Outcome after chimeric antigen receptor (CAR) T-cell therapy failure in large B-cell lymphomas.

This study retrospectively evaluated the outcome of salvage therapy in 51 patients who failed axicabtagene ciloleucel or tisagenlecleucel for relapsed/refractory large B-cell lymphomas. Of these patients, 22 (43%) were enrolled in clinical trials (glofitamab or loncastuximab tesirine + ibrutinib), whereas 29 received standard therapies (lenalidomide [Len], checkpoint inhibitors [CPIs], ibrutinib [I], chemoimmunotherapy and radiotherapy) or supportive care. Overall, 26 of 39 (67%) treated patients received a treatment based on immunotherapy (glofitamab, CPI, Len) that was mainly represented by bispecific antibody (n = 18). In this subgroup, plasma samples were collected and analysed for circulating tumour DNA (ctDNA) using cancer-personalized profiling by deep sequencing (CAPP-seq). The study found that patients with high ctDNA had poor outcomes. At a median follow-up of 11.7 months, the estimated 12-month overall survival (OS) was 35%. Factors adversely affecting the prognosis in the multivariable model were the absence of response to CAR T-cell therapy (HR: 3.08; p = 0.0109) and a diagnosis other than PMBCL and t-FL (HR: 4.54; p = 0.0069). The outcome of patients failing CAR T cells is poor and requires further investigation.

Allogeneic transplantation after immunotherapy for relapsed/refractory non-Hodgkin lymphoma: a comparison with a historical cohort.

BACKGROUND AIMS: New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody-drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. METHODS: We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. RESULTS: The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. CONCLUSIONS: Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy.

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy.

INTRODUCTION: Seizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated. METHODS: Consecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development. RESULTS: One hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs. CONCLUSION: Our data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

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

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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 2 h the time required to complete the entire segmentation process. CONCLUSION: DL models can streamline the TMLI contouring process of OARs. Manual revision is still necessary for lymph node delineation using AB models.

Automatic planning of the lower extremities for total marrow irradiation using volumetric modulated arc therapy.

PURPOSE: Total marrow (and lymphoid) irradiation (TMI-TMLI) is limited by the couch travel range of modern linacs, which forces the treatment delivery to be split into two plans with opposite orientations: a head-first supine upper-body plan, and a feet-first supine lower extremities plan. A specific field junction is thus needed to obtain adequate target coverage in the overlap region of the two plans. In this study, an automatic procedure was developed for field junction creation and lower extremities plan optimization. METHODS: Ten patients treated with TMI-TMLI at our institution were selected retrospectively. The planning of the lower extremities was performed automatically. Target volume parameters (CTV_J­V98% > 98%) at the junction region and several dose statistics (D98%, Dmean, and D2%) were compared between automatic and manual plans. The modulation complexity score (MCS) was used to assess plan complexity. RESULTS: The automatic procedure required 60-90 min, depending on the case. All automatic plans achieved clinically acceptable dosimetric results (CTV_J­V98% > 98%), with significant differences found at the junction region, where Dmean and D2% increased on average by 2.4% (p < 0.03) and 3.0% (p < 0.02), respectively. Similar plan complexity was observed (median MCS = 0.12). Since March 2022, the automatic procedure has been introduced in our clinic, reducing the TMI-TMLI simulation-to-delivery schedule by 2 days. CONCLUSION: The developed procedure allowed treatment planning of TMI-TMLI to be streamlined, increasing efficiency and standardization, preventing human errors, while maintaining the dosimetric plan quality and complexity of manual plans. Automated strategies can simplify the future adoption and clinical implementation of TMI-TMLI treatments in new centers.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Nonmyeloablative Conditioning Regimen before T Cell Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Advanced Hodgkin and Non-Hodgkin Lymphomas.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation.

Donor-Specific Anti-HLA Antibodies in Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: Risk of Graft Failure, Poor Graft Function, and Impact on Outcomes.

The presence of donor-specific anti-HLA antibodies (DSA) is associated with a 10-fold increased risk of graft failure in haploidentical stem cell transplantation (haplo-SCT). Consensus guidelines from the European Society for Blood and Marrow Transplantation set a mean fluorescence intensity (MFI) >1000 as a cutoff for DSA positivity. In the absence of an alternative donor, it is recommended that patients undergo desensitization therapy, especially with high DSA levels (>5000 MFI). The aim of this study was to analyze the impact of DSA on risk of graft failure and poor graft function, as well as on major outcomes in a consecutive cohort of patients who were systematically screened for DSA before haplo-SCT. A total of 141 consecutive patients were candidates for unmanipulated haplo-SCT with post-transplantation cyclophosphamide (PT-Cy) at our center between January 2012 and January 2018, and 135 were analyzed for the presence of HLA antibodies. Of these 134 patients underwent haplo-SCT. HLA antibodies were detected in 40 patients, including 19 with DSA and 21 without DSA. Ten of the 19 patients with DSA underwent transplantation using that donor, whereas 2 underwent a desensitization program before transplantation. Only 2 patients experienced primary graft failure (1.4 %), both of whom were without DSA. Twenty patients developed a poor graft function (15%). The 3-year overall survival (OS), 3-year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were analyzed according to the presence or absence of DSA. No statistically significant difference was found. No impact of the presence of DSA on the risk of developing graft failure and poor graft function was revealed. Major outcomes of transplantation were analyzed separately in patients with poor graft function and those with good graft function. The 3-year OS, 3-year PFS, and 1-year NRM in good graft function and poor graft function populations were 62% versus 20% (P < .0001), 53% versus 20% (P < .0001), and 12% versus 40% (P = .009), respectively. The presence of low-level DSA in the absence of desensitization did not correlate with the risk of developing graft failure and poor graft function. Patients who experienced poor graft function had worse outcomes than patients with good graft function.

Peripheral Blood Stem Cells versus Bone Marrow for T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Hodgkin Lymphoma.

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) when a matched related or unrelated donor is not available. The role of graft source, either bone marrow (BM) or peripheral blood stem cells (PBSCs), in this setting has not been fully elucidated. We performed a retrospective study on 91 patients with HL to compare the outcome after BM (n = 53) or PBSC (n = 38) transplant. Eighty-nine patients engrafted with no difference between BM and PBSCs in terms of median time for neutrophil (20 versus 20 days, P = .405) and platelet (26 versus 26.5 days, P = .994) engraftment. With a median follow-up of 40.2 months, 100-day cumulative incidences of grades II to IV acute graft-versus host disease (GVHD) and grades II to IV acute GVHD were 24% and 4%, respectively. Graft source was not associated with a different risk of acute GVHD both by univariate and multivariate analyses. Consistently, 1-year cumulative incidence of chronic GVHD was 7% with no differences between the 2 graft types (P = .761). Two-year rates of overall survival (OS), progression-free survival (PFS), nonrelapse mortality, and GVHD/relapse-free survival (GRFS) were 67%, 58%, 20%, and 52%, respectively. By univariate analysis, pretransplant disease status was the main variable affecting all outcomes. By multivariate analysis, PBSCs resulted in a protective factor for OS (hazard ratio [HR], .29; P = .006), PFS (HR, .38; P = .001), and GRFS (HR, .44; P = .020). The other independent variables affecting the final outcome were pretransplant disease status and hematopoietic cell transplant-specific comorbidity index. In conclusion, when planning a haplo-SCT with PT-Cy for patients with poor-risk HL, graft type is an important variable to take into account when selecting the best available donor.

Caspofungin for primary antifungal prophylaxis after T-cell-replete haploidentical stem cell transplantation with post-transplant cyclophosphamide.

OBJECTIVES: T-cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is at high risk of invasive fungal infections (IFI), and anti-mold-active drug is required for primary antifungal prophylaxis (PAP) according to international guidelines. No data are available on the efficacy of caspofungin as PAP in this setting. METHODS: Here, we report our retrospective experience with 103 consecutive patients treated with caspofungin as PAP after Haplo-SCT. Caspofungin was administered only during the pre-engraftment phase. RESULTS: Hundred-day cumulative incidence of proven-probable IFI (PP-IFI) was 8.7% and median day of onset was 19 post-SCT. No patient died of PP-IFI, and overall survival (OS) and non-relapse mortality (NRM) hazard ratio (HR) for patients experiencing IFI were 1.02 (P = 0.9) and 0.7 (P = 0.7), respectively. Three-year overall survival (OS) and 1-year non-relapse mortality (NRM) were 55% and 19%, respectively. By univariate analysis, duration of neutropenic phase and partial remission pre-transplant disease status were associated with increased incidence of IFI, but were not confirmed by multivariate analysis. CONCLUSION: In summary, PAP with caspofungin is an effective strategy for preventing IFI in the context of Haplo-SCT with PT-Cy. Further efforts are required in order to identify more potent strategies able to avoid the occurrence of breakthrough infections.

A reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a HLA identical sibling.

BACKGROUND: Invasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo-SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy-five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo-SCT, especially for low-risk transplants. However, the ideal dosage of fluconazole has never been tested. METHODS: Here, we report the experience of our institution on 113 consecutive patients receiving an allo-SCT from a HLA identical sibling between 1999 and 2015, where PAP consisted of fluconazole 100 mg/d only during the pre-engraftment phase. At the time of transplant, all patients were considered at low-risk for mold infection according to ECIL-5 guidelines. RESULTS: Cumulative incidence of possible-probable-proven IFI was 11.7%, while proven-probable (PP-IFI) occurred in 5.5% of patients by day 100 post transplant. Of note, only 1 patient developed invasive Candidiasis due to a non-albicans strain and stool-screening tests were negative for colonization by Candida albicans species. The incidence of 1-year acute and 2-year chronic graft-versus-host-disease (GVHD) was 30% and 45%, respectively. Three-year OS and 1-year NRM were 53% and 11.3%, respectively. CONCLUSION: In summary, fungal prophylaxis with fluconazole 100 mg/d results in very low incidence of PP-IFI, GVHD and NRM in low-risk allo-SCT.

Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation Cyclophosphamide Graft-versus-Host Disease Prophylaxis.

Allogeneic (allo) hematopoietic cell transplantation (HCT) currently represents the only potentially curative therapy for patients affected by multiple myeloma (MM). Up to 30% of patients in western countries do not have a matched donor. Haploidentical HCT (haplo-HCT) may be an option, but currently, there are little available data regarding this treatment. We analyzed survival outcomes of 30 heavily pretreated MM patients who received haplo-HCT with post-transplantation cyclophosphamide as graft-versus-host-disease (GVHD) prophylaxis. Median neutrophil and platelet engraftments at day +30 were 87% (95% confidence interval [CI], 66% to 95%) and 60% (95% CI, 40% to 75%), respectively. The cumulative incidences of relapse or progression of disease (PD) and nonrelapse mortality at 18 months were 42% (95% CI, 23% to 59%) and 10% (95% CI, 2% to 24%), respectively. The cumulative incidence of grade II to IV acute GVHD at day +100 was 29% (95% CI, 14% to 47%). The cumulative incidence of chronic GVHD at 18 months was 7% (95% CI, 1% to 21%). With a median follow-up in survivors of 25 months (range, 15 to 73 months), the 18-month progression-free survival (PFS) and overall survival (OS) were 33% (95% CI, 17% to 50%) and 63% (95% CI, 44% to 78%), respectively. No differences were observed between peripheral blood and bone marrow graft in terms of engraftment, GVHD, or PD incidence. Chemorefractory disease at transplantation was associated with a lower/reduced 18-month PFS (9% versus 47%, P = .01) and OS (45% versus 74%, P = .03). This was explained by a higher PD incidence (55% versus 33%, P = .05). In this multicenter study, we report encouraging results with haplo-HCT for patients with heavily pretreated MM.

Next-generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles.

BACKGROUND: The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele. METHODS: The authors performed whole-exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach. RESULTS: The authors identified gene mutations and single-nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family. CONCLUSIONS: To the authors' knowledge, the current study is the first to provide a whole-exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017;123:3701-3708. © 2017 American Cancer Society.

Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens.

The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.

Deep learning-based optimization of field geometry for total marrow irradiation delivered with volumetric modulated arc therapy.

BACKGROUND: Total marrow (lymphoid) irradiation (TMI/TMLI) is a radiotherapy treatment used to selectively target the bone marrow and lymph nodes in conditioning regimens for allogeneic hematopoietic stem cell transplantation. A complex field geometry is needed to cover the large planning target volume (PTV) of TMI/TMLI with volumetric modulated arc therapy (VMAT). Five isocenters and ten overlapping fields are needed for the upper body, while, for patients with large anatomical conformation, two specific isocenters are placed on the arms. The creation of a field geometry is clinically challenging and is performed by a medical physicist (MP) specialized in TMI/TMLI. PURPOSE: To develop convolutional neural networks (CNNs) for automatically generating the field geometry of TMI/TMLI. METHODS: The dataset comprised 117 patients treated with TMI/TMLI between 2011 and 2023 at our Institute. The CNN input image consisted of three channels, obtained by projecting along the sagittal plane: (1) average CT pixel intensity within the PTV; (2) PTV mask; (3) brain, lungs, liver, bowel, and bladder masks. This "averaged" frontal view combined the information analyzed by the MP when setting the field geometry in the treatment planning system (TPS). Two CNNs were trained to predict the isocenters coordinates and jaws apertures for patients with (CNN-1) and without (CNN-2) isocenters on the arms. Local optimization methods were used to refine the models output based on the anatomy of the patient. Model evaluation was performed on a test set of 15 patients in two ways: (1) by computing the root mean squared error (RMSE) between the CNN output and ground truth; (2) with a qualitative assessment of manual and generated field geometries-scale: 1 = not adequate, 4 = adequate-carried out in blind mode by three MPs with different expertise in TMI/TMLI. The Wilcoxon signed-rank test was used to evaluate the independence of the given scores between manual and generated configurations (p < 0.05 significant). RESULTS: The average and standard deviation values of RMSE for CNN-1 and CNN-2 before/after local optimization were 15 ± 2/13 ± 3 mm and 16 ± 2/18 ± 4 mm, respectively. The CNNs were integrated into a planning automation software for TMI/TMLI such that the MPs could analyze in detail the proposed field geometries directly in the TPS. The selection of the CNN model to create the field geometry was based on the PTV width to approximate the decision process of an experienced MP and provide a single option of field configuration. We found no significant differences between the manual and generated field geometries for any MP, with median values of 4 versus 4 (p = 0.92), 3 versus 3 (p = 0.78), 4 versus 3 (p = 0.48), respectively. Starting from October 2023, the generated field geometry has been introduced in our clinical practice for prospective patients. CONCLUSIONS: The generated field geometries were clinically acceptable and adequate, even for an MP with high level of expertise in TMI/TMLI. Incorporating the knowledge of the MPs into the development cycle was crucial for optimizing the models, especially in this scenario with limited data.

Case report: Reversible punctate inflammatory foci in the corpus callosum: A novel radiological finding of CAR T-cell therapy-related neurotoxicity.

Introduction: Chimeric antigen receptor T-cell therapy-related neurotoxicity is a novel cytokine-mediated neurological syndrome that may present with a broad spectrum of manifestations. Descriptions of novel distinctive features are pivotal to untangling this condition's clinical and instrumental signature in order to inform diagnosis and pathophysiology. Case: A 27-year-old female patient received anti-CD19 CAR T cells for a refractory primary mediastinal B-cell lymphoma. At 6 days after the infusion, she developed mild ideo-motor slowing, dysgraphia, and drowsiness. Despite specific treatment with dexamethasone, her neurological status progressively worsened to a comatose state within 24 h. EEG and CSF analyses were non-specific, showing background slowing and inflammatory findings. Brain MRI revealed multiple focal punctate areas of T2-weighted hyperintensity localized in the body and isthmus of the corpus callosum. Following the administration of high-dose intravenous methylprednisolone, her neurological status resolved within 48 h. Notably, the follow-up brain MRI did not reveal any abnormalities in the corpus callosum, except for a reduction of fractional anisotropy. Conclusion: Reversible punctate inflammatory foci of the body and isthmus of the corpus callosum may represent a novel radiological finding of CAR T-cell therapy-related neurotoxicity.

EASIX predicts non-relapse mortality after haploidentical transplantation with post-transplant cyclophosphamide.

Endothelial Activation and Stress Index (EASIX) is a prognostic score reflecting endothelial damage. It can identify cohorts of patients at higher risk of non-relapse mortality (NRM) after allogeneic stem cell transplantation (SCT) from a matched-related or -unrelated donor. No data are available in the setting of haploidentical-SCT with post-transplant cyclophosphamide (PT-Cy). We retrospectively analyzed the role of EASIX score in a cohort of 266 patients receiving Haplo-SCT with PT-Cy at our center. By a decision-tree model, 1-year NRM was 16% vs. 29% and overall survival was 59% vs. 32%, respectively, for patients with a pre-transplant EASIX (EASIX-PRE) <0.8 vs. ≥0.8 (p < 0.001). By multivariable analysis, EASIX-PRE was an independent predictor of NRM (hazard ratio [HR] 2.43, p < 0.001) and overall survival (HR: 1.64, p = 0.011). EASIX-PRE did not predict patients at higher risk of developing acute graft-versus-host disease (GVHD) but was an independent predictor of 1-year NRM (3.2 cutoff, HR 6.61, p = 0.002; <3.2 vs. ≥3.2: 10% vs. 56%, p < 0.001) in patients developing acute GVHD. EASIX score can also represent an important tool to predict mortality in the setting of Haplo-SCT with PT-Cy. It may help to make therapeutic decisions both before the transplant and at the onset of acute GVHD.