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This study investigated the predictive role of baseline 18F-FDG PET/CT (bPET/CT) radiomics from two distinct target lesions in patients with classical Hodgkin's lymphoma (cHL). cHL patients examined with bPET/CT and interim PET/CT between 2010 and 2019 were retrospectively included. Two bPET/CT target lesions were selected for radiomic feature extraction: Lesion_A, with the largest axial diameter, and Lesion_B, with the highest SUVmax. Deauville score at interim PET/CT (DS) and 24-month progression-free-survival (PFS) were recorded. Mann-Whitney test identified the most promising image features (p < 0.05) from both lesions with regards to DS and PFS; all possible radiomic bivariate models were then built through a logistic regression analysis and trained/tested with a cross-fold validation test. The best bivariate models were selected based on their mean area under curve (mAUC). A total of 227 cHL patients were included. The best models for DS prediction had 0.78 ± 0.05 maximum mAUC, with a predominant contribution of Lesion_A features to the combinations. The best models for 24-month PFS prediction reached 0.74 ± 0.12 mAUC and mainly depended on Lesion_B features. bFDG-PET/CT radiomic features from the largest and hottest lesions in patients with cHL may provide relevant information in terms of early response-to-treatment and prognosis, thus representing an earlier and stronger decision-making support for therapeutic strategies. External validations of the proposed model are planned.

Simple Summary: CD79b, a B-cell-specific antigen, is highly expressed in mature B-cell lymphomas, making it a promising therapeutic target. This study employs flow cytometry to assess CD79b in lymph node biopsies from 127 cases of large B-cell lymphomas (LBCLs), compared to benign reactive hyperplasia. We found that LBCLs exhibited lower and heterogeneous CD79b expression, with 18% of cases showing almost exclusively intracellular positivity and, in particular, low surface expression in primary mediastinal B-cell lymphomas. A positive correlation was observed between CD79b expression and surface immunoglobulin light chains. Patients over 60 years old and those with high-risk disease (Revised International Prognostic Index of 3–5) demonstrated higher surface CD79b expression. These findings align with results from the POLARIX study, where the addition of a CD79b-ADC (antibody–drug conjugate) to first-line therapy improved outcomes for patients with similar characteristics. Flow cytometry on tissue biopsies may offer valuable insights into target antigen expression, including CD79b. Background: CD79b is a B-cell-specific antigen that is crucial to the B-cell receptor and is considered a key target for treatment in aggressive B-cell lymphomas. Methods: While immunohistochemical studies have shown widespread expression of CD79b in mature B-cell-derived lymphomas, flow cytometry allows for precise measurement and differentiation between surface and intracellular localization. Results: In our comparative analysis, we discovered that CD79b expression percentages and mean fluorescence intensity (MFI) were lower in a group of 127 cases of aggressive B-cell lymphomas compared to a control group of benign reactive hyperplasia. We also observed significant variability in the surface expression of CD79b among lymphoma cases, with 18% showing predominantly intracellular positivity. There was a strong correlation between the surface expression of CD79b and clonal light chains. Notably, primary mediastinal B-cell lymphomas exhibited significantly lower surface CD79b expression compared to other lymphoma subtypes (median 0.8% IQR 0–48.5 vs. 80% IQR 24–97, p = 0.0005). Furthermore, patients over 60 years old and those with a higher Revised International Prognostic Index (R-IPI) had significantly higher CD79b expression, both of which are associated with a significant benefit from adding an anti-CD79b drug conjugate to first-line chemotherapy in diffuse large B-cell lymphomas. Conclusions: In conclusion, the quantitative flow cytometric analysis of CD79b surface expression in aggressive B-cell lymphomas provides clinically relevant information, highlighting its potential usefulness in guiding therapeutic decisions. [ABSTRACT FROM AUTHOR]

Introduction: Agarose gel‐based conventional and real‐time allele‐specific polymerase chain reaction (AS‐PCR) assays are currently used for sensitive detection and quantification of MYD88 L265P mutation. Visual inspection of an agarose gel can often be ambiguous. We propose a new allele‐specific quantification PCR (AS‐qPCR) assay, PlentiPlex™ MYD88 Waldenström lymphoma qPCR assay, that uses Intercalating Nucleic Acid (INA®) technology for increased affinity and specificity. Methods: This study compares PlentiPlex™ MYD88 Waldenström lymphoma qPCR assay with conventional AS‐PCR. We included a total of 102 peripheral and bone marrow blood samples from 94 patients with a lymphoproliferative disorder. Droplet digital PCR (ddPCR) was used as a third method in case of discrepancy. Results: A positive percent agreement of 100% (95% CI 0.92–1.0) and a negative percent agreement of 98% (95% CI 0.90–1.0) were found between the conventional AS‐PCR and the AS‐qPCR methods. Including the ddPCR results to validate the discrepant cases, the sensitivity and specificity of PlentiPlex™ MYD88 Waldenström lymphoma qPCR Assay were 1.0 (95% CI 0.97–1.0) and 1.0 (95% CI 0.96–1.0), respectively. Conclusion: Our data demonstrate that PlentiPlex™ MYD88 Waldenström lymphoma qPCR assay is a fast, highly sensitive, and specific method for the detection of MYD88 L265P compared with conventional AS‐PCR. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma is the most common type of B cell neoplasm, and can be cured by traditional chemoimmunotherapy in 60–70% of cases. Relapsed/refractory patients usually have a dismal prognosis and most of them finally succumb to lymphoma. In the last decade, several new innovative therapies have been approved against DLBCL, targeting both surface antigens and the intracellular pathways of neoplastic B cells. Compared to standard chemotherapy, new monoclonal antibodies and engineered T cells have shown an increased response rate, progression-free survival and overall survival, but, on the other side of the coin, patients have been experiencing new kinds of toxicities, previously unknown, that clinicians have been learning to manage. Here, we review new drugs that are already approved or under investigation for DLBCL and the corresponding molecular target on lymphoma cells. Since the introduction of rituximab in the late 1990s, significant progress has been made in advancing targeted therapies for B cell lymphomas, improving patients' chance of being cured and clinicians' therapeutic armamentarium. A better understanding of disease biology and pathogenic pathways, coupled with refinements in immunophenotypic and molecular diagnostics, have been instrumental in these achievements. While traditional chemotherapy remains fundamental in most cases, concerns surrounding chemorefractoriness and cumulative toxicities, particularly the depletion of the hemopoietic reserve, underscore the imperative for personalized treatment approaches. Integrating targeted agents, notably monoclonal antibodies, alongside chemotherapy has yielded heightened response rates and prolonged survival. A notable paradigm shift is underway with innovative-targeted therapies replacing cytotoxic drugs, challenging conventional salvage strategies like stem cell transplantation. This review examines the landscape of emerging targets for lymphoma cells and explores innovative therapies for diffuse large B cell lymphoma (DLBCL). From Chimeric Antigen Receptor-T cells to more potent monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, checkpoint inhibitors, and small molecules targeting intracellular pathways, each modality offers promising avenues for therapeutic advancement. This review aims to furnish insights into their potential implications for the future of DLBCL treatment strategies. [ABSTRACT FROM AUTHOR]

Flow cytometry (FCM) and quantitative PCR (qPCR) are conventional methods for assessing CAR-T expansion, while digital droplet PCR (ddPCR) is emerging as a promising alternative. We monitored CAR-T transcript expansion in 40 B-NHL patients post-infusion of CAR-T products (axi-cel; tisa-cel; and brexu-cel) with both His-Tag FCM and ddPCR techniques. Sensitivity and predictive capacity for efficacy and safety outcomes of ddPCR were analyzed and compared with FCM. A significant correlation between CAR-T counts determined by FCM and CAR transcripts assessed by ddPCR (p < 0.001) was observed. FCM revealed median CD3+CAR+ cell counts at 7, 14, and 30 days post-infusion with no significant differences. In contrast, ddPCR-measured median copies of CAR-T transcripts demonstrated significant lower copy numbers in tisa-cel recipients compared to the other products at day 7 and day 14. Patients with a peak of CAR transcripts at day 7 exceeding 5000 copies/microg gDNA, termed "good CAR-T expanders", were more likely to achieve a favorable response at 3 months (HR 10.79, 95% CI 1.16–100.42, p = 0.036). Good CAR-T expanders showed superior progression-free survival at 3, 6, and 12 months compared to poor CAR-T expanders (p = 0.088). Those reaching a peak higher than 5000 copies/microg gDNA were more likely to experience severe CRS and ICANS. DdPCR proves to be a practical method for monitoring CAR-T expansion, providing quantitative information that better predicts both treatment outcomes and toxicity. [ABSTRACT FROM AUTHOR]

This study investigated the predictive role of baseline 18F-FDG PET/CT (bPET/CT) radiomics from two distinct target lesions in patients with classical Hodgkin's lymphoma (cHL). cHL patients examined with bPET/CT and interim PET/CT between 2010 and 2019 were retrospectively included. Two bPET/CT target lesions were selected for radiomic feature extraction: Lesion_A, with the largest axial diameter, and Lesion_B, with the highest SUVmax. Deauville score at interim PET/CT (DS) and 24-month progression-free-survival (PFS) were recorded. Mann–Whitney test identified the most promising image features (p < 0.05) from both lesions with regards to DS and PFS; all possible radiomic bivariate models were then built through a logistic regression analysis and trained/tested with a cross-fold validation test. The best bivariate models were selected based on their mean area under curve (mAUC). A total of 227 cHL patients were included. The best models for DS prediction had 0.78 ± 0.05 maximum mAUC, with a predominant contribution of Lesion_A features to the combinations. The best models for 24-month PFS prediction reached 0.74 ± 0.12 mAUC and mainly depended on Lesion_B features. bFDG-PET/CT radiomic features from the largest and hottest lesions in patients with cHL may provide relevant information in terms of early response-to-treatment and prognosis, thus representing an earlier and stronger decision-making support for therapeutic strategies. External validations of the proposed model are planned. [ABSTRACT FROM AUTHOR]

In a previous preliminary study, radiomic features from the largest and the hottest lesion in baseline 18F-FDG PET/CT (bPET/CT) of classical Hodgkin’s Lymphoma (cHL) predicted early response-to-treatment and prognosis. Aim of this large retrospectively-validated study is to evaluate the predictive role of two-lesions radiomics in comparison with other clinical and conventional PET/CT models. cHL patients with bPET/CT between 2010 and 2020 were retrospectively included and randomized into training-validation sets. Target lesions were: Lesion_A, with largest axial diameter (Dmax); Lesion_B, with highest SUVmax. Total-metabolic-tumor-volume (TMTV) was calculated and 212 radiomic features were extracted. PET/CT features were harmonized using ComBat across two scanners. Outcomes were progression-free-survival (PFS) and Deauville Score at interim PET/CT (DS). For each outcome, three predictive models and their combinations were trained and validated: - radiomic model “R”; - conventional PET/CT model “P”; - clinical model “C”. 197 patients were included (training = 118; validation = 79): 38/197 (19%) patients had adverse events and 42/193 (22%) had DS ≥ 4. In the training phase, only one radiomic feature was selected for PFS prediction in model “R” (Lesion_B F_cm.corr, C-index 66.9%). Best “C” model combined stage and IPS (C-index 74.8%), while optimal “P” model combined TMTV and Dmax (C-index 63.3%). After internal validation, “C”, “C + R”, “R + P” and “C + R + P” significantly predicted PFS. The best validated model was “C + R” (C-index 66.3%). No model was validated for DS prediction. In this large retrospectively-validated study, a combination of baseline 18F-FDG PET/CT two-lesions radiomics and other conventional models showed an added prognostic power in patients with cHL. As single models, conventional clinical parameters maintain their prognostic power, while radiomics or conventional PET/CT alone seem to be sub-optimal to predict survival. [ABSTRACT FROM AUTHOR]

Disease burden is a critical determinant of outcomes in CAR-T therapy for B-cell lymphomas, and one of the most widely used techniques for its assessment is Total Metabolic Tumor Volume (TMTV) measured via [ 18 F]FDG PET/CT. Biological parameters may further refine the risk profile. We analyzed baseline [ 18 F]FDG PET/CT scans from 40 patients treated with CAR-T, using an AI-based automated segmentation algorithm to determine TMTV. Our analysis identified that a baseline TMTV greater than 48.4 cm³ and elevated LDH independently predicted progression-free survival (PFS) after CAR-T therapy (HR 4.28, p = 0.007, and HR 8.20, p < 0.001, respectively). We then proposed a 0-to-2 risk score, assigning one point each for elevated TMTV and elevated LDH. All patients with a score of two experienced a PFS of less than 90 days following CAR-T infusion. Among the remaining patients, those with 0 points versus 1 point demonstrated a 3-month PFS of 100% versus 85%, a 6-month PFS of 92% versus 53%, and a 12-month PFS of 83% versus 53%, respectively. Importantly, patients with high baseline TMTV who achieved a TMTV reduction to less than 1.99 cm³ by day 30 had a PFS of 66%, significantly better compared to those who did not achieve this reduction. AI-guided TMTV assessment, combined with LDH levels, provides a rapid and sensitive method for risk stratification at the bedside, which could help optimize patient management prior to CAR-T therapy., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Impaired function of hematopoiesis after treatment with chimeric antigen T-cells (CAR-T) is a frequent finding and can interest a wide range of patients, regardless of age and underlying disease. Trilinear cytopenias, as well as hypogammaglobulinemia, B-cell aplasia, and T-cell impairment, can severely affect the infectious risk of CAR-T recipients, as well as their quality of life. In this review, we provide an overview of defects in hematopoiesis after CAR-T, starting with a summary of different definitions and thresholds. We then move to summarize the main pathogenetic mechanisms of cytopenias, and we offer insight into cytomorphological aspects, the role of clonal hematopoiesis, and the risk of secondary myeloid malignancies. Subsequently, we expose the major findings and reports on T-cell and B-cell quantitative and functional impairment after CAR-T. Finally, we provide an overview of current recommendations and leading experiences regarding the management of cytopenias and defective B- and T-cell function., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: Healthy organs uptake, including cerebellar and liver SUVs have been reported to be inversely correlated to total metabolic tumor volume (TMTV), a controversial predictor of event-free survival (EFS) in classical Hodgkin's Lymphoma (cHL). The objective of this study was to estimate TMTV by using healthy organs SUV measurements and assess the performance of this new index (UF, Uptake Formula) to predict EFS in cHL., Methods: Patients with cHL were retrospectively included. SUV values and TMTV derived from baseline 18 F-FDG PET/CT were harmonized using ComBat algorithm across PET/CT systems. UF was estimated using ANOVA analysis. Optimal thresholds of TMTV and UF were calculated and tested using Cox models., Results: 163 patients were included. Optimal UF model of TMTV included age, lymphoma maximum SUVmax, hepatic SUVmean and cerebellar SUVmax (R 2 14.0% - p < 0.001). UF > 236.8 was a significant predictor of EFS (HR: 2.458 [1.201-5.030], p = 0.01) and was not significantly different from TMTV > 271.0 (HR: 2.761 [1.183-5.140], p = 0.001). UF > 236.8 remained significant in a bivariate model including IPS score ( p = 0.02) and determined two populations with different EFS (63.7 vs. 84.9%, p = 0.01)., Conclusion: The Uptake Formula, a new index including healthy organ SUV values, shows similar performance to TMTV in predicting EFS in Hodgkin's Lymphoma. Validation cohorts will be needed to confirm this new prognostic parameter., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morland, Triumbari, Maiolo, Cuccaro, Treglia, Hohaus and Annunziata.)