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RATIONALE: The implication of T cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is controversial. CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) are pivotal in maintaining immune homeostasis, but their role in IPF pathophysiology has not yet been studied. OBJECTIVES: To explore Treg dynamics and function in IPF. Methods: Treg levels and dynamics were analyzed by flow cytometry in the peripheral blood (PB) and bronchoalveolar lavage (BAL) of 21 patients with IPF, 35 patients with lung diseases other than IPF (patients without IPF), 20 patients with collagen vascular diseases with pulmonary parenchymal involvement (CVD-IP), and 28 healthy volunteers. The suppression of autologous CD4(+)CD25(-) cell-proliferative responses and cytokine release by magnetic bead-isolated Tregs was evaluated by proliferation assays and cytometric bead array. Correlations of Treg function and levels with lung function parameters were also performed. MEASUREMENTS AND MAIN RESULTS: In patients with IPF, both BAL and PB Tregs were reduced compared with those of healthy volunteers and patients without IPF, although not always significantly. Treg levels were not affected by the administration of low-dose prednisone in four nonresponding patients. The suppressor potential of BAL and PB Tregs was compromised in patients with IPF and patients with CVD-IP, compared with healthy volunteers and patients without IPF. Similarly, the Treg-induced suppression of helper T-cell type 1 and 2 cytokine secretion was impaired in the BAL of patients with IPF and patients with CVD-IP. Moreover, the defective function of BAL Tregs correlated highly with parameters of disease severity. CONCLUSIONS: This study provides the first evidence of global Treg impairment in IPF that strongly correlates with disease severity, suggesting a role for Tregs in the fibrotic process. [ABSTRACT FROM AUTHOR]

CD4+CD25+FOXP3+ T regulatory cells (Tregs) prevent autoimmunity by restricting overexuberant immune responses, but the same subpopulation can incur detrimental effects on antitumor responses. In both cases, the suppressor potential of Tregs appears to be strongly influenced by their compartmentalization. In myelodysplastic syndromes (MDS), immune deregulation and autoimmunity in the early stages might lead to ineffective hematopoiesis and bone marrow (BM) failure, whereas late-stage disease is characterized by the immune escape of the malignant clone. We show that these two stages of MDS are associated with differential Treg activity. Specifically, we found that in early stage MDS, compared with normal hematopoiesis and late stage MDS, Tregs are dysfunctional and their BM homing through the CXCL12/CXCR4 axis is seriously impaired as a result of CXCR4 downregulation. Conversely, in late stage MDS, Tregs are systemically and locally expanded and retain their function and migratory capacity. Moreover, Treg levels follow the disease course and are significantly reduced in treatment responding patients. Our findings indicate Treg involvement in the pathophysiology of MDS; defective suppressor function and BM trafficking of Tregs may be important in the autoimmune process of early MDS, but increased Treg activity could favor leukemic clone progression in late stage disease.Leukemia (2009) 23, 510–518; doi:10.1038/leu.2008.333; published online 20 November 2008 [ABSTRACT FROM AUTHOR]

The article presents information on the effectiveness of anagrelide and hydroxyurea combination therapy for patients diagnosed with chronic myeloproliferative diseases resistant or intolerant to monotherapy. It discusses some considerable side effects with either therapies which could lead to the reduction of the dose and thus interfere with their efficacy. It describes the characteristics of the patients, the criteria for combined therapy, and response of the patients to the treatment.

The illumination of cellular processes in cancer has revolutionized oncology drug development leading to a shift from non-specific chemotherapy to the selective targeting of tumorigenic signal transduction pathways. Farnesyltransferase inhibitors (FTIs) target proteins needing prenylation for functioning, thus inhibiting a wide variety of molecular targets crucial for cell proliferation and survival. Tipifarnib (R115777, Zarnestra®), a potent and specific inhibitor of Farnesyltransferase, can attain strong inhibition of tumor growth in preclinical models. As a single agent, tipifarnib has demonstrated activity in several hematologic malignancies, namely acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and multiple myeloma. However, considering the complexity of the molecular aberrations implicated in the pathogenesis of hematologic neoplasms, it is rather unlikely that monotherapy with tipifarnib will serve as a stand-alone treatment approach. Indeed, improved results have been achieved by combining tipifarnib with other anticancer agents, whereas the first efforts for the identification of molecular predictors of response are reporting intriguing results. Ongoing trials are anticipated to define the exact role of tipifarnib in the treatment of hematologic malignancies. [ABSTRACT FROM AUTHOR]

Abstract Background Idiopathic pulmonary fibrosis represents a lethal form of progressive fibrotic lung disorder with gradually increasing incidence worldwide. Despite intense research efforts its pathogenesis is still elusive and controversial reflecting in the current disappointing status regarding its treatment. Patients and Methods: We report the first protocol proposal of a prospective, unicentric, non-randomized, phase Ib clinical trial to study the safety and tolerability of the adipose-derived stem cells (ADSCs) stromal vascular fraction (SVF) as a therapeutic agent in IPF. After careful patient selection based on functional criteria (forced vital capacity-FVC > 50%, diffuse lung capacity for carbon monoxide-DLCO > 35% of the predicted values) all eligible subjects will be subjected to lipoaspiration resulting in the isolation of approximately 100- 500 gr of adipose tissue. After preparation, isolation and labelling ADSCs-SVF will be endobronchially infused to both lower lobes of the fibrotic lungs. Procedure will be repeated thrice at monthly intervals. Primary end-point represent safety and tolerability data, while exploratory secondary end-points include assessment of clinical functional and radiological status. Results: Preliminary results recently presented in the form of an abstract seem promising and tantalizing since there were no cases of clinically significant allergic reactions, infections, disease acute exacerbations or ectopic tissue formation. In addition 6 months follow-up data revealed a marginal improvement at 6-minute walking distance and forced vital capacity. Conclusions Adipose tissue represents an abundant, safe, ethically uncontested and potentially beneficial source of stem cells for patients with IPF. Larger multicenter phase II and III placebo-controlled clinical trials are sorely needed in order to prove efficacy. However, pilot safety studies are of major importance and represent the first hamper that should be overcome to establish a rigid basis for larger clinical trials.

• Aging leads to chronic inflammation and immune dysfunction, heightening the risk of myeloid malignancies like MDS and CMML. • Both aging and MDS show alterations in monocyte subtypes and function. Aging boosts inflammatory genes upregulation, whereas MDS favors antigen presentation, reflecting distinct immune and disease-specific adaptations. • MDS shows reduced inflammatory activity in CD14 + cells, whereas CMML exhibits heightened inflammation, highlighting distinct disease mechanisms., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

CD8+ T cells are crucial for antitumor immunity. In higher-risk myelodysplastic neoplasms (HR-MDS) and acute myeloid leukemia (AML), CD8+ T cells exhibit altered functionality. To address their role in the course of the disease, we performed in-depth immunophenotypic analysis of 104 pre-treatment bone marrow (BM) samples using mass and flow cytometry and observed an increased frequency of the CD57+CXCR3+ subset of CD8+ T cells in patients who failed azacitidine (AZA) therapy. Furthermore, an increased baseline frequency (>29%) of the CD57+CXCR3+CD8+ T cell subset was correlated with poor overall survival. We performed scRNA-seq to assess the transcriptional profile of BM CD8+ T cells from treatment-naive patients. The response to AZA was positively associated with the enrichment of IFN-mediated pathways, whereas an enhanced TGF-β signaling signature was observed in non-responders. Our results suggest that targeting CD8+ T cells with inhibitors of TGF-β signaling in combination with AZA is a potential therapeutic strategy for HR-MDS and AML.

Abstract: Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

MiRNAs have been identified as participants in leukemogenesis by controlling several cellular functions, such as differentiation, proliferation, and apoptosis. Their role in myelodysplastic neoplasms (MDS) pathogenesis is researched due to implementations in early identification, classification, and therapeutical options. IPSS-R, being the most widely used MDS classification, underestimates early biological events that can alter the disease's prognosis. The purpose of this study is to determine whether miRNA levels are aligned to MDS risk stratification groups and can therefore be used as diagnostic biomarkers. To evaluate miRNAs as possible biomarkers, we measured the levels of miR-181a-2-3p, miR-124-3p, miR-550a-3p, miR-155-5p, miR-151a-3p, and miR-125b-5p by a quantitative real-time PCR in bone marrow samples of 41 MDS patients. In conclusion, in myeloid malignancies, genomic characteristics may provide a wider apprehension of its clinical course and prognosis. MiRNAs constitute a possible diagnostic biomarker and therapeutic target, allowing intermediate-risk patients that express high levels of specific miRNAs to be re-classified and receive more advanced therapeutic agents. In our study, an association between high levels of miRNAs and worsening outcomes is established, supporting the need for further incorporation of molecular data into currently used classification systems.

Competing Interests: Thomas Chatzikonstantinou received honoraria from AbbVie. Lydia Scarfò received honoraria from AbbVie, AstraZeneca, BeiGene, Lilly, Janssen, Octapharma. Gloria Iacoboni received honoraria and travel support from Novartis, Kite/Gilead, Bristol‐Myers Squibb, Abbvie, Autolus, Miltenyi, and AstraZeneca. Rosa Collado received support for attending meetings from Janssen‐Cilag and S.A. Sara Galimberti received honoraria support for attending meetings from AbbVie, AstraZeneca, Jazz, Novartis, and Incyte, honoraria from Roche, Celgene, Pfizer, and Janssen, and support for attending meetings from Jazz, AstraZeneca, and Roche. Romain Guieze received honoraria, consulting fees, and support for attending meetings from AbbVie, Beigene, Roche, Janssen, and AstraZeneca. Eleftheria Hatzimichael received honoraria from AbbVie, Janssen‐Cilag, AstraZeneca, and Roche. Yair Herishanu received honoraria from Janssen, AbbVie, Roche, AstraZeneca, Medion, and Lilly. José‐Ángel Hernández‐Rivas received honoraria as a consultant from Janssen, AbbVie, AstraZeneca, Lilly, and BeiGene and support for attending meetings from Janssen, AbbVie, AstraZeneca, and BeiGene. Ozren Jaksic received honoraria from Johnson and Johnson, AstraZeneca, and Lilly, honoraria from Johnson and Johnson, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Johnson and Johnson, and AbbVie. Kamel Laribi received consulting fees from AbbVie, AstraZeneca, Janssen, Beigene, Takeda, and Novartis. Maya Koren‐Michowitz received honoraria from Novartis, Pfizer, and Gad Medical LTD. and support for attending meetings from Novartis. Arnon P. Kater received advisory board fees and research money from Janssen, AbbVie, BMS, AstraZeneca, and Roche/Genentech, and support for attending meetings from Janssen and AbbVie. Ioannis Kotsianidis received honoraria and consulting fees from AbbVie and Janssen. Ivana Milosevic received honoraria from AbbVie, Roche, Sandoz, AstraZeneca, and Janssen, and support for attending meetings from AbbVie, Roche, and Takeda. Almudena Navarro‐Bailón received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Takeda, Janssen, and Beigene. Jacopo Olivieri received honoraria from AbbVie, AstraZeneca, and Janssen. Gianluigi Reda received consulting fees from AbbVie, AstraZeneca, Janssen, and Beigene, and is currently employed by AstraZeneca. Gian M. Rigolin received honoraria for participation in speaker's bureau from AbbVie, Astra Zeneca, Beigene, and Janssen, and support for attending meetings from Janssen. Mattia Schipani received honoraria and support for attending meetings from AstraZeneca, AbbVie, and Janssen‐Cilag and owns shares of stock in AbbVie, AstraZeneca, Merck, Eli Lilly, Sanofi, Johnson and Johnson, Pfizer, Gilead, and GSK. Tereza Shokralla and Stephan Stilgenbauer reports research funding from, consultancy or advisory role for, honoraria from, speakers' bureau participation for, and travel support from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Gilead, GlaxoSmithKline, Hoffmann‐La Roche, Incyte, Infinity, Janssen, Novartis, and Sunesis. Eric Tse received support for attending meetings from Takeda. Theodoros Vassilakopoulos received honoraria from Takeda, Roche, Genesis Pharma, Merck, Novartis, Gilead, Sandoz, AstraZeneca, Integris, and Servier, and support for attending meetings from Takeda, Roche, Genesis Pharma, Merck, Pfizer, and Winmedica. Candida Vitale received honoraria from AbbVie, consulting fees from AstraZeneca, and support for attending meetings from AstraZeneca, Takeda, and Janssen. Renata Walewska received honoraria from AbbVie, AstraZeneca, and Beigene, support for attending meetings from Janssen, AbbVie, and AstraZeneca, and advisory board fees from AbbVie, AstraZeneca, Janssen, Beigene, and SecuraBio. Lucrecia Yañez received honoraria from AbbVie, AstraZeneca, Novartis, Gilead, Janssen, Jazz, MSD, and Pfizer, support for attending meetings from AbbVie, AstraZeneca, Gilead, Janssen, and Pfizer, and advisory board fees from AbbVie, AstraZeneca, Jazz, Janssen, Beigene, and Celgene. Francesc Bosch received consulting fees, honoraria, and payment for expert testimony from AbbVie, Genentech, Novartis, Takeda, Janssen, Roche, Mundipharma, Celgene/BMS, AstraZeneca, Lilly, Beigene, Gilead and TG Therapeutics, Advantage Allogene, Lava Therapeutics, and Enterome. Stephen Mulligan received advisory board fees from AbbVie, AstraZeneca, Janssen, Roche, and BeiGene. Maria Angelopoulou received consulting fees from AbbVie, Takeda, Janssen, Roche, Genesis, Gilead, and Amgen and honoraria from AbbVie, Takeda, Roche, Genesis, Gilead, and Novartis. Fatih Demirkan received support for attending meetings from Janssen and AbbVie. Tomas Papajík received honoraria and advisory board fees from AbbVie, Janssen‐Cilag, and AstraZeneca, and support for attending meetings from AstraZeneca. Marta Coscia received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. Constantine Tam received honoraria from AbbVie, Beigene, Janssen, and LOXO. Antonio Cuneo received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Beigene, Janssen, and Lilly. Gianluca Gaidano received honoraria from Abbvie, AstraZeneca, BeiGene, Hikma, Incyte, Janssen, and Lilly. Niki Stavroyianni received honoraria from Janssen, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Janssen and AstraZeneca. Lukas Smolej received consulting fees, honoraria, and support for attending meetings from AbbVie, AstraZeneca, and Janssen and advisory board fees from AbbVie and AstraZeneca. Martin Spacek received honoraria and consulting and advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. Michael Doubek received research support and honoraria from AbbVie, AstraZeneca, and Janssen. Eugene Nikitin received honoraria from AbbVie. Kostas Stamatopoulos received research support from AbbVie, AstraZeneca, Janssen, Novartis, and Roche; honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Lilly, and Janssen. Paolo Ghia received research support from AbbVie, AstraZeneca, BMS, Janssen and honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Genmab, Janssen, Loxo Oncology @Lilly, MSD, Roche, and is an Editor of HemaSphere. Georgios Karakatsoulis, Eva Minga, Dimitra Chamou, Jana Kotaskova, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al‐Shemari, Thérèse Aurran‐Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El‐Ashwah, Alicia Enrico, Andrzej Frygier, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Sean Harrop, Elżbieta Kalicińska, Volkan Karakus, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez‐Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor‐Bastida, Biljana Mihaljevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Irina Panovska‐Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Rosa Ruchlemer, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Tamar Tadmor, Kristina Tomic, Andrea Visentin, George Vrachiolias, Vojin Vukovic, Zhenshu Xu, Munci Yagci, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Blanca Espinet, Paolo Sportoletti, Gerassimos A. Pangalis, Viola M. Popov, Bella Biderman, Roberta Murru, Rainer Claus, Livio Trentin, Darko Antic, Olga B. Kalashnikova, Mark Catherwood, Sarka Pospisilova, and Anastasia Chatzidimitriou have no conflict of interest to disclose.

Abstract: Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The spectrum of HHV-8-associated disorders includes Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and the recently described KSHV inflammatory cytokine syndrome (KICS), a life-threatening disorder complicating HIV infection. There have been no reports in the literature concerning non-immunosuppressed individuals affected with KICS. We report here a KICS-like illness occurring in two elderly Greek men without HIV infection or other recognizable cause of immunosuppression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Imaging flow cytometry (ImFC) represents a significant technological advancement in the field of cytometry, effectively merging the high-throughput capabilities of flow analysis with the detailed imaging characteristics of microscopy. In our comprehensive review, we adopt a historical perspective to chart the development of ImFC, highlighting its origins and current state of the art and forecasting potential future advancements. The genesis of ImFC stemmed from merging the hydraulic system of a flow cytometer with advanced camera technology. This synergistic coupling facilitates the morphological analysis of cell populations at a high-throughput scale, effectively evolving the landscape of cytometry. Nevertheless, ImFC's implementation has encountered hurdles, particularly in developing software capable of managing its sophisticated data acquisition and analysis needs. The scale and complexity of the data generated by ImFC necessitate the creation of novel analytical tools that can effectively manage and interpret these data, thus allowing us to unlock the full potential of ImFC. Notably, artificial intelligence (AI) algorithms have begun to be applied to ImFC, offering promise for enhancing its analytical capabilities. The adaptability and learning capacity of AI may prove to be essential in knowledge mining from the high-dimensional data produced by ImFC, potentially enabling more accurate analyses. Looking forward, we project that ImFC may become an indispensable tool, not only in research laboratories, but also in clinical settings. Given the unique combination of high-throughput cytometry and detailed imaging offered by ImFC, we foresee a critical role for this technology in the next generation of scientific research and diagnostics. As such, we encourage both current and future scientists to consider the integration of ImFC as an addition to their research toolkit and clinical diagnostic routine.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. The identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus, clinicians must be vigilant in searching for the cause of eosinophilia and basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article, we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and give prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

Antiphospholipid syndrome is an autoimmune disorder which is characterized by the presence of heterogeneous antiphospholipid antibodies. There is an evidence on antiphospholipid (aPL) antibodies related to thromboembolic events in cancer patients. In fact, the thrombotic complications in patients with malignancy occur at a rather high frequency, compared to other risk factors. In parallel with standard therapies available, there is need of case-by-case monitoring of each patient and the introduction of new therapies and need for more clinical trials which will address many questions for the optimal management of patients. This paper presents a basic review of the literature on the aPL antibodies associated with cardiovascular disease and cancer, as well as its complications, which are reported so far in the bibliography., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work., Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022., Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001)., Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS., Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026., Competing Interests: TC received honoraria from AbbVie. LS received consulting fees from AbbVie, BeiGene, AstraZeneca, Lilly, and Janssen, honoraria from Janssen and Octapharma, support for attending meetings from BeiGene and Janssen and advisory board fees from Merck. SMu received advisory board fees from AbbVie, AstraZeneca, Janssen, Roche and BeiGene. JAHR received honoraria as a consultant from Janssen, AbbVie, AstraZeneca, Lilly, and BeiGene and support for attending meetings from Janssen, AbbVie, AstraZeneca, and BeiGene. LI received honoraria from AbbVie, Roche, and Janssen-Cilag. APK received advisory board fees and research money from Janssen, AbbVie, BMS, AstraZeneca, Roche/Genentech, support for attending meetings from Janssen and AbbVie. M-DL received travel expenses from Janssen and AbbVie. GMR received honoraria for participation to speaker's bureau from AbbVie, Astra Zeneca, Beigene, and Janssen, and support for attending meetings from Janssen. JVT received consulting fees from AbbVie, AstraZeneca, BeiGene, and Janssen, honoraria for scientific talks from AbbVie, AstraZeneca, BeiGene, Janssen, Lilly, and Roche, travel support from AbbVie, AstraZeneca, BeiGene, Janssen, Roche, and Lilly, and advisory boards fees for AbbVie, Amgen, AstraZeneca, BeiGene. GI received honoraria from Novartis, BMS, Sandoz, AstraZeneca, Janssen, Kite/Gilead, and Miltenyi, support for attending meetings from Kite/Gilead, AstraZeneca, and AbbVie and advisory board fees from Kite/Gilead, Novartis, BMS, and Autolus. FBi received support for attending meetings from AbbVie. RCo received support for attending meetings from Janssen-Cilag and S.A. SG received honoraria support for attending meetings from AbbVie, AstraZeneca, Jazz, Novartis, and Incyte, honoraria from Roche, Celgene, Pfizer, and Janssen, and support for attending meetings from Jazz, AstraZeneca, and Roche. RGS received support for attending meetings from AbbVie and S.L.U. RG received honoraria, consulting fees, and support for attending meetings from AbbVie, Beigene, Roche, Janssen, AstraZeneca. YH received honoraria from Janssen, AbbVie, Roche, AstraZeneca, Medion, and Lilly. OJ received honoraria from Johnson and Johnson, AstraZeneca, and Lilly, honoraria from Johnson and Johnson, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Johnson and Johnson, and AbbVie. LK received consulting fees from AbbVie, AstraZeneca, Janssen, Beigene, Takeda, and Novartis. MKM received honoraria from Novartis, Pfizer, and Gad Medical LTD and support for attending meetings from Novartis. IKo received honoraria and consulting fees from AbbVie and Janssen. IM received honoraria from AbbVie, Roche, Sandoz, AstraZeneca, and Janssen, and support for attending meetings from AbbVie, Roche, and Takeda. ANB received honoraria, advisory board fees and support for attending meetings from AbbVie, AstraZeneca, Takeda, Janssen, and Beigene. JO received honoraria from AbbVie, AstraZeneca, and Janssen. GR received consulting fees from AbbVie, AstraZeneca, Janssen, and Beigene, and is currently employed by AstraZeneca. TP received honoraria and advisory board fees from AbbVie, Janssen-Cilag, and AstraZeneca and support for attending meeting from AstraZeneca. MS received honoraria and support for attending meeting from AstraZeneca, AbbVie, and Janssen-Cilag and owns shares of stock in AbbVie, AstraZeneca, Merck, Eli Lilly, Sanofi, Johnson and Johnson, Pfizer, Gilead, and GSK. MSp received honoraria and consulting and advisory board fees, and support for attending meeting from AbbVie, AstraZeneca, and Janssen. ET received support for attending meetings from Takeda. TV received honoraria from Takeda, Roche, Genesis Pharma, Merck, Novartis, Gilead, Sandoz, AstraZeneca, Integris, and Servier and support for attending meetings from Takeda, Roche, Genesis Pharma, Merck, Pfizer, and Winmedica. CV received honoraria from AbbVie, consulting fees from AstraZeneca and support for attending meeting from AstraZeneca, Takeda, and Janssen. RW received honoraria from AbbVie, AstraZeneca, and Beigene, support for attending meetings from Janssen, AbbVie, and AstraZeneca and advisory board fees from AbbVie, AstraZeneca, Janssen, Beigene, and SecuraBio. EWS received honoraria from AbbVie, Roche, and Janssen-Cilag and support for attending meetings from AbbVie. LY received honoraria from AbbVie, AstraZeneca, Novartis, Gilead, Janssen, Jazz, MSD, and Pfizer, support for attending meetings from AbbVie, AstraZeneca, Gilead, Janssen, and Pfizer, and advisory board fees from AbbVie, AstraZeneca, Jazz, Janssen, Beigene, and Celgene. MAn received consulting fees from AbbVie, Takeda, Janssen, Roche, Genesis, Gilead, and Amgen and honoraria from AbbVie, Takeda, Roche, Genesis, Gilead, and Novartis. MC received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, and Janssen. ACu received honoraria, advisory board fees, and support for attending meetings from AbbVie, AstraZeneca, Beigene, Janssen, and Lilly. FD support for attending meetings from Janssen and AbbVie. GG received honoraria, and advisory board fees from AbbVie, AstraZeneca, Beigene, Janssen and advisory board fees from Lilly. EN received honoraria from AbbVie. LSm received consulting fees, honoraria and support for attending meetings from AbbVie, AstraZeneca, and Janssen and advisory board fees from AbbVie and AstraZeneca. NS received honoraria from Janssen, AbbVie, AstraZeneca, and Lilly, and support for attending meetings from Janssen and AstraZeneca. CT received honoraria from AbbVie, Beigene, Janssen, and LOXO. FB received consulting fees, honoraria and payment for expert testimony from AbbVie, Genentech, Novartis, Takeda, Janssen, Roche, Mundipharma, Celgene/BMS, AstraZeneca, Lilly, Beigene, Gilead and TG Therapeutics, Advantage Allogene, Lava Therapeutics, and Enterome. MDo received honoraria and advisory board fees from AbbVie, AstraZeneca and Janssen, advisory board fees from Swixx, and support for attending meetings from Janssen. PG received honoraria and consulting fees from AbbVie, AstraZeneca, BMS, Janssen, Lilly/Loxo Oncology, MSD, and Roche; grant support from AbbVie, AstraZeneca, BMS, Janssen. KS received honoraria from Janssen, AbbVie, Lilly and AstraZeneca, consulting fees and support for attending meetings from Janssen and AstraZeneca. GK, EM, DC, JK, CD, MA, SA, TAS, FBa, MB, ACa, AM, AKM, RC, SC, ACh, ZD, MDi, DD, GDS, BD, ME, SEA, AE, AF, AG, EG, IGGM, AGo, AjG, RGu, SH, EH, SJ, EKa, VK, BK, MK, EK, RJK, JL, DL, IL, TL, ALG, JM, LMR, MMa, SM, CMB, BM, FM, RM, MMo, RMu, UKN, ACO, DO, IPS, MP, ZK, PP, CP, AP, LR, RR, MDDS, AS, YS, MSi, SS, DSAS, TT, KT, AV, GV, VV, ZX, MYa, MY, JZ, DA, BB, MCa, RCl, BE, OBK, LL, GP, PPa, VMP, SP, PS, LT, AC, have no conflict of interest to disclose., (© 2023 Published by Elsevier Ltd.)

Personalized prediction is ideal in chronic lymphocytic leukemia (CLL). Although refined models have been developed, stratifying patients in risk groups, it is required to accommodate time-dependent information of patients, to address the clinical heterogeneity observed within these groups. In this direction, this study proposes a personalized stepwise dynamic predictive algorithm (PSDPA) for the time-to-first-treatment of the individual patient. The PSDPA introduces a personalized Score, reflecting the evolution in the patient's follow-up, employed to develop a reference pool of patients. Score evolution's similarity is used to predict, at a selected time point, the time-to-first-treatment for a new patient. Additional patient's biological information may be utilized. The algorithm was applied to 20 CLL patients, indicating that stricter assessment criteria for the Score evolution's similarity, and biological similarity exploitation, may improve prediction. The PSDPA capitalizes on both the follow-up and the biological background of the individual patient, dynamically promoting personalized prediction in CLL., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 μg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin <10 g/dL (1.34, 1.12-1.61), and high body mass index (≥30 vs 23-29.9 kg/m2: 1.26, 1.02-1.57). Sex, KPS, comorbidity burden, hemoglobin count, and transfusion burden were determinants for all EQ-5D dimensions. Low HRQoL is determined by multiple factors, which should be considered in the management and shared decision making of patients with MDS. This trial was registered at www.clinicaltrials.gov as #NCT00600860., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Central nervous system (CNS) involvement is rare in primary mediastinal large B-cell lymphoma (PMLBCL). We aimed to evaluate the incidence of CNS relapse as first treatment failure event and the effect of the induction chemotherapy regimen, central nervous system - international prognostic index (CNS-IPI) and other clinical and laboratory variables on the risk of CNS relapse in 564 PMLBCL patients treated with immunochemotherapy. Only 17 patients (3.0%) received CNS prophylaxis. During a 55-month median follow-up only 8 patients experienced CNS relapse as first event, always isolated. The 2-year cumulative incidence of CNS relapse (CI-CNSR) was 1.47% and remained unchanged thereafter. The CI-CNSR was not affected by the chemotherapy regimen (R-CHOP or R-da-EPOCH). None of the established International Prognostic Index factors for aggressive lymphomas predicted CNS relapse in PMLBCL. The 2-year CI-CNSR in patients with versus without kidney involvement was 13.3% versus 0.96% (p < 0.001); 14.3% versus 1.13% with versus without adrenal involvement (p < 0.001); and 10.2% versus 0.97% with versus without either kidney or adrenal involvement. CNS-IPI was also predictive (2-year CI-CNSR in high-risk vs. intermediate/low-risk: 10.37% vs. 0.84%, p < 0.001). However, this association may be driven mainly by kidney and/or adrenal involvement. In conclusion, in PMLBCL, CNS relapse is rare and appears to be strongly associated with kidney and/or adrenal involvement., (© 2022 John Wiley & Sons Ltd.)

Competing Interests: Declaration of Competing Interest No conflicts of interest.

Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in innate immunity, they have not been incorporated in any prognostic scoring system for MDS. In this study, we analyzed national registry data from 1719 adults with MDS. Monocytopenia was present in 29.5% of the patients and was correlated with the presence of excess blasts and higher revised international prognostic scoring system categories. Univariate analysis showed that monocytopenia was prognostic of a lower overall survival [(OS), 32.0 versus 65.0 months, p < 0.001], while it retained its prognostic significance in a multivariate model comprising anemia, neutropenia and thrombocytopenia [hazard ratio (HR) for OS, 1.320, p < 0.001]. Moreover, it was prognostic of a lower leukemia free survival (LFS) both in univariate analysis and in a multivariate model comprising cytopenias, bone marrow blasts, and cytogenetic risk (HR for LFS 1.27, p = 0.031). The findings regarding OS and LFR were exclusive or more pronounced in lower risk patients, respectively. Moreover, monocytopenia could divide the low and intermediate risk groups of IPSS-R in prognostically distinct subgroups. Our results redefine the prognostic role of monocytes in MDS and set the basis for further studies to validate our results and expand our knowledge on the prognostic significance of monocytopenia in MDS., (© 2022. The Author(s).)

Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.

BACKGROUND: Risk stratification and therapeutic decision-making for myelodysplastic syndromes (MDS) are based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities. Somatic gene mutations are not yet used in the risk stratification of patients with MDS. METHODS: To develop a clinical-molecular prognostic model (IPSS-Molecular [IPSS-M]), pretreatment diagnostic or peridiagnostic samples from 2957 patients with MDS were profiled for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival. Feature selection was applied to determine the set of independent IPSS-M prognostic variables. The relative weights of the selected variables were estimated using a robust Cox multivariable model adjusted for confounders. The IPSS-M was validated in an external cohort of 754 Japanese patients with MDS. RESULTS: We mapped at least one oncogenic genomic alteration in 94% of patients with MDS. Multivariable analysis identified TP53multihit, FLT3 mutations, and MLLPTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. Using hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, the IPSS-M resulted in a unique risk score for individual patients. We further derived six IPSS-M risk categories with prognostic differences. Compared with the IPSS-R, the IPSS-M improved prognostic discrimination across all clinical end points and restratified 46% of patients. The IPSS-M was applicable in primary and secondary/therapy-related MDS. To simplify clinical use of the IPSS-M, we developed an open-access Web calculator that accounts for missing values. CONCLUSIONS: Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making. (Funded by Celgene Corporation through the MDS Foundation, the Josie Robertson Investigators Program, the Edward P. Evans Foundation, the Projects of National Relevance of the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro, the Japan Agency for Medical Research and Development, Cancer Research UK, the Austrian Science Fund, the MEXT [Japanese Ministry of Education, Culture, Sports, Science and Technology] Program for Promoting Research on the Supercomputer Fugaku, the Japan Society for the Promotion of Science, the Taiwan Department of Health, and Celgene Corporation through the MDS Foundation.)

Background/aim: Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients' population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14., Patients and Methods: We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes., Results: CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS)., Conclusion: Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter's methylation. Patients with low RRM1 levels had a high RRM1 methylation status ( p  = 0.005) and a better response to treatment with 5-azacytidine ( p  = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels ( p  = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS.

Objectives: The role of hereditary thrombophilia in reproductive failure (RF) is strongly debatable. In this retrospective single-center study, we analyzed pregnancy outcome in 175 women screened for thrombophilia after at least one event of RF., Results: The prevalence of thrombophilia in our cohort was 33.4%. Pregnancy survival curves were not different according to severity (log-rank, p = 0.302) or type of thrombophilia (log-rank, p = 0.532). In total, 81.7% of 175 subsequent pregnancies were proceeded with LMWH. Concomitant use of ASA was prescribed in 75 pregnancies according to physician choice. The primary endpoint was live birth rate (LBR) that succeeded in 152/175 next pregnancies (86.8%) and late obstetric complications (LOBC) which occurred in 17/175 next pregnancies (9.8%). In logistic regression analysis, neither the severity nor the type of thrombophilia was important for any pregnancy outcome (LBR or LOBC). Considering therapeutic interventions, the use of LMWH ± ASA was not related to LBR or LOBC. The only factor inversely related to LBR was age above the cutoff value of 35.5 years (p = 0.049)., Conclusions: Incidence of thrombophilia is increased among women with RF, but the severity or type of thrombophilia is not related to pregnancy outcome., (© 2021 S. Karger AG, Basel.)

Chronic myelomonocytic leukemia (CMML) is a rare clonal haematological malignancy bearing characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. It primarily affects older people (median age at diagnosis ~72 years). There are many challenges encountered in its treatment. One striking issue is the lack of strong clinical evidence from large randomized clinical trials for treating this disease. Another issue is that patients with CMML have highly variable outcomes with current treatments. Additional challenges include a wider application of current knowledge, an improved understanding of pathogenesis, development of new therapies, and management of refractory cases/disease progression. It is clear that there is still progress to be made. Here, we review the available first-line treatment options for advanced CMML. Emphasis has been placed on choosing between hypomethylating agents and cytotoxic treatments, on the basis on disease-specific and patient-specific characteristics. A proper selection between these two treatments could lead to a better quality of care for patients with CMML., 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 © 2021 Liapis and Kotsianidis.)

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

We present a noninvasive Web-based app to help exclude or diagnose myelodysplastic syndrome (MDS), a bone marrow (BM) disorder with cytopenias and leukemic risk, diagnosed by BM examination. A sample of 502 MDS patients from the European MDS (EUMDS) registry (n > 2600) was combined with 502 controls (all BM proven). Gradient-boosted models (GBMs) were used to predict/exclude MDS using demographic, clinical, and laboratory variables. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models, and performance was validated using 100 times fivefold cross-validation. Model stability was assessed by repeating its fit using different randomly chosen groups of 502 EUMDS cases. AUC was 0.96 (95% confidence interval, 0.95-0.97). MDS is predicted/excluded accurately in 86% of patients with unexplained anemia. A GBM score (range, 0-1) of less than 0.68 (GBM < 0.68) resulted in a negative predictive value of 0.94, that is, MDS was excluded. GBM ≥ 0.82 provided a positive predictive value of 0.88, that is, MDS. The diagnosis of the remaining patients (0.68 ≤ GBM < 0.82) is indeterminate. The discriminating variables: age, sex, hemoglobin, white blood cells, platelets, mean corpuscular volume, neutrophils, monocytes, glucose, and creatinine. A Web-based app was developed; physicians could use it to exclude or predict MDS noninvasively in most patients without a BM examination. Future work will add peripheral blood cytogenetics/genetics, EUMDS-based prospective validation, and prognostication., (© 2021 by The American Society of Hematology.)