioimmunotherapy (RIT) Using a 90Y-Anti-CD25 Monoclonal Antibody (Mab) with CT-guided Total Marrow and Lymphoid Irradiation (TMLI) in Relapsed and Refractory (R/R) Acute Leukemia

Patients with R/R acute leukemia after allogeneic hematopoietic cell transplant (alloHCT) have a dismal prognosis with 3-year survival rates of < 20%. To improve outcomes, innovative targeted forms of organ sparing radiotherapy, such as tumor-specific RIT and TMLI, are needed to dose escalate with acceptable toxicities, especially in patients ≥ age 60 years who cannot tolerate total body irradiation (TBI) / myeloablative regimens and who have a poor prognosis. CD25 is an ideal RIT target given its expression in acute leukemias, association with poor prognosis, and expression by leukemia stem cells. In this phase I trial (NCT05139004) we hypothesized that combining dose escalated 90Y-anti-CD25 RIT with fixed dose TMLI 12 Gy, fludarabine (flu), and melphalan (mel) in patients with R/R disease is safe and associated with acceptable toxicities. The primary objective of this trial is to determine the maximum tolerated dose and recommended phase 2 dose of 90Y-anti-CD25 Mab (Day -15) with 12 Gy TMLI (1.5 Gy twice a day, days -8 to -5), flu (30 mg/m2/d days -5 to -2), and mel (100 mg/m2, day -2) in patients ≥ 60 years old or with a HCT-comorbidity index ≥ 2 and with R/R AML, ALL or myelodysplastic syndrome (MDS) scheduled to undergo alloHCT from a matched donor. TMLI mean organ dose constraints for kidney, lung and liver were 4 Gy. Planned dose levels of 90Y-anti-CD25 were 0.3, 0.4, and 0.5 mCi/kg. 111In-anti-CD25 (5 mCi) was co-infused followed by serial nuclear scans to assess dosimetry and biodistribution. To date 5 patients (ages 31-74) with R/R AML have been treated. Marrow and circulating blasts ranged from 10-36% and 9-44%, respectively. For the 3 patients at 0.3 mCi/kg, follow-up ranged from 89-191+ days. 90Y/111In-anti-CD25 nuclear scans demonstrated persistent uptake in bone out to 144 hours, which was associated with a decline in circulating blasts. After combined RIT and TMLI, mean doses (Gy) to lungs ranged from 5.7-6.5, to kidneys from 7.5-8.2 and to liver from 7.2-11.6. No dose-limiting toxicities (DLT) were observed. All 3 patients achieved CR on day +30 bone marrow biopsies and 2 remained in CR on day +90 biopsies. Two patients have recently been treated at the 0.4 mCi/kg dose level. The results of patients treated at the higher dose levels will be provided. Dose escalation by adding 90Y-anti-CD25 RIT at 0.3 mCi/kg to 12 Gy TMLI was safe, including in older patients, with no dose-limiting toxicities, mean critical organ doses lower than conventional myeloablative TBI, and encouraging response rates. The toxicity profile and dose estimates at 0.3 mCi/kg predict that the planned higher dose levels will also be feasible with acceptable toxicities. RIT and TMLI are complementary and when combined address the limitations of each modality. Combining these targeted therapies may be a superior strategy to intensify dose to leukemia compared to dose escalation of either modality alone.

Dosimetric Evaluation of Targets and Organs at Risk in Dose Escalation Study for Total Marrow and Lymphoid Irradiation

Total marrow and lymphoid irradiation (TMLI) delivers radiation dose to the bone marrow and lymph nodal region while reducing the dose to non-target organs. We conducted a dose-escalation study of TMLI to improve treatment outcomes while reducing OAR doses using intensity-modulated radiation therapy. However, this dose escalation strategy may cause increasing risk of recurrence and adverse events because of dose uniformity compromises of the target. We hypothesized that the homogeneity index (HI) could become worse with increased target's dose while maintaining reduced OAR doses for the nine patients enrolled in the TMLI phase Ⅰ clinical trial. Nine patients treated with TMLI using a treatment delivery system from September 2019 to August 2021 were included. The prescribed doses were 14 Gy/6 fr, 16 Gy/6 fr, and 18 Gy/6 fr twice daily for 3 days, with three patients allocated each prescription. Bone marrow, lymph nodal region, spleen, testis, brain, and liver were designated as targets. The bone marrow was divided into eight parts (see Table); an individual PTV margin was added to each structure. We intended to deliver the D80% prescription dose for PTV. For the brain and liver, the prescribed dose was 12 Gy in consideration of function preservation. Lenses, oral cavity, parotid glands, lungs, heart, esophagus, stomach, kidneys, intestines, and breasts were defined as OAR. Targets were evaluated with HI that was calculated using the formula HI = (D2%-D98%)/D50%, based on ICRU report 83. For OARs, Dmax, D2%, D10%, and mean dose constraint were evaluated. The table lists HI for the PTV_ALL and each target. The HI of PTV_ALL rose with increasing prescription dose and was highest at 18 Gy. The highest HI was 0.632 for PTV_Rib at 18 Gy, and the lowest HI was 0.045 for PTV_testis at 14 Gy. OAR Dose constraints were achieved in all patients. The average OAR doses in all cases for lenses, oral cavity, parotid glands, lungs, heart, esophagus, intestines, kidneys, and breast were 4.7±0.80, 4.4±0.51, 6.7±0.48, 7.6±0.22, 7.8±0.19, 6.7±0.18, 7.4±1.12, 6.9±0.96, and 14.7 Gy, respectively. The Dmax of the lenes, D2% of the esophagus, and D10% of the stomach were 7.2 ± 1.09, 11.5 ± 0.47, and 10.9 ± 0.98 Gy, respectively. In the TMLI phase I clinical trial, we evaluated the dose uniformity to the targets and the OAR dose constraints. Although the HI for PTV_ALL worsened with increasing prescription dose, compliance with OAR dose constraints was achieved in all patients.

Dosimetric Study of Total Marrow and Lymphoid Irradiation on a Ring Gantry-Based Medical Linac with a Two-Layer Multi-Leaf Collimator

In this study, we aimed to evaluate dosimetric quality of total marrow and lymphoid irradiation (TMLI) plans for a ring gantry-based medical Linac with a two-layer multi-leaf collimator. We retrospectively retrieved treatment planning CT images, structure sets, and plan dose for four adult patients, two male and two female, who previously received TMLI treatments on helical tomotherapy (HT) at our institution. TMLI plans were optimized for a ring gantry-based medical Linac with a two-layer multi-leaf collimator (Halcyon, Varian Medical Systems, Inc., Palo Alto, CA). A prescription dose of 12 Gy in 8 fractions was prescribed to the skeletal bones from the skull to mid-thigh, spleen, spinal canal, and lymphoid volume. Five or six isocenters were placed with equal spacing along the patient's longitudinal direction in each TMLI plan with two 6-MV flattening filter-free volumetric modulated arc therapy (VMAT) fields at each isocenter. Isocenter separation ranged from 15 cm to 16.5 cm. Each VMAT field has a field size of 28 cm to 28 cm with the collimator at 90° and a full gantry rotation. The nominal dose rate was 800 MU/minute, and the maximum gantry rotation speed was 24°/sec. Institutional dosimetric constraints were used for optimization including a mean lung dose limit of less than 8 Gy. All the plans were normalized so that 85% the primary planning target volume received the prescription dose. The average mean doses to the target volumes ranged from 12.2 to 12.6 Gy in the Halcyon TMLI plans, while they ranged from 12.1 to 12.5 Gy in the HT TMLI plans. Relative to the prescription dose, the average mean dose for normal organs ranged from 21.3% to 56.6% in the Halcyon TMLI plans, while it ranged from 10.1% to 68.4% in the clinical HT plans. The difference in the average mean dose to normal organs was less than 0.5 Gy except two organs between the Halcyon and HT TMLI plans. The average median dose for normal organs ranged from 18.2% to 48.8% relative to the prescription dose in the Halcyon TMLI plans. The mean lung dose (MLD) in the Halcyon TMLI plans met the institutional limit with an average dose of 6.75±0.42 Gy (range: 6.44 - 7.36 Gy), while the average MLD was 6.54±0.77 Gy (range: 6.24 - 7.22 Gy) in the HT plans (p-value = 0.71 in the paired t-test). The average total monitor unit in the Halcyon TMLI plans was 4,425±906 MU (range: 3,470 - 5,575 MU) with an average beam-on time of 5.1±1.3 minutes (range: 4.1 - 7.0 minutes), which excludes isocenter setup time, while the average beam-on time was 22.2±3.2 minutes (range: 19.6 - 26.1 minutes) with the HT plans. Halcyon TMLI plans met our institutional dosimetric constraints with adequate normal organ sparing and target dose coverage. The beam-on time with the Halcyon plans was significantly shorter than that with the HT plans, which could lead to shorter treatment time and increased patient comfort. This study showed the feasibility of TMLI treatments on the Halcyon machine. The same method could be used for total body irradiation on Halcyon.

Evaluation of plan complexity and dosimetric plan quality of total marrow and lymphoid irradiation using volumetric modulated arc therapy

To assess the impact of the planner's experience and optimization algorithm on the plan quality and complexity of total marrow and lymphoid irradiation (TMLI) delivered by means of volumetric modulated arc therapy (VMAT) over 2010-2022 at our institute. Eighty-two consecutive TMLI plans were considered. Three complexity indices were computed to characterize the plans in terms of leaf gap size, irregularity of beam apertures, and modulation complexity. Dosimetric points of the target volume (D2%) and organs at risk (OAR) (Dmean) were automatically extracted to combine them with plan complexity and obtain a global quality score (GQS). The analysis was stratified based on the different optimization algorithms used over the years, including a knowledge-based (KB) model. Patient-specific quality assurance (QA) using Portal Dosimetry was performed retrospectively, and the gamma agreement index (GAI) was investigated in conjunction with plan complexity. Plan complexity significantly reduced over the years (r=-0.50, p<0.01). Significant differences in plan complexity and plan dosimetric quality among the different algorithms were observed. Moreover, the KB model allowed to achieve significantly better dosimetric results to the OARs. The plan quality remained similar or even improved during the years and when moving to a newer algorithm, with GQS increasing from 0.019±0.002 to 0.025±0.003 (p<0.01). The significant correlation between GQS and time (r=0.33, p=0.01) indicated that the planner's experience was relevant to improve the plan quality of TMLI plans. Significant correlations between the GAI and the complexity metrics (r=-0.71, p<0.01) were also found. Both the planner's experience and algorithm version are crucial to achieve an optimal plan quality in TMLI plans. Thus, the impact of the optimization algorithm should be carefully evaluated when a new algorithm is introduced and in system upgrades. Knowledge-based strategies can be useful to increase standardization and improve plan quality of TMLI treatments.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3+3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Phase I Dose Escalation Trial of 3-Day Total Marrow and Lymphoid Irradiation for Leukemia as Part of Myeloablative Conditioning in Unrelated Bone Marrow Transplantation

<h3>Purpose/Objective(s)</h3> Increasing the total body irradiation (TBI) dose during allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to decrease relapse rates. However, higher doses of TBI increase toxicity and long-term morbidity. Total marrow and lymphoid irradiation (TMLI) allow for increased treatment intensity while avoiding dose escalation for at-risk organs. TMLI is expected to improve long-term survival outcomes of HSCT for hematologic malignancies. This prospective phase I trial aimed to determine the recommended dose of 3-day TMLI for a myeloablative conditioning regimen, by increasing the dose per fraction. <h3>Materials/Methods</h3> The eligibility criteria for this study were as follows, 1) diagnosed with hematologic malignancy, 2) planned HSCT with a myeloablative regimen, 3) with clinical remission status at pre-transplantation, and 4) with no evidence of extramedullary disease. The primary endpoint of this single-institution dose escalation study was the recommended TMLI dose, based on the frequency of dose-limiting toxicity (DLT) within 100 days after HSCT; a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in 6 fractions over 3 days) were set, and the treatment protocol began at 14 Gy. DLTs were defined as grade 3 or 4 non-hematological toxicities including those of cardiac, bladder, renal, pulmonary, hepatic, and central nervous system tissues, oral mucositis, gastrointestinal toxicities according to Bearman's criteria, and other grade 3 or higher non-hematological toxicities according to the Common Terminology Criteria for Adverse Events version 4.0. Grade 4 neutropenia (as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) associated with fever or infection lasting beyond 3 weeks, or grade 4 neutropenia persisting for at least 28 days were also considered DLTs. <h3>Results</h3> The median follow-up period after HSCT was 453 (range, 131–915) days. Three patients were enrolled for each dose level. None of the patients exhibited DLT within 100 days of HSCT. Three patients experienced relapse, and no non-relapse mortality was documented during the observation period. One patient died 306 days after HSCT due to disease relapse. <h3>Conclusion</h3> The recommended dose of 3-day TMLI for a myeloablative conditioning regimen was 18 Gy in 6 fractions. The efficacy of this regimen is currently being planned in a phase II study.

Automatic Segmentation of Target Structures for Total Marrow and Lymphoid Irradiation in Bone Marrow Transplantation.

The use of total marrow and lymphoid irradiation (TMLI) as part of conditioning regimens for bone marrow transplantation is trending due to its advantages in disease control and low toxicity. Accurate contouring of target structures such as bone and lymph nodes plays an important role in irradiation planning. However, this process is often time-consuming and prone to inter-observer variation. Recently, deep learning methods such as convolutional neural networks (CNNs) and vision transformers have achieved tremendous success in medical image segmentation, therefore enabling fast semiautomatic radiotherapy planning. In this paper, we propose a dual-encoder U-shaped model named DE-Net, to automatically segment the target structures for TMLI. To enhance the learned features, the encoder of DE-Net is composed of parallel CNNs and vision transformers, which can model both local and global contexts. The multi-level features from the two branches are progressively fused by intermediate modules, therefore effectively preserving low-level details. Our experiments demonstrate that the proposed method achieves state-of-the-art results and a significant improvement in lymph node segmentation compared with existing methods.

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide

AbstractPosttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission

Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days −4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow up of 24.5 months, two-year estimates of OS and relapse-free survival were 86.7% and 83.3%, respectively. Disease relapse at 2 years was 16.7%. The estimates of NRM at 2 years was 0%. The GVHD/GRFS rate at 2 years was 59.3% (95% confidence interval, 28.8-80.3). This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Patterns and Outcomes of Relapse Treated With Radiotherapy Following Total Marrow and Lymphoid Irradiation in High-Risk and/or Relapsed/Refractory Acute Leukemia

Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk and/or relapsed/refractory acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), which has poor 5-yr OS at ∼15%. Extramedullary (EM) relapse rates in patients treated with this regimen has been reported to be ∼13%. This study evaluates patterns and outcomes of radiotherapy (RT) used to treat patients with EM relapse previously treated with TMLI.An IRB-approved analysis of 5 prospective TMLI trials was interrogated (IRB 04199, 05013, 05021, 14012, and 14106). Pre-transplant conditioning consisted of TMLI and etoposide (VP-16)/cyclophosphamide, fludarabine/melphalan, or bulsulfan/VP-16. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20Gy delivered twice daily. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort.In total, 254 patients with AML or ALL were treated with TMLI at our institution between 2006 and 2018. 21 of these patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median = 2 sites/patient, range = 1-16) were treated (6 lymph node, 34 soft tissue, 23 bone, and 4 CNS). At time of transplant, median age was 31 yrs (21-61 years). The median follow-up from date of transplant of these patients was 32.2 mo (3.9-154.1 mo). Of the 21 patients, 17 had active disease (MRD+ and/or bone marrow+) at transplant and 6 had prior history of EM disease. 12 patients had EM relapse only without BM relapse, while 5 had prior BM relapse and 4 had simultaneous EM and BM relapse. 12 recurrences were treated with systemic therapy prior to RT. The median mean TMLI dose to these sites was 12.0 Gy (4.0-20.8 Gy). 1-yr and 5-yr estimates of OS were 80.9% (95% CI = 56.9-92.4%) and 35.6% (95% CI = 13.8-58.3%), respectively. 1 and 2-yr OS following salvage RT to the first site of EM recurrence was 45.4% (95% CI = 23.1-65.3%) and 38.9% (95% CI = 17.7-59.8%), respectively. The median salvage RT dose was 24 Gy (6-30 Gy). Following RT, 86.6% of the sites had durable local control.To our knowledge, this is the largest analysis to date of patients treated with TMLI. Relapse incidence was as frequent in regions receiving ≥12 Gy as those receiving < 12 Gy, suggesting TMLI is not associated with an increased EM relapse risk. These patients did not have significantly different OS compared to historical controls. RT is an effective modality to treat EM relapse in patients with acute leukemia who were previously treated with TMLI.

Total Marrow and Lymphoid Irradiation to 20 Gy Combined With Post-Transplant Cyclophosphamide Graft vs. Host Disease (GvHD) Prophylaxis is Associated With Low Non-Relapse Mortality Rates and Favorable GvHD-Free/Relapse-Free Survival in AML

<h3>Purpose/Objective(s)</h3> Allogeneic hematopoietic cell transplantation (alloHCT) offers the highest curative rate for AML with intermediate or high-risk cytogenetics in remission. GvHD is a main cause of alloHCT mortality and morbidity. This trial evaluated the feasibility of a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 20 Gy combined with post-transplant cyclophosphamide (PTCy), which was designed to reduce the chronic GvHD risks using PTCy and reduce relapse rates with TMLI, thereby improving GRFS rates compared to standard myeloablative conditioning regimens. <h3>Materials/Methods</h3> Eighteen patients with AML in first or second complete remission were treated with TMLI 20 Gy (2 Gy twice daily) to bone, lymph nodes and spleen (liver and brain 12 Gy) on days -4 to 0; stem cell infusion on day 0; PTCy 50 mg/kg/day on days +3 and +4; and tacrolimus 1 mg continuous infusion on days +5 to +90. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). GRFS was defined as grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic treatment, relapse, or death (from any cause). <h3>Results</h3> The median age was 40 (range 19-56). Seventeen of 18 patients had intermediate to high-risk cytogenetics. The average (range) Dmean organ doses (Gy) were lungs 8.1 (7.5-9.5), kidneys 7.5 (6.3-9.2), heart 7.3 (6.6-8.3), oral cavity 4.4 (3.0–6.7), esophagus 6.4 (4.7-7.6), upper GI 9.1 (7.3-12.0), lower GI 10.2 (8.9-12.1), and bladder 10.0 (6.8-14.6). Median follow-up was 12.5 months (range 5.9 to 25.4) for surviving patients (n = 17). All patients engrafted. Bearman toxicity data were available for all patients. Grade 2 toxicities were bladder (n = 3) and stomatitis (n = 1). No grade 3-4 toxicities or toxicity-related deaths were observed. aGvHD developed in 2 patients with grade III-IV in only 1 patient (100-day Grade III-IV aGvHD: 5.6%, 95% CI: 0.3-23.1). Five patients developed chronic GvHD with one patient developing moderate to severe cGVHD (1-year cGvHD rate: 28.6%, 95% CI: 7.5%-54.7%). The GRFS rate at 1 year was 60.6% (95% CI: 34.6-79.0). One-year estimates of OS and relapse-free survival were 100% and 83.3% (95% CI: 62.8-96.1), respectively. Disease relapse at 1 year was 16.7% (95% CI: 3.9-37.2). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. <h3>Conclusion</h3> This TMLI 20 Gy only conditioning regimen, together with PTCy and tacrolimus, is associated with low toxicity and NRM. All patients achieved engraftment. Participants with ≥ 1-year follow-up have discontinued immunosuppressive therapy. The results suggest an improved GRFS rate compared to traditional myeloablative regimens reported. A larger phase II trial is planned.

Pulmonary Toxicity After Total Body Irradiation - Critical Review of the Literature and Recommendations for Toxicity Reporting.

IntroductionTotal body irradiation is an effective conditioning regimen for allogeneic stem cell transplantation in pediatric and adult patients with high risk or relapsed/refractory leukemia. The most common adverse effect is pulmonary toxicity including idiopathic pneumonia syndrome (IPS). As centers adopt more advanced treatment planning techniques for TBI, total marrow irradiation (TMI), or total marrow and lymphoid irradiation (TMLI) there is a greater need to understand treatment-related risks for IPS for patients treated with conventional TBI. However, definitions of IPS as well as risk factors for IPS remain poorly characterized. In this study, we perform a critical review to further evaluate the literature describing pulmonary outcomes after TBI.Materials and MethodsA search of publications from 1960-2020 was undertaken in PubMed, Embase, and Cochrane Library. Search terms included “total body irradiation”, “whole body radiation”, “radiation pneumonias”, “interstitial pneumonia”, and “bone marrow transplantation”. Demographic and treatment-related data was abstracted and evidence quality supporting risk factors for pulmonary toxicity was evaluated.ResultsOf an initial 119,686 publications, 118 met inclusion criteria. Forty-six (39%) studies included a definition for pulmonary toxicity. A grading scale was provided in 20 studies (17%). In 42% of studies the lungs were shielded to a set mean dose of 800cGy. Fourteen (12%) reported toxicity outcomes by patient age. Reported pulmonary toxicity ranged from 0-71% of patients treated with TBI, and IPS ranged from 1-60%. The most common risk factors for IPS were receipt of a TBI containing regimen, increasing dose rate, and lack of pulmonary shielding. Four studies found an increasing risk of pulmonary toxicity with increasing age.ConclusionsDefinitions of IPS as well as demographic and treatment-related risk factors remain poorly characterized in the literature. We recommend routine adoption of the diagnostic workup and the definition of IPS proposed by the American Thoracic Society. Additional study is required to determine differences in clinical and treatment-related risk between pediatric and adult patients. Further study using 3D treatment planning is warranted to enhance dosimetric precision and correlation of dose volume histograms with toxicities.

A Phase II Study of Total Marrow and Lymphoid Irradiation (TMLI) in Combination with Cyclophosphamide and Etoposide in Patients with Relapsed/Refractory Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Background : Although total body irradiation (TBI)-based ablative conditioning regimens prior to allogeneic stem cell transplantation (alloHCT) have been demonstrated to be efficacious in multiple hematologic malignancies, the relapse rate and survival outcomes for relapsed/refractory (R/R) acute leukemia remain poor due in large part to limited disease control and high non-relapse mortality, which over time has led to the exclusion of these patients from such treatment. In one report, standard myeloablative alloHCT regimens, frequently in combination with TBI, yielded 1-year overall survival (OS) of only 29% and 28% for active acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), respectively (Duval et al., J Clin Oncol, 2010). In response to these limitations, our group in a phase I trial reported that replacing TBI with targeted conformal total marrow and lymphoid irradiation (TMLI) at 2000 cGy as a conditioning regimen with cyclophosphamide (Cy) and etoposide (VP16) is safe in patients with R/R AML and ALL. Here, we report the results to date of a phase II study in which we combined the recommended dose of TMLI (2000 cGy) in combination with Cy and VP16. The objective is to evaluate the anti-leukemia activity and safety/tolerability of the TMLI/Cy/VP16 alloHCT conditioning regimen in patients with R/R acute leukemia.Patients and Methods : TMLI was administered on days -9 to -5, VP16 60 mg/kg (adjusted body weight) on day -4, and Cy 100 mg/kg (ideal body weight) on day -2. The radiation dose for all patients (n=35) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Bone marrow (n=2) or peripheral blood stem cells (n=33) were given on day 0. The primary endpoint is progression free survival (PFS); secondary endpoints include overall survival (OS), non-relapse mortality (NRM), and toxicity. Tacrolimus and sirolimus were administered for graft versus host disease (GVHD) prophylaxis. Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. Stopping rules for unacceptable adverse events (AEs) were incorporated; the rate of unacceptable toxicity should not be ≥33% in the first 30 days post stem cell infusion.Results : A total of 35 patients were enrolled and treated (see Table) between 5/21/2014 and 12/14/2016, with a median follow up of 11.8 months (range 1.8-35.9) for all patients and 12.0 months (range 2.9-35.9) for surviving patients (n=17). All patients engrafted. The complete remission rate at day +30 was 100%. One-year estimates of OS and PFS were 62.4% (95% CI: 43.1-76.8) and 44.7% (95% CI: 27.1-60.9), respectively. Disease relapse/progression at 1 year was 52.4% (95% CI: 37.6-73.2). The estimates of NRM at 100 days and 1 year were both 2.9% (95% CI: 0.4-19.7). Relapsed disease after transplant occurred in 21 patients (60%). Two patients died in remission; the causes were West Nile encephalitis and infection, respectively.Acute GVHD (aGVHD) developed in 20 (57%) of patients; of those, only 2 patients (6%) developed grades 3-4. Bearman toxicity data are available for 30 patients. Among these patients, grade ≥2 toxicities were bladder (Gr 2 n=1), central nervous system (Gr 2 n=1), gastrointestinal (Gr 2 n=4), hepatic (Gr 2 n=1, Gr 3 n=1), pulmonary (Gr 2 n=1), and renal (Gr 2 =1, Gr 3 n=1). Additionally, 11 and 1 patients experienced grade 2 and 3 stomatitis, respectively. No grade 4 toxicities or toxicity-related deaths were observed. The stopping rules for unacceptable AEs were not met.Conclusions : 1) TMLI allows a dose of 2000 cGy to be safely delivered to targeted sites, with a 100 day and 1 year NRM of 2.9% in this high-risk patient population; 2) One-year OS and PFS are very encouraging in patients with R/R acute leukemia; 3) Toxicities and acute GVHD were manageable and in line with previous experience with this regimen. [Display omitted] DisclosuresStein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Khaled:City of Hope: Research Funding; Daiichi Sankyo, Inc: Other: Travel Support. Salhotra:Kadmon: Consultancy.