150 results on '"Buccisano, Francesco"'
Search Results
2. Risk-adapted MRD-directed therapy for young adults with acute myeloid leukemia: 6-year update of the GIMEMA AML1310 trial.
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Venditti A, Piciocchi A, Candoni A, Arena V, Palmieri R, Filì C, Carella AM, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Curti A, Luppi M, Ingrosso C, Martelli MP, Cuneo A, Albano F, Mulè A, Tafuri A, Cudillo L, Tieghi A, Fracchiolla NS, Capelli D, Trisolini SM, Alati C, La Sala E, Maurillo L, Del Principe MI, Irno Consalvo MA, Divona MD, Ottone T, Cerretti R, Sconocchia G, Voso MT, Fazi P, Vignetti M, and Buccisano F
- Subjects
- Humans, Young Adult, Adult, Male, Female, Adolescent, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute therapy, Neoplasm, Residual
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- 2024
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3. Acute Leukemia and Latent Tuberculosis Infection in Italy: Quantiferon-Tb Test Screening in a Low Tuberculosis Incidence Country.
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Nunzi A, Della Valle L, Lindfors Rossi EL, Ranucci G, Mallegni F, Moretti F, Meddi E, Guarnera L, Tiravanti I, Taka K, Buzzatti E, Esposito F, Secchi R, Di Giuliano F, Chirico F, Palmieri R, Maurillo L, Buccisano F, Gurnari C, Paterno G, Venditti A, and Del Principe MI
- Abstract
Background: Identification of latent tuberculosis infection (LTBI) is a critical step of tuberculosis surveillance, especially in low-incidence countries. However, it is limited to situations with a higher probability of developing active disease, e.g., patients with hematological malignancies. According to guidelines, in TB non-endemic countries, no clear screening program is established at diagnosis for patients with acute leukemia (AL). The primary endpoint of this study was to establish the prevalence of LTBI in patients with a diagnosis of AL using QuantiFERON (QFT)-TB. Secondarily, radiological and clinical features driving the increased risk of LTBI were evaluated., Methods: QFT-TB screening was performed before induction or consolidation in all patients with AL (myeloid and lymphoid) treated at our Institution between October 2019 and August 2023., Results: We accrued 62 patients, of whom 7 (11,3%) tested positive, without any symptoms or signs of active TB, and 2 (3,2%) resulted as indeterminate. All positive patients started prophylaxis with isoniazid 300 mg daily, while patients whose test was indeterminate did not receive any prophylaxis. Active TB was excluded by imaging, as well as microscopic, cultural, and molecular examination on bronchoalveolar lavage if signs of any infection were detected. During the 46 months of observation, no patients developed TB reactivation., Conclusions: Despite the low sample size, 1/10 of our patients had prior TB exposure, hinting that LTBI could be more common than expected in Italy. This finding suggests implementing TB screening in the pre-treatment setting, particularly at a time when more active treatments are becoming available also for patients ineligible for intensive chemotherapy., Competing Interests: Competing interests: The authors declare no conflict of Interest.
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- 2024
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4. Relapse Prevention in Acute Myeloid Leukemia: The Role of Immunotherapy with Histamine Dihydrochloride and Low-Dose Interleukin-2.
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Montesinos P, Buccisano F, Cluzeau T, Vennström L, and Heuser M
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The treatment and management of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy for subgroups of patients, expanded indications for allogeneic stem cell transplantation (allo-SCT) and surveillance of residual or arising leukemia. However, hematological relapse among patients who have attained complete remission (CR) after the initial courses of chemotherapy remains a significant cause of morbidity and mortality. Here, we review an immunotherapeutic option using histamine dihydrochloride and low-dose interleukin-2 (HDC/LD-IL-2) for remission maintenance in AML. The treatment is approved in Europe in the post-consolidation phase to avoid relapse among patients in CR who are not candidates for upfront allo-SCT. We present aspects of the purported anti-leukemic mechanism of this regimen, including translation of preclinical results into the clinical setting, along with relapse prevention in subgroups of patients. We consider that HDC/LD-IL-2 is a conceivable option for younger adults, in particular patients with AML of normal karyotype and those with favorable responses to the initial chemotherapy. HDC/LD-IL-2 may form an emerging landscape of remission maintenance in AML., Competing Interests: P.M. declares research grant, honoraria for advisory board, speaker bureau from Bristol Myers Squibb, Delbert Pharma, Daiichi and Abbvie. F.B. has received honoraria for consultancy from Jazz Pharmaceuticals, Novartis, Delbert Pharma, and as invited speaker from Abbvie, Jazz Pharmaceuticals, Bristol Myers Squibb, Janssen-Cilag, Astellas, Servier. T.C has received clinical research support from Novartis, Alexion, Celgene/BMS, Amgen, Syros, Kartos, Arog, Takeda, Servier, Janssen, Keros, has received honoraria for advisory boards from BMS/Celgene, Abbvie, Delbert Pharma, Jazz Pharma, Novartis, Agios, Servier, BluePrint, for education from Novartis, Astellas, Celgene/BMS, Jazz Pharma, Servier, Incyte and as speaker in international congresses from Pfizer, Celgene/BMS, Novartis, Abbvie, Servier, Gilead. L.V. has received honoraria for consultancy from Abbvie and Delbert Pharma. M.H. declares research funding to institution from Abbvie, Servier, Astellas, BergenBio, Glycostem, Jazz Pharmaceuticals, Karyopharm, Loxo Oncology, Novartis, PinotBio, and honoraria from Abbvie, Bristol Myers Squibb, Janssen, Jazz Pharmaceuticals, Pfizer, Qiagen, Servier, Sobi, and has received honoraria for consultancy from AvenCell, Abbvie, Astellas, Glycostem, Janssen, Delbert Pharma, Miltenyi, Novartis, Pfizer, PinotBio, Servier.
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- 2024
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5. The ISTH DIC-score predicts early mortality in patients with non-promyelocitic acute myeloid leukemia.
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Paterno G, Palmieri R, Tesei C, Nunzi A, Ranucci G, Mallegni F, Moretti F, Meddi E, Tiravanti I, Marinoni M, Page C, Fagiolo S, Buzzatti E, Secchi R, Gurnari C, Maurillo L, Buccisano F, Venditti A, and Del Principe MI
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- Humans, Male, Aged, Female, Retrospective Studies, Prognosis, Blood Coagulation, Disseminated Intravascular Coagulation etiology, Leukemia, Myeloid, Acute complications
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Coagulation disorders frequently complicate the clinical course of acute myeloid leukemia (AML) patients. This study examined the frequency and prognostic significance, with regards of early mortality, of the presence of overt disseminated intravascular coagulation (DIC) at AML diagnosis and its correlation with clinical and biological characteristics. A retrospective analysis of 351 newly diagnosed non-promyelocytic AML patients was conducted, utilizing the 2018 ISTH DIC-Score criteria to evaluate the presence of overt DIC at AML onset. The study cohort had a median age of 65 years with a predominance of male gender (59 %). Overt DIC was present in 21 % of cases and was associated with advanced age, comorbidities, poor performance status, hyperleukocytosis, LDH levels, NPM1 mutations, expression of CD33 and CD4, and lack of expression of CD34. With a median follow-up of 72 months (3-147 months), the 6-year overall survival (OS) was 17.4 %, with patients having overt DIC showing significantly poorer outcomes (7.2 % compared to 20.3 % of those without DIC, p < 0.001). Patients with overt DIC showed markedly high early mortality rates at 30 (42.5 % vs 8 %), 60 (49.3 % vs 16.9 %), and 120 days (64.4 % vs 25.6 %) from disease onset. In multivariate analysis overt DIC retained its independent prognostic value for early mortality. In conclusion, the prevalence and clinical relevance of DIC in non-promyelocytic AML is not negligible, underlining its potential as an unfavorable prognostic marker. In newly diagnosed patients with AML, early recognition and measure to counteract coagulation disturbances might help mitigate the elevated mortality risk associated with DIC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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6. Unlocking the potential of synthetic patients for accelerating clinical trials: Results of the first GIMEMA experience on acute myeloid leukemia patients.
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Piciocchi A, Cipriani M, Messina M, Marconi G, Arena V, Soddu S, Crea E, Feraco MV, Ferrante M, La Sala E, Fazi P, Buccisano F, Voso MT, Martinelli G, Venditti A, and Vignetti M
- Abstract
Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost-effective methods also enable the development of personalized subject-specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real-world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco-hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials., Competing Interests: Giovanni Marconi acts as a consultant or is included in the speaker bureau of Abbvie, Astellas, AstraZeneca, Immunogen, Jansenn, Menarini/Stemline, Pfizer, Ryvu, Servier, Syros, Takeda and received research funding from Abbvie, Astellas, AstraZeneca, Daiichi Sankyo, and Pfizer.Adriano Venditti acts as a consultant or is included in the speaker bureau of Novartis, Pfizer, Jazz Pharmaceuticals, Amgen, AbbVie, Gilead, Astellas, Incyte, Medac, AstraZeneca, Servier, Daiichi‐Sankyo, Janssen‐Cilag, Menarini‐StemLine Laboratories Delbert, and Bristol Myers Squibb and received research funding from Sandoz and Jazz Pharmaceuticals. All other co‐authors declare no conflict of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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7. Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower-intensity therapy: Roadmap from an ELN-DAVID expert panel.
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Ravandi F, Cloos J, Buccisano F, Dillon R, Döhner K, Freeman SD, Hourigan CS, Ossenkoppele GJ, Roboz GJ, Subklewe M, Thiede C, Arnhardt I, Valk PJM, Venditti A, Wei AH, Walter RB, and Heuser M
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- Humans, Prognosis, Treatment Outcome, Neoplasm, Residual diagnosis, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with intensive chemotherapy to refine prognosis and, possibly, inform treatment decision-making, its value in the context of lower-intensity regimens is unclear. As such regimens have gained in popularity and can be associated with higher response rates, the need to better define the role of MRD assessment and the appropriate time points and assays used for this purpose has increased. This report outlines a roadmap for MRD testing in patients with AML treated with lower-intensity regimens. Experts from the European LeukemiaNet (ELN)-DAVID AML MRD working group reviewed all available data to propose a framework for MRD testing in future trials and clinical practice. A Delphi poll served to optimize consensus. Establishment of uniform standards for MRD assessments in lower-intensity regimens used in treating patients with AML is clinically relevant and important for optimizing testing and, ultimately, improving treatment outcomes of these patients., (© 2023 Wiley Periodicals LLC.)
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- 2023
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8. Reliability of flow-cytometry in diagnosis and prognostic stratification of myelodysplastic syndromes: correlations with morphology and mutational profile.
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Guarnera L, Fabiani E, Attrotto C, Hajrullaj H, Cristiano A, Latagliata R, Fenu S, Buccisano F, Irno-Consalvo M, Conti C, Voso MT, and Maurillo L
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- Humans, Female, Male, Middle Aged, Aged, Adult, Retrospective Studies, Aged, 80 and over, Prognosis, Reproducibility of Results, Immunophenotyping, Young Adult, Adolescent, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes mortality, Flow Cytometry, Mutation
- Abstract
Diagnosis and prognostic stratification of myelodysplastic syndromes (MDS) have been complemented by new techniques, including flow cytometry and NGS. To analyze the relationship between molecular and cytofluorimetric data, we enrolled in this retrospective study, 145 patients, including 106 diagnosed with MDS and 39 controls. At disease onset, immunophenotypic (IF), cytogenetic tests, and cytomorphological (CM) examination on bone marrow were carried out in all patients, while NGS was performed in 58 cases. Ogata score presented a specificity of 100% and a sensitivity of 59%. The detection of at least two phenotypic aberrancies in Ogata negative patients increased the sensitivity to 83% and specificity to 87%. Correlations were identified between IF aberrancies and mutations, including positive Ogata>2 and mutations in SRSF2 (p=0.035), CD15 and U2AF1 (0.032), CD56 and DNMT3A (p=0.042), and CD38 and TP53 (p=0.026). In multivariate analysis, U2AF1 mutations, associated with del(20q) and/or abnormalities of chromosome 7 (group 4 as defined by the EuroMDS score), significantly correlated with an inferior overall survival (p=0.019). These parameters and Ogata score>2 also showed a significant correlation with inferior event-free survival (p=0.023 and p=0.041, respectively). Both CM and FC features correlated with prognosis and mutational patterns. In an integrated MDS work-up, these tools may guide indications for mutational screening for optimal risk stratification., (© 2023. The Author(s).)
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- 2023
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9. Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS).
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Oliva EN, Riva M, Niscola P, Santini V, Breccia M, Giai V, Poloni A, Patriarca A, Crisà E, Capodanno I, Salutari P, Reda G, Cascavilla N, Ferrero D, Guarini A, Tripepi G, Iannì G, Russo E, Castelli A, Fattizzo B, Beltrami G, Bocchia M, Molteni A, Fenaux P, Germing U, Ricco A, Palumbo GA, Impera S, Di Renzo N, Rivellini F, Buccisano F, Stamatoullas-Bastard A, Liberati AM, Candoni A, Delfino IM, Arcadi MT, Cufari P, Rizzo L, Bova I, D'Errigo MG, Zini G, and Latagliata R
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- Adult, Humans, Disease Progression, Hemorrhage chemically induced, Hemorrhage complications, Hemorrhage drug therapy, Neoplasm Recurrence, Local drug therapy, Quality of Life, Single-Blind Method, Hydrazines adverse effects, Hydrazines therapeutic use, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes drug therapy, Thrombocytopenia complications, Thrombocytopenia drug therapy
- Abstract
Purpose: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia., Methods: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10
3 /mm3 ) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 103 /mm3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics., Results: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times., Conclusion: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.- Published
- 2023
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10. Therapy-related Myeloid Neoplasms: Considerations for Patients' Clinical Evaluation.
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Palmieri R, Paterno G, Mallegni F, Frenza F, De Bernardis I, Moretti F, Meddi E, Del Principe MI, Maurillo L, Venditti A, and Buccisano F
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Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio., Competing Interests: Competing interests: The authors declare no conflict of Interest.
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- 2023
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11. MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs' patients.
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Catalano G, Zaza A, Banella C, Pelosi E, Castelli G, de Marinis E, Smigliani A, Travaglini S, Ottone T, Divona M, Del Principe MI, Buccisano F, Maurillo L, Ammatuna E, Testa U, Nervi C, Venditti A, Voso MT, and Noguera NI
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- Humans, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Hexokinase, Leukemia, Myeloid, Acute
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We characterize the metabolic background in distinct Acute Myeloid Leukemias (AMLs), by comparing the metabolism of primary AML blasts isolated at diagnosis with that of normal hematopoietic maturing progenitors, using the Seahorse XF Agilent. Leukemic cells feature lower spare respiratory (SRC) and glycolytic capacities as compared to hematopoietic precursors (i.e. day 7, promyelocytes). According with Proton Leak (PL) values, AML blasts can be grouped in two well defined populations. The AML group with blasts presenting high PL or high basal OXPHOS plus high SRC levels had shorter overall survival time and significantly overexpressed myeloid cell leukemia 1 (MCL1) protein. We demonstrate that MCL1 directly binds to Hexokinase 2 (HK2) on the outer mitochondrial membrane (OMM). Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs' cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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12. Editorial: Measurable residual disease in hematologic malignancies.
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Buccisano F, Palmieri R, Guzman ML, and Galimberti S
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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.
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- 2023
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13. Consensus for Flow Cytometry Clinical Report on Multiple Myeloma: A Multicenter Harmonization Process Merging Laboratory Experience and Clinical Needs.
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Cordone I, Amodeo R, Bellesi S, Bottan F, Buccisano F, De Propris MS, Masi S, Panichi V, Scerpa MC, Annibali O, Bongarzoni V, Caravita di Toritto T, Coppetelli U, Cupelli L, de Fabritiis P, Franceschini L, Garzia M, Fiorini A, Laverde G, Mengarelli A, Za T, and Petrucci MT
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Flow cytometry is a highly sensitive and specific approach for discriminating between normal and clonal plasma cells in multiple myeloma. Uniform response criteria after treatment have been established by the International Myeloma Working Group and the EuroFlow Group; however, the way in which flow cytometry data are reported has suffered from no collaborative or multicentre efforts. This study, involving 8 expert laboratories and 12 clinical hematology units of the Lazio region in Italy, aims to produce a uniform and shared report among the various Centres. From the pre-analytical phase to sample processing, data acquisition, analysis, and evaluation of the potential limitations and pitfalls of the entire process, the study reaches a final conclusion shared by laboratories and clinicians according to the most updated principles and recommendations. The aim was to identify the necessary data to be included in the clinical report by using multiple-choice questionnaires at every single stage of the process. An agreement of more than 75% of the laboratories was considered mandatory for the data to be included in the report. By ensuring the operational autonomy of each laboratory, this study provides a clear report that limits subjective interpretations and highlights possible bias in the process, better supporting clinical decision-making.
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- 2023
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14. Acute leukemia diagnosis during the COVID-19 pandemic.
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Guarnera L, Buzzatti E, Marchesi F, Armiento D, Mazzone C, Capria S, Scalzulli E, Malfona F, Chiaretti S, Palmieri R, Paterno G, Franzese C, Bonanni F, Savi A, Pasqualone G, Moretti F, Maurillo L, Buccisano F, Venditti A, and Del Principe MI
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- Humans, Pandemics, Acute Disease, Retrospective Studies, COVID-19 Testing, COVID-19, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute therapy
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- 2023
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15. Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML.
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Meddi E, Savi A, Moretti F, Mallegni F, Palmieri R, Paterno G, Buzzatti E, Del Principe MI, Buccisano F, Venditti A, and Maurillo L
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- Humans, Remission Induction, Biomarkers, Neoplasm, Residual diagnosis, Recurrence, Leukemia, Myeloid, Acute drug therapy
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In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint.
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- 2023
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16. Flow Cytometric Identification and Enumeration of Monocyte Subsets in Bovine and Water Buffalo Peripheral Blood.
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Grandoni F, Fraboni D, Canonico B, Papa S, Buccisano F, Schuberth HJ, and Hussen J
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- Animals, Cattle, Female, Pregnancy, Antibodies, Monoclonal metabolism, Buffaloes, Flow Cytometry veterinary, Monocytes metabolism, Mastitis, Bovine metabolism
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Monocytes are innate immune system key players with pivotal roles during infection and inflammation. They migrate into tissues and differentiate into myeloid effect cells (macrophages, dendritic cells) which orchestrate inflammatory processes and are interfaces between the innate and adaptive immune responses. Their clinical relevance to health and disease of cattle (Bos taurus) and water buffalo (Bubalus bubalis), two of the most important livestock species, has been highlighted in physiologic (pregnancy) and pathologic (mastitis, metritis, and viral infections) conditions. The existence of three different monocyte subsets in cattle was established by flow cytometry (FC), as follows: classical (cM; CD14
++ CD16-/low ), intermediate (intM; CD14++/+ CD16+ ), and non-classical (ncM; CD14-/low CD16++ ) monocytes. FC applications for studying the immune system of cattle and water buffalo still have significant limitations. In this article, we describe some practical approaches to overcome these limitations and, in particular, allow the identification and enumeration of cM, intM, and ncM subpopulations in cattle and buffalo peripheral blood. Indeed, we propose the new procedure lyse/wash/no-centrifugation (L/W/NC) that can be combined with the FC absolute counting procedures and can overcome specific issues of the lyse/no-wash protocols (L/NW). Finally, for the first time, we demonstrated the existence of cM, intM, and ncM monocyte subsets also in the water buffalo, showing some interesting differences with cattle, such as the bubaline cM are mainly CD14+/++ /CD16+ . These subtle differences may influence inflammatory disease regulation in, for example, mastitis and metritis. The upregulation of CD16 expression on cM may reveal different monocyte priming, leading to different functional features of macrophages/dendritic cells in tissues after infection. © 2023 Wiley Periodicals LLC. Basic Protocol: Absolute count of cM, intM, and ncM without compensation Alternate Protocol: Absolute count of cM, intM, and ncM for single laser platform Support Protocol 1: In-house monoclonal antibody labeling using a Pacific Blue™ kit Support Protocol 2: In-house monoclonal antibody labeling using an Alexa Fluor® 647 kit Support Protocol 3: Titration of fluorochrome-conjugated antibodies., (© 2023 Wiley Periodicals LLC.)- Published
- 2023
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17. Measurable Residual Disease and Clonal Evolution in Acute Myeloid Leukemia from Diagnosis to Post-Transplant Follow-Up: The Role of Next-Generation Sequencing.
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Sperotto A, Bochicchio MT, Simonetti G, Buccisano F, Peccatori J, Piemontese S, Calistri E, Ciotti G, Pierdomenico E, De Marchi R, Ciceri F, and Gottardi M
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It has now been ascertained that acute myeloid leukemias-as in most type of cancers-are mixtures of various subclones, evolving by acquiring additional somatic mutations over the course of the disease. The complexity of leukemia clone architecture and the phenotypic and/or genotypic drifts that can occur during treatment explain why more than 50% of patients-in hematological remission-could relapse. Moreover, the complexity and heterogeneity of clone architecture represent a hindrance for monitoring measurable residual disease, as not all minimal residual disease monitoring methods are able to detect genetic mutations arising during treatment. Unlike with chemotherapy, which imparts a relatively short duration of selective pressure on acute myeloid leukemia clonal architecture, the immunological effect related to allogeneic hematopoietic stem cell transplant is prolonged over time and must be overcome for relapse to occur. This means that not all molecular abnormalities detected after transplant always imply inevitable relapse. Therefore, transplant represents a critical setting where a measurable residual disease-based strategy, performed during post-transplant follow-up by highly sensitive methods such as next-generation sequencing, could optimize and improve treatment outcome. The purpose of our review is to provide an overview of the role of next-generation sequencing in monitoring both measurable residual disease and clonal evolution in acute myeloid leukemia patients during the entire course of the disease, with special focus on the transplant phase.
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- 2023
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18. Fever of Unknown Origin and Multidrug Resistant Organism Colonization in AML Patients.
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Guarnera L, Trotta GE, Boldrini V, Cardillo L, Cerroni I, Mezzanotte V, Pasqualone G, Savi A, Borsellino B, Buzzatti E, Palmieri R, Paterno G, Maurillo L, Buccisano F, Venditti A, and Del Principe MI
- Abstract
Background: Colonization by multidrug-resistant organisms (MDRO) is a frequent complication in hematologic departments, which puts patients at risk of life-threatening bacterial sepsis. Fever of unknown origin (FUO) is a condition related to the delivery of chemotherapy in hematologic malignancies, in which the use of antibiotics is debated. The incidence, risk factors, and influence on the outcome of these conditions in patients with acute myeloid leukemia (AML) are not clearly defined., Methods: We retrospectively analyzed 132 consecutive admissions of non-promyelocytic AML patients at the Hematology Unit of the University Tor Vergata in Rome between June 2019 and February 2022. MDRO swab-based screening was performed in all patients on the day of admission and once weekly after that. FUO was defined as fever with no evidence of infection., Results: Of 132 consecutive hospitalizations (69 AML patients), MDRO colonization was observed in 35 cases (26%) and resulted independently related to a previous MDRO colonization (p=0.001) and length of hospitalization (p=0.03). The colonization persistence rate in subsequent admissions was 64%. MDRO-related bloodstream infection was observed in 8 patients (23%) and correlated with grade III/IV mucositis (p=0.008) and length of hospitalization (p=0.02). FUO occurred in 68 cases (51%) and correlated with an absolute neutrophilic count <500μ/L at admission (0.04)., Conclusion: In our experience, MDRO colonization is a frequent and difficult-to-eradicate condition that can arise at all stages of treatment. Prompt discharge of patients as soon as clinical conditions allow could limit the spread of MDRO. In addition, the appropriate use of antibiotics, especially in the case of FUO, and the contraction of hospitalization length, when feasible, are measures to tackle the further spread of MDRO., Competing Interests: Competing interests: The authors declare no conflict of Interest.
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- 2023
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19. Time for Dynamic Assessment of Fitness in Acute Myeloid Leukemia.
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Palmieri R, Maurillo L, Del Principe MI, Paterno G, Walter RB, Venditti A, and Buccisano F
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Informed treatment decision-making in acute myeloid leukemia (AML) requires a comprehensive evaluation of all clinical and biological features that may affect the outcome with any given type or intensity of therapy [...].
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- 2022
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20. Clinical relevance of an objective flow cytometry approach based on limit of detection and limit of quantification for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial.
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Buccisano F, Palmieri R, Piciocchi A, Arena V, Maurillo L, Del Principe MI, Paterno G, Irno-Consalvo MA, Ottone T, Divona M, Conti C, Fraboni D, Lavorgna S, Arcese W, Voso MT, and Venditti A
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- Adult, Humans, Flow Cytometry methods, Limit of Detection, Neoplasm, Residual diagnosis, Prospective Studies, Leukemia, Myeloid, Acute diagnosis
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Using a multiparametric flow cytometry assay, we assessed the predictive power of a threshold calculated applying the criteria of limit of detection (LOD) and limit of quantitation (LOQ) in adult patients with acute myeloid leukemia. This was a post-hoc analysis of 261 patients enrolled in the GIMEMA AML1310 prospective trial. According to the protocol design, using the predefined measurable residual disease (MRD) threshold of 0.035% bone marrow residual leukemic cells (RLC) calculated on mononuclear cells, 154 (59%) of the 261 patients were negative (MRD <0.035%) and 107 (41%) were positive (MRD ≥0.035%). Using LOD and LOQ, we selected the following categories of patients: (i) LODneg if RLC were below the LOD (74; 28.4%); (ii) LODpos-LOQneg if RLC were between the LOD and LOQ (43; 16.5%); and (iii) LOQpos if RLC were above the LOQ (144; 54.4%). Two-year overall survival of these three categories of patients was 75.4%, 79.8% and 66.4%, respectively (P=0.1197). Given their superimposable outcomes, the LODneg and LODpos-LOQneg categories were combined. Two-year overall survival of LODneg/LODpos-LOQneg patients was 77.0% versus 66.4% of LOQpos individuals (P=0.043). This figure was challenged in univariate analysis (P=0.046, hazard ratio=1.6, 95% confidence interval: 1.01-2.54) which confirmed the independent role of the LOD-LOQ approach in determining overall survival. In the AML1310 protocol, using the threshold of 0.035%, 2-year overall survival of patients with MRD <0.035% and MRD ≥0.035% was 74.5% versus 66.4%, respectively (P=0.3521). In conclusion, the use of the LOD-LOQ method results in more sensitive detection of MRD that, in turn, translates into a more accurate recognition of patients with different outcomes.
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- 2022
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21. Predictors of Early Thrombotic Events in Adult Patients with Acute Myeloid Leukemia: A Real-World Experience.
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Paterno G, Palmieri R, Forte V, Del Prete V, Gurnari C, Guarnera L, Mallegni F, Pascale MR, Buzzatti E, Mezzanotte V, Cerroni I, Savi A, Buccisano F, Maurillo L, Venditti A, and Del Principe MI
- Abstract
Information regarding the incidence and the prognostic impact of thrombotic events (TE) in non-promyelocytic acute myeloid leukemia (AML) is sparse. Although several risk factors associated with an increased risk of TE development have been recognized, we still lack universally approved guidelines for identification and management of these complications. We retrospectively analyzed 300 consecutive patients with newly diagnosed AML. Reporting the incidence of venous TE (VTE) and arterial TE (ATE) was the primary endpoint. Secondarily, we evaluated baseline patient- and disease-related characteristics with a possible influence of VTE-occurrence probability. Finally, we evaluated the impact of TE on survival. Overall, the VTE incidence was 12.3% and ATE incidence was 2.3%. We identified three independent predictors associated with early-VTE: comorbidities (p = 0.006), platelets count >50 × 109/L (p = 0.006), and a previous history of VTE (p = 0.003). Assigning 1 point to each variable, we observed an overall cumulative incidence of VTE of 18.4% in the high-risk group (≥2 points) versus 6.4% in the low-risk group (0−1 point), log-rank = 0.002. Overall, ATE, but not VTE, was associated with poor prognosis (p < 0.001). In conclusion, TE incidence in AML patients is not negligible. We proposed an early-VTE risk score that could be useful for a proper management of VTE prophylaxis.
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- 2022
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22. Validation of the T-Lymphocyte Subset Index (TLSI) as a Score to Predict Mortality in Unvaccinated Hospitalized COVID-19 Patients.
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Di Lorenzo A, Tedde S, Pace PG, Campogiani L, Ansaldo L, Lodi A, Zordan M, Barreca F, Caldara F, Rossi B, Imeneo A, Alessio G, Crea AMA, Checchi D, Malagnino V, Teti E, Coppola L, Palmieri R, Buccisano F, Andreoni M, Sarmati L, and Iannetta M
- Abstract
Lymphopenia has been consistently reported as associated with severe coronavirus disease 2019 (COVID-19). Several studies have described a profound decline in all T-cell subtypes in hospitalized patients with severe and critical COVID-19. The aim of this study was to assess the role of T-lymphocyte subset absolute counts measured at ward admission in predicting 30-day mortality in COVID-19 hospitalized patients, validating a new prognostic score, the T-Lymphocyte Subset Index (TLSI, range 0−2), based on the number of T-cell subset (CD4+ and CD8+) absolute counts that are below prespecified cutoffs. These cutoff values derive from a previously published work of our research group at Policlinico Tor Vergata, Rome, Italy: CD3+CD4+ < 369 cells/μL, CD3+CD8+ < 194 cells/μL. In the present single-center retrospective study, T-cell subsets were assessed on admission to the infectious diseases ward. Statistical analysis was performed using JASP (Version 0.16.2. JASP Team, 2022, Amsterdam, The Netherlands) and Prism8 (version 8.2.1. GraphPad Software, San Diego, CA, USA). Clinical and laboratory parameters of 296 adult patients hospitalized because of COVID-19 were analyzed. The overall mortality rate was 22.3% (66/296). Survivors (S) had a statistically significant lower TLSI score compared to non-survivors (NS) (p < 0.001). Patients with increasing TLSI scores had proportionally higher rates of 30-day mortality (p < 0.0001). In the multivariable logistic analysis, the TLSI was an independent predictor of in-hospital 30-day mortality (OR: 1.893, p = 0.003). Survival analysis showed that patients with a TLSI > 0 had an increased risk of death compared to patients with a TLSI = 0 (hazard ratio: 2.83, p < 0.0001). The TLSI was confirmed as an early and independent predictor of COVID-19 in-hospital 30-day mortality.
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- 2022
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23. Pulmonary function testing for fitness assessment in asymptomatic adults with newly diagnosed acute myeloid leukemia.
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Palmieri R, Othus M, Cheng GS, Buccisano F, Paterno G, Maurillo L, Del Principe MI, Sconocchia G, Venditti A, and Walter RB
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- Adult, Humans, Aged, Geriatric Assessment, Exercise, Leukemia, Myeloid, Acute diagnosis
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- 2022
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24. Longitudinal Evaluation of the QuantiFERON-TB Gold Plus Assay in Hospitalized COVID-19 Patients with a First Indeterminate Result: Resolution of Inflammation and Restoration of T-Lymphocyte Counts and Interferon-Gamma Production.
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Alessio G, Imeneo A, Di Lorenzo A, Rossi B, Sorace C, Compagno M, Coppola L, Campogiani L, Crea AMA, Malagnino V, Buccisano F, Andreoni M, Sarmati L, and Iannetta M
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- Humans, Interferon-gamma, Interferon-gamma Release Tests, Tuberculin Test, Inflammation, Lymphocyte Count, COVID-19 diagnosis, Latent Tuberculosis
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- 2022
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25. Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment.
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Sconocchia G, Lanzilli G, Cesarini V, Silvestris DA, Rezvani K, Arriga R, Caratelli S, Chen K, Dou J, Cenciarelli C, Toietta G, Baldari S, Sconocchia T, De Paolis F, Aureli A, Iezzi G, Irno Consalvo M, Buccisano F, Del Principe MI, Maurillo L, Venditti A, Ottaviani A, and Spagnoli GC
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- Animals, CD28 Antigens metabolism, Cetuximab metabolism, Female, Humans, Ligands, Mice, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms therapy, T-Lymphocytes
- Abstract
The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice from subcutaneous growth of MDA-MB-468 BC cells. RNAseq analysis identified a 42 gene fingerprint predicting BC cell sensitivity and favorable outcomes in advanced BC. ICAM1 was a major regulator of CD32-CR T cell-mediated cytotoxicity. CD32-CR T cells may help identify cell surface CD32 ligand(s) and novel prognostically relevant transcriptomic signatures and develop innovative BC treatments., (© 2022 Sconocchia et al.)
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- 2022
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26. Case report: A Saprochaete clavata ( Magnusiomyces clavatus ) severe infection effectively treated with granulocyte transfusion in a young patient with myeloid sarcoma.
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Pasqualone G, Buzzatti E, Palmieri R, Savi A, Pascale MR, Borsellino B, Guarnera L, Buccisano F, Voso MT, Maurillo L, Sconocchia G, Venditti A, and Del Principe MI
- Abstract
Myeloid sarcoma is a hematologic malignancy consisting of extramedullary tissue involvement by myeloid blasts, usually considered as acute myeloid leukemia and treated accordingly. The disease itself, together with chemotherapy and disease-associated factors, may have an impact in increasing the risk of developing severe and frequently life-threatening infections. Herein, we describe the case of a patient with a right breast skin lesion, histologically diagnosed myeloid sarcoma, who developed a severe disseminated fungal infection by Saprochaete clavata ( Magnusiomyces clavatus ), during the first consolidation course of chemotherapy. Despite maximum antifungal therapy, the infection progressed and the fungus continued to be isolated until granulocyte transfusion therapy was initiated. Our experience suggests that patients with profound and long-lasting neutropenia could benefit from granulocyte transfusions as additional therapy in severe fungal infections resistant to broad-spectrum antimicrobial therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that may represent a potential conflict of interest., (Copyright © 2022 Pasqualone, Buzzatti, Palmieri, Savi, Pascale, Borsellino, Guarnera, Buccisano, Voso, Maurillo, Sconocchia, Venditti and Del Principe.)
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- 2022
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27. Myelodysplastic syndromes with del(5q): A real-life study of determinants of long-term outcomes and response to lenalidomide.
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Gurnari C, Piciocchi A, Soddu S, Bonanni F, Scalzulli E, Niscola P, Di Veroli A, Piccioni AL, Piedimonte M, Maiorana G, Salutari P, Cicconi L, Santopietro M, Gumenyuk S, Sarlo C, Fenu S, Tafuri A, Latagliata R, Fianchi L, Criscuolo M, Maciejewski JP, Maurillo L, Buccisano F, Breccia M, and Voso MT
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- Humans, Lenalidomide therapeutic use, Thalidomide therapeutic use, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
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- 2022
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28. AML: making residual disease more measurable.
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Voso MT and Buccisano F
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- Humans, Neoplasm, Residual, Prospective Studies, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Neoplasm Recurrence, Local
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- 2022
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29. Occult central nervous system involvement guides therapeutic choices in blastic plasmacytoid dendritic cell neoplasms.
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Buzzatti E, Paterno G, Palmieri R, Esposito F, Pascale MR, Mallegni F, Guarnera L, Pasqualone G, Irno Consalvo MA, Fraboni D, Moretti F, Savi A, Borsellino B, Maurillo L, Buccisano F, Sconocchia G, Venditti A, and Del Principe MI
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- Central Nervous System, Dendritic Cells, Humans, Hematologic Neoplasms diagnosis, Hematologic Neoplasms therapy, Myeloproliferative Disorders, Skin Neoplasms
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- 2022
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30. An Polycythemia Vera Evolve from Acute Myeloid Leukemia? Report of a Case Showing a Simultaneous Minor JAK2 V617F Mutated Clone.
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Borsellino B, Savi A, Pascale MR, Meddi E, Del Principe MI, Cristiano A, Ottone T, Rapanotti MC, Divona M, Travaglini S, Attardi E, Palmieri R, Buzzatti E, Buccisano F, and Voso MT
- Abstract
The evolution of myeloproliferative neoplasms (MPN) to acute myeloid leukemia (AML) occurs in 2-10% of patients, depending on the MPN subtype, treatment, and follow-up length. The reverse-path from AML to MPN has been rarely reported. We herein present a 75 years old woman with AML, in whom a JAK2 -V617F positive polycythemia vera (PV) emerged during follow-up, 19 months from the end of consolidation treatment. JAK2- V617F mutation screening retrospectively performed by Next Generation Sequencing (NGS) and JAK2 MutaScreen was negative on the bone marrow sample collected at AML diagnosis. However, using digital droplet PCR (ddPCR), we detected a minor JAK2 V617F mutated clone at AML onset. In addition, a TET2 R550 mutated clone persisted at stable levels throughout the disease course. This case shows that a very small MPN clone masked at AML diagnosis may expand after treatment end and be erroneously interpreted as MPN evolving from AML. Very sensitive techniques such as ddPCR may help to unravel the true disease history in these cases., Competing Interests: Competing interests: The authors declare no conflict of Interest.
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- 2022
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31. CD99 as a novel therapeutic target on leukemic progenitor cells in FLT3-ITD mut AML.
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Travaglini S, Ottone T, Angelini DF, Fiori V, Dominici S, Noguera NI, Śniegocka M, Antonelli S, Irno Consalvo MA, De Bardi M, Banella C, Divona M, Marchesi F, Masciarelli S, Fazi F, Pieraccioli M, Palmieri R, De Angelis G, Buccisano F, Venditti A, Battistini L, Magnani M, and Voso MT
- Subjects
- 12E7 Antigen, Humans, Mutation, Nuclear Proteins genetics, Stem Cells, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 therapeutic use, Leukemia, Myeloid, Acute drug therapy
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- 2022
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32. Myelodysplastic Syndromes with Isolated 20q Deletion: A New Clinical-Biological Entity?
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Campagna A, De Benedittis D, Fianchi L, Scalzulli E, Rizzo L, Niscola P, Piccioni AL, Di Veroli A, Mancini S, Villivà N, Martini T, Mohamed S, Carmosino I, Criscuolo M, Fenu S, Aloe Spiriti MA, Buccisano F, Mancini M, Tafuri A, Breccia M, Poloni A, and Latagliata R
- Abstract
Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1−51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7−66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6−71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis.
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- 2022
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33. The Venetoclax/Azacitidine Combination Targets the Disease Clone in Acute Myeloid Leukemia, Being Effective and Safe in a Patient with COVID-19.
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Cristiano A, Palmieri R, Fabiani E, Ottone T, Divona M, Savi A, Buccisano F, Maurillo L, Tarella C, Arcese W, and Voso MT
- Abstract
The addition of Venetoclax (VEN) to Hypomethylating agents (HMAs) significantly improves the probability of complete remission and prolongs survival in patients with Acute Myeloid Leukemia (AML) when compared to HMA alone. However, the mutated clone composition may impact the probability of response and its duration. Here, we describe the molecular profile of a patient with AML rapidly evolved from a previous therapy-related-Chronic MyeloMonocytic Leukemia, who achieved safely complete remission after treatment with the VEN/Azacitidine combination, even in the presence of SARS-COVID-2 infection. The targeted NGS analysis showed that the VEN/AZA combination led to the eradication of the FLT3-ITD and RUNX1 mutated clone/s primarily associated with AML evolution, and subsequently, the SRSF2, NRAS , and ASXL1 mutated clone/s. This case also underlines the importance of the sequential use of targeted NGS for disease monitoring: the deep molecular remission achieved by this patient allowed to safely guide adjustments of drug dosage and treatment intervals in the presence of neutropenia, helping to rule out disease progression., Competing Interests: Competing interests: The authors declare no conflict of Interest. Competing Interests. MTV received honoraria from Celgene/BMS and Abbvie.
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- 2022
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34. Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives.
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Vianelli N, Auteri G, Buccisano F, Carrai V, Baldacci E, Clissa C, Bartoletti D, Giuffrida G, Magro D, Rivolti E, Esposito D, Podda GM, and Palandri F
- Subjects
- Humans, Receptors, Fc therapeutic use, Receptors, Thrombopoietin agonists, Recombinant Fusion Proteins therapeutic use, Rituximab therapeutic use, Splenectomy, Thrombopoietin therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic therapy, Thrombocytopenia chemically induced
- Abstract
Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician's expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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35. ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol.
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Buccisano F, Palmieri R, Piciocchi A, Arena V, Candoni A, Melillo L, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Capria S, Maurillo L, Del Principe MI, Paterno G, Irno Consalvo MA, Ottone T, Lavorgna S, Voso MT, Fazi P, Vignetti M, Arcese W, and Venditti A
- Subjects
- Humans, Neoplasm, Residual, Prognosis, Prospective Studies, Risk Assessment, Transplantation, Homologous
- Abstract
The 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646., (© 2022 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.)
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- 2022
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36. CD34 + CD38-CLL1+ leukemic stem cells persistence measured by multiparametric flow cytometry is a biomarker of poor prognosis in adult patients with acute myeloid leukemia.
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Palmieri R, Buccisano F, Arena V, Irno Consalvo MA, Piciocchi A, Maurillo L, DelPrincipe MI, Di Veroli A, Paterno G, Conti C, Fraboni D, Voso MT, Arcese W, and Venditti A
- Subjects
- ADP-ribosyl Cyclase 1, Adult, Antigens, CD34, Flow Cytometry, Humans, Neoplastic Stem Cells, Prognosis, Stem Cells, Leukemia, Myeloid, Acute diagnosis
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- 2022
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37. In BCR-ABL1 Positive B-Cell Acute Lymphoblastic Leukemia, Steroid Therapy Induces Hypofibrinogenemia.
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Buzzatti E, Forghieri F, Paterno G, Marchesi F, Sarlo C, Giglio F, Fracchiolla N, Sciumè M, Palmieri R, Esposito F, Guarnera L, Mercante L, Pascale MR, Mallegni F, Savi A, Forte V, Maurillo L, Buccisano F, Venditti A, and Del Principe MI
- Abstract
Hypofibrinogenemia (HF) in adult acute lymphoblastic leukemia (ALL) of B lineage is uncommon and mostly associated with asparaginase (ASP) delivery. Since we noticed a significant reduction in fibrinogen (FBG) plasma levels even before the first ASP dose, we aim to assess the levels of FBG during induction treatment and explore if the FBG fall correlated with therapies other than asparaginase and/or specific leukemia biological features. We retrospectively analyzed FBG levels in 115 patients with B-ALL. In 74 (64%) out of 115 patients FBG decline occurred during the steroid prephase. In univariate analysis, such a steroid-related HF was significantly associated with BCR-ABL1 rearrangement ( p = 0.00158). None of those experiencing HF had significant modifications of liver function tests during induction treatment. Our retrospective study suggests that in B-ALL, steroid therapy can also induce HF and that such an event is preferentially observed in patients carrying BCR-ABL1 rearrangements. The pathogenesis of this phenomenon is still unclear. We attempt to explain it by applying the International Society of Thrombosis and Hemostasis-Disseminated Intravascular Coagulation score (ISTH-DIC score); nonetheless additional studies are needed to clarify further the mechanisms of HF in this subset of patients.
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- 2022
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38. Pneumocystis jirovecii pneumonia in patients with previously untreated acute myeloid leukaemia.
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Paterno G, Guarnera L, Palmieri R, Del Prete V, Bonanni F, Buzzatti E, Moretti F, Casciani P, Savi A, Di Cave D, Maurillo L, Buccisano F, Venditti A, and Del Principe MI
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- Aged, Female, Humans, Male, Pneumocystis carinii, Retrospective Studies, Leukemia, Myeloid, Acute complications, Pneumonia, Pneumocystis epidemiology
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Background: Several studies in immunocompromised patients, such as those with HIV infection, undergoing cancer chemotherapy or organ transplant, have led to the development of guidelines on the use of prophylaxis to prevent Pneumocystis jirovecii pneumonia (PJP), in these specific conditions. Instead, since the association between PJP and acute myeloid leukaemia (AML) is not clearly defined, the role of prophylaxis in patients with AML is not yet established., Methods: We retrospectively analysed 251 consecutive patients with newly diagnosed non-M3-AML, admitted at the Hematology Unit of University Tor Vergata in Rome, during the period 2010-2020. The aim of the study was to evaluate the incidence of PJP among AML patients during their first hospital admission, and to identify subjects at a high risk to develop PJP., Results: Among 251 consecutive patients with non-M3-AML, 67 bronchoalveolar lavages (BAL) were performed. PJP was proven in 11/67 (16.7%) subjects undergoing BAL (11 males, median age 71 years), with an incidence of 4.3%. The most common reason for BAL execution were radiological findings such as ground-glass opacities (6/11, 55%) and atypical patterns like consolidations and nodules (5/11, 45%). One patient died because of PJP after 11 days of trimethoprim/sulfamethoxazole therapy. In multivariate analysis older age and smoking habit were independent factors significantly associated with PJP (p = .021 and 0.017 respectively)., Conclusion: We conclude that PJP infection is not uncommon among patients with AML. If intensive chemotherapy is planned, physicians should be aware of this risk and prophylaxis should be considered, particularly in older patients., (© 2021 Wiley-VCH GmbH.)
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- 2022
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39. B- and T-Cell Responses After SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Receiving Disease Modifying Therapies: Immunological Patterns and Clinical Implications.
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Iannetta M, Landi D, Cola G, Campogiani L, Malagnino V, Teti E, Coppola L, Di Lorenzo A, Fraboni D, Buccisano F, Grelli S, Mozzani M, Zingaropoli MA, Ciardi MR, Nisini R, Bernardini S, Andreoni M, Marfia GA, and Sarmati L
- Subjects
- Adult, BNT162 Vaccine immunology, Female, Humans, Male, Middle Aged, Multiple Sclerosis therapy, B-Lymphocytes immunology, BNT162 Vaccine administration & dosage, COVID-19 immunology, COVID-19 prevention & control, Multiple Sclerosis immunology, SARS-CoV-2 immunology, T-Lymphocytes immunology, Vaccination
- Abstract
Background: Vaccination campaign to contrast the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised the issue of vaccine immunogenicity in special populations such as people with multiple sclerosis (PwMS) on highly effective disease modifying treatments (DMTs). While humoral responses to SARS-CoV-2 mRNA vaccines have been well characterized in the general population and in PwMS, very little is known about cell-mediated responses in conferring protection from SARS-CoV-2 infection and severe coronavirus disease-2019 (COVID-19)., Methods: PwMS on ocrelizumab, fingolimod or natalizumab, vaccinated with two doses of mRNABNT162b2 (Comirnaty
® ) vaccine were enrolled. Anti-Spike (S) and anti-Nucleoprotein (N) antibody titers, IFN-gamma production upon S and N peptide libraries stimulation, peripheral blood lymphocyte absolute counts were assessed after at least 1 month and within 4 months from vaccine second dose administration. A group of age and sex matched healthy donors (HD) were included as reference group. Statistical analysis was performed using GraphPad Prism 8.2.1., Results: Thirty PwMS and 9 HDs were enrolled. All the patients were negative for anti-N antibody detection, nor reported previous symptoms of COVID-19. Peripheral blood lymphocyte counts were assessed in PwMS showing: (i) reduction of circulating B-lymphocytes in PwMS on ocrelizumab; (ii) reduction of peripheral blood B- and T-lymphocyte absolute counts in PwMS on fingolimod and (iii) normal B- and T-lymphocyte absolute counts with an increase in circulating CD16+CD56+ NK-cells in PwMS on natalizumab. Three patterns of immunological responses were identified in PwMS. In patients on ocrelizumab, anti-S antibody were lacking or reduced, while T-cell responses were normal. In patients on fingolimod both anti-S titers and T-cell mediated responses were impaired. In patients on natalizumab both anti-S titers and T-cell responses were present and comparable to those observed in HD., Conclusions: The evaluation of T-cell responses, anti-S titers and peripheral blood lymphocyte absolute count in PwMS on DMTs can help to better characterize the immunological response after SARS-CoV-2 vaccination. The evaluation of T-cell responses in longitudinal cohorts of PwMS will help to clarify their protective role in preventing SARS-CoV-2 infection and severe COVID-19. The correlation between DMT treatment and immunological responses to SARS-CoV-2 vaccines could help to better evaluate vaccination strategies in PwMS., Competing Interests: MI received honoraria for lectures from Biogen Italia, AIM Educational, MICOM srl. DL received travel funding from Biogen, Merk-Serono, Sanofi-Genzyme, Teva, speaking or consultation fees from Sanofi-Genzyme, Merk-Serono, Teva, Biogen, Novartis, Roche. LC received honoraria for lectures from MICOM srl. VM received honoraria for lectures from Janssen-Cilag. ET received honoraria for lectures from Gilead, AbbVie and MSD, and research grants from Gilead, outside the submitted work. FB received honoraria for lectures from Novartis. MA reports honoraria for lectures and research grants from Merk, Gilead, Abbvie, Angelini SpA, outside the submitted work. GM is an Advisory Board member of Biogen Idec, Genzyme, Merck-Serono, Novartis, Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Roche, Mylan, Teva. LS reports honoraria for lectures and research grants from Merk, Gilead, Abbvie, Angelini SpA, outside the submitted work. The remaining 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 Iannetta, Landi, Cola, Campogiani, Malagnino, Teti, Coppola, Di Lorenzo, Fraboni, Buccisano, Grelli, Mozzani, Zingaropoli, Ciardi, Nisini, Bernardini, Andreoni, Marfia and Sarmati.)- Published
- 2022
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40. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party.
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Heuser M, Freeman SD, Ossenkoppele GJ, Buccisano F, Hourigan CS, Ngai LL, Tettero JM, Bachas C, Baer C, Béné MC, Bücklein V, Czyz A, Denys B, Dillon R, Feuring-Buske M, Guzman ML, Haferlach T, Han L, Herzig JK, Jorgensen JL, Kern W, Konopleva MY, Lacombe F, Libura M, Majchrzak A, Maurillo L, Ofran Y, Philippe J, Plesa A, Preudhomme C, Ravandi F, Roumier C, Subklewe M, Thol F, van de Loosdrecht AA, van der Reijden BA, Venditti A, Wierzbowska A, Valk PJM, Wood BL, Walter RB, Thiede C, Döhner K, Roboz GJ, and Cloos J
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- Europe, Flow Cytometry methods, High-Throughput Nucleotide Sequencing methods, Humans, Leukemia, Myeloid, Acute genetics, Neoplasm, Residual genetics, Prognosis, Leukemia, Myeloid, Acute diagnosis, Neoplasm, Residual diagnosis
- Abstract
Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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41. Technical Aspects of Flow Cytometry-based Measurable Residual Disease Quantification in Acute Myeloid Leukemia: Experience of the European LeukemiaNet MRD Working Party.
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Tettero JM, Freeman S, Buecklein V, Venditti A, Maurillo L, Kern W, Walter RB, Wood BL, Roumier C, Philippé J, Denys B, Jorgensen JL, Bene MC, Lacombe F, Plesa A, Guzman ML, Wierzbowska A, Czyz A, Ngai LL, Schwarzer A, Bachas C, Cloos J, Subklewe M, Fuering-Buske M, and Buccisano F
- Abstract
Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
- Published
- 2021
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42. Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia: Italian Delphi-based consensus recommendations.
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Carpenedo M, Baldacci E, Baratè C, Borchiellini A, Buccisano F, Calvaruso G, Chiurazzi F, Fattizzo B, Giuffrida G, Rossi E, Palandri F, Scalzulli PR, Siragusa SM, Vitucci A, and Zaja F
- Abstract
Introduction: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP., Methods: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting., Results: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 10
9 /L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 109 /L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life., Conclusion: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP., Plain Language Summary: Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP).The Delphi technique was used to obtain consensus for five statements.The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CM received honoraria from Amgen and Novartis for serving on advisory boards; SS received honoraria from CSL, AMGEN, Novartis, Novo Nordisk, SOBI, and Bayer; ZF received honoraria and funding from Novartis, Amgen, and Grifols; PF received honoraria from Novartis; FB received consultation honoraria from Amgen, Novartis, and Momenta; BC received honoraria from Novartis and Amgen; BA has received honoraria from Amgen, Novartis, Novo Nordisk, Bayer, and Takeda; GG, SPR, BE, CF, CG, RE, VA have no conflict of interest to declare., (© The Author(s), 2021.)- Published
- 2021
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43. T-cell responses to SARS-CoV-2 in multiple sclerosis patients treated with ocrelizumab healed from COVID-19 with absent or low anti-spike antibody titers.
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Iannetta M, Landi D, Cola G, Malagnino V, Teti E, Fraboni D, Buccisano F, Grelli S, Coppola L, Campogiani L, Andreoni M, Marfia GA, and Sarmati L
- Subjects
- Antibodies, Viral blood, Humans, Spike Glycoprotein, Coronavirus immunology, Antibodies, Monoclonal, Humanized therapeutic use, COVID-19 immunology, Multiple Sclerosis drug therapy, T-Lymphocytes immunology
- Abstract
Background: Disease modifying therapies for multiple sclerosis (MS) can impair the specific immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Specifically, it is recognized that ocrelizumab reduces or abrogates anti-SARS-CoV-2 antibody production after natural infection or vaccination, while very little is known about T-cell responses., Methods: We developed an interferon (IFN)-γ release assay (IGRA) to detect T-cell responses specific to SARS-CoV-2 after overnight stimulation of whole blood with peptide libraries covering the immunodominant sequence domains of the Spike glycoprotein (S) and the Nucleocapsid phosphoprotein (N)., Results: Five patients with MS receiving ocrelizumab treatment for at least 1 year and recovered from SARS-CoV-2 infection were enrolled in the study. Despite the absence or the very low concentration of anti-S antibodies, a T-cell response was detectable in all the five MS patients. These results are in accordance with the marked reduction of peripheral B-lymphocyte absolute counts induced by ocrelizumab, that, conversely, did not affect peripheral blood T-lymphocyte subset absolute and relative counts and CD4/CD8 ratio., Conclusions: The detection of specific T-cell responses to SARS-CoV-2 in patients receiving B-cell depleting therapies represents a useful tool to improve the diagnostic approach in SARS-CoV-2 infection and to accurately assess the immunological response after natural infection or vaccination., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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44. AMELIORATE: early intensification in FLT3 -mutated acute myeloid leukemia based on peripheral blast clearance - MYNERVA-GIMEMA AML1919 trial.
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Mannelli F, Gianfaldoni G, Guglielmelli P, Buccisano F, Caporale R, Chiarini M, Rossi G, Venditti A, Fazi P, Crea E, Piciocchi A, Voso MT, Vignetti M, Amadori S, and Vannucchi AM
- Subjects
- Female, Humans, Male, Middle Aged, Mutation, Neoplasm, Residual, Precision Medicine, Prospective Studies, Remission Induction, Risk Assessment, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, fms-Like Tyrosine Kinase 3 genetics
- Abstract
AMELIORATE is a Phase III, randomized trial aiming to personalize treatment intensity in FLT3 -mutated acute myeloid leukemia. The current study provides an early appraisal of chemosensitivity based on peripheral blasts clearance, as assessed by multiparameter flow cytometry, from baseline to day 4 of induction. This biomarker was previously demonstrated to predict complete remission achievement and measurable residual disease status. For patients experiencing low peripheral blast cells (i.e., ≤2.0 logs), two major adjustments of treatment as compared with current standard of care are envisioned in the experimental arm: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m
2 b.i.d. on days 5-7 of induction); and the early allocation of the patient to high-risk disease category, to be further refined later based on postinduction measurable residual disease status.- Published
- 2021
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45. Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study.
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Iannetta M, Buccisano F, Fraboni D, Malagnino V, Campogiani L, Teti E, Spalliera I, Rossi B, Di Lorenzo A, Palmieri R, Crea A, Zordan M, Vitale P, Voso MT, Andreoni M, and Sarmati L
- Subjects
- Aged, Aged, 80 and over, COVID-19 epidemiology, COVID-19 virology, Female, Hospital Mortality, Humans, Lymphocyte Count, Male, Middle Aged, Nasopharynx virology, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Rome epidemiology, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, COVID-19 blood, COVID-19 mortality, SARS-CoV-2 genetics, Severity of Illness Index, T-Lymphocyte Subsets
- Abstract
The aim of this study was to evaluate the role of baseline lymphocyte subset counts in predicting the outcome and severity of COVID-19 patients. Hospitalized patients confirmed to be infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were included and classified according to in-hospital mortality (survivors/nonsurvivors) and the maximal oxygen support/ventilation supply required (nonsevere/severe). Demographics, clinical and laboratory data, and peripheral blood lymphocyte subsets were retrospectively analyzed. Overall, 160 patients were retrospectively included in the study. T-lymphocyte subset (total CD3+, CD3+ CD4+, CD3+ CD8+, CD3+ CD4+ CD8+ double positive [DP] and CD3+ CD4- CD8- double negative [DN]) absolute counts were decreased in nonsurvivors and in patients with severe disease compared to survivors and nonsevere patients (p < 0.001). Multivariable logistic regression analysis showed that absolute counts of CD3+ T-lymphocytes < 524 cells/µl, CD3+ CD4+ < 369 cells/µl, and the number of T-lymphocyte subsets below the cutoff (T-lymphocyte subset index [TLSI]) were independent predictors of in-hospital mortality. Baseline T-lymphocyte subset counts and TLSI were also predictive of disease severity (CD3+ < 733 cells/µl; CD3+ CD4+ < 426 cells/µl; CD3+ CD8+ < 262 cells/µl; CD3+ DP < 4.5 cells/µl; CD3+ DN < 18.5 cells/µl). The evaluation of peripheral T-lymphocyte absolute counts in the early stages of COVID-19 might represent a useful tool for identifying patients at increased risk of unfavorable outcomes.
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- 2021
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46. Measurable residual disease as a biomarker in acute myeloid leukemia: theoretical and practical considerations.
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Walter RB, Ofran Y, Wierzbowska A, Ravandi F, Hourigan CS, Ngai LL, Venditti A, Buccisano F, Ossenkoppele GJ, and Roboz GJ
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- Combined Modality Therapy, Humans, Leukemia, Myeloid, Acute therapy, Neoplasm Recurrence, Local therapy, Leukemia, Myeloid, Acute diagnosis, Models, Theoretical, Neoplasm Recurrence, Local diagnosis, Neoplasm, Residual pathology, Risk Assessment methods
- Abstract
Several methodologies that rely on the detection of immunophenotypic or molecular abnormalities of the neoplastic cells are now available to quantify measurable ("minimal") residual disease (MRD) in acute myeloid leukemia (AML). Although the perfect MRD test does not (yet) exist, the strong association between MRD and adverse patient outcomes has provided the impetus to use measures of MRD as biomarker in the routine care of AML patients and during clinical trials. MRD test results may inform the selection of postremission therapy in some patients but evidence supporting the use of MRD as predictive biomarker is still limited. Several retrospective studies have shown that conversion from undetectable to detectable MRD or increasing MRD over time is associated with overt disease recurrence, and MRD testing may therefore be valuable as a monitoring biomarker for early detection of relapse. Interpreting serial MRD data is complex, with open questions regarding the optimal timing and frequency of testing, as well as the identification of test-specific thresholds to define relapse. Importantly, it is unknown whether intervening at the time of MRD detection, rather than at overt disease recurrence, improves outcomes. Finally, using MRD as a surrogate efficacy-response biomarker to accelerate drug development/approval has already been accepted by regulatory authorities in other diseases and is of great interest as a potential strategy in AML. While the prognostic value of MRD in AML is well established, data from prospective clinical trials confirming that treatment effects on MRD directly relate to clinical outcomes are needed to further establish the role of MRD as a surrogate endpoint in AML.
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- 2021
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47. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.
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Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, Falantes J, Reda G, Buccisano F, Fenaux P, Buckstein R, Diez Campelo M, Larsen S, Valcarcel D, Vyas P, Giai V, Olíva EN, Shortt J, Niederwieser D, Mittelman M, Fianchi L, La Torre I, Zhong J, Laille E, Lopes de Menezes D, Skikne B, Beach CL, and Giagounidis A
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Myelodysplastic Syndromes pathology, Prognosis, Prospective Studies, Survival Rate, Azacitidine administration & dosage, Myelodysplastic Syndromes drug therapy
- Abstract
Purpose: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia., Methods: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI)., Results: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10
9 /L, and absolute neutrophil count was 1.3 × 109 /L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109 /L., Conclusion: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed., Competing Interests: Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbvieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol-Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, Abbvie, Bristol-Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Valeria SantiniHonoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-CilagConsulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, Pfizer, Geron, Gilead SciencesResearch Funding: CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Celgene Antonio AlmeidaHonoraria: Novartis, CelgeneConsulting or Advisory Role: Novartis, CelgeneSpeakers' Bureau: Novartis, CelgeneTravel, Accommodations, Expenses: Bristol-Myers Squibb Uwe PlatzbeckerHonoraria: Celgene/JazzConsulting or Advisory Role: Celgene/JazzResearch Funding: Amgen, Janssen, Novartis, BerGenBio, CelgenePatents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Lewis R. SilvermanResearch Funding: Celgene, MedImmune, Onconova Therapeutics, BayerPatents, Royalties, Other Intellectual Property: Patent for the combination of azacitidine and rigosertib Francesco BuccisanoConsulting or Advisory Role: NovartisSpeakers' Bureau: Novartis Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Rena BucksteinHonoraria: Celgene, Taiho PharmaceuticalConsulting or Advisory Role: CelgeneResearch Funding: Celgene, Takeda, Otsuka USUncompensated Relationships: Celgene/Jazz Maria Diez CampeloHonoraria: Celgene, NovartisConsulting or Advisory Role: Celgene, Takeda, Novartis, BerGenBioTravel, Accommodations, Expenses: Celgene, Novartis David ValcarcelConsulting or Advisory Role: Celgene, Amgen, GlaxoSmithKline, Novartis, Takeda, Pfizer, Bristol-Myers Squibb, Sanofi, Jazz Pharmaceuticals, SOBISpeakers' Bureau: Celgene, Novartis, Amgen, GlaxoSmithKline, Astellas Pharma, Pfizer, Jazz Pharmaceuticals, Sanofi/Aventis, Bristol-Myers SquibbTravel, Accommodations, Expenses: Celgene, Amgen, Pfizer, GlaxoSmithKline, Jazz Pharmaceuticals Paresh VyasStock and Other Ownership Interests: OxStemHonoraria: Celgene, Pfizer, Jazz Pharmaceuticals, Abbvie, Daiichi SankyoResearch Funding: Celgene, Forty SevenPatents, Royalties, Other Intellectual Property: Patent for flow cytometric detection of leukaemic stem cells Esther Natalie OlívaHonoraria: Celgene, Novartis, Amgen, Alexion PharmaceuticalsConsulting or Advisory Role: Amgen, Celgene, NovartisSpeakers' Bureau: Celgene, NovartisPatents, Royalties, Other Intellectual Property: Royalties for QOL-E instrument Jake ShorttConsulting or Advisory Role: Astellas Pharma, NovartisSpeakers' Bureau: Bristol-Myers SquibbResearch Funding: Astex Pharmaceuticals, Amgen, Celgene/Bristol-Myers Squibb Dietger NiederwieserConsulting or Advisory Role: Cellectis, Amgen, NovartisSpeakers' Bureau: NovartisResearch Funding: Daiichi Sankyo Moshe MittelmanHonoraria: CelgeneConsulting or Advisory Role: Onconova TherapeuticsSpeakers' Bureau: NovartisResearch Funding: Novartis, Takeda, Janssen-Cilag, Roche, Medison, Abbvie, Gilead Sciences Luana FianchiConsulting or Advisory Role: SanofiTravel, Accommodations, Expenses: Celgene Ignazia La TorreEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Jianhua ZhongEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Eric LailleEmployment: Bristol-Myers Squibb, Celgene, Catalent,Stock and Other Ownership Interests: Bristol-Myers Squibb, Moderna Therapeutics, Catalent Daniel Lopes de MenezesEmployment: Celgene, Bristol-Myers SquibbStock and Other Ownership Interests: Celgene, Bristol-Myers Squibb, NovartisPatents, Royalties, Other Intellectual Property: Published and Issues patents at BMS, Novartis Barry SkikneEmployment: Celgene/Bristol-Myers SquibbConsulting or Advisory Role: Celgene/Bristol-Myers SquibbResearch Funding: Daiichi Sankyo/UCB Japan C.L. BeachEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Celgene, Amgen, NovartisConsulting or Advisory Role: CelgeneNo other potential conflicts of interest were reported.- Published
- 2021
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48. ESCCA/ISCCA protocol for the analysis of cerebrospinal fluid by multiparametric flow-cytometry in hematological malignancies.
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Del Principe MI, Gatti A, Johansson U, Buccisano F, and Brando B
- Subjects
- Central Nervous System pathology, Humans, Prospective Studies, Cerebrospinal Fluid metabolism, Cytodiagnosis methods, Flow Cytometry methods, Hematologic Neoplasms diagnosis, Hematologic Neoplasms pathology
- Abstract
Central nervous system (CNS) involvement is a serious but often underdiagnosed complication of hematological malignancies. Currently, the gold standard to detect CNS involvement is conventional cytology (CC) whose sensitivity though is lower than 50%. Multiparametric flow cytometry (MFC) demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies are few, a positive finding by MFC appears to anticipate an adverse outcome even if CC shows no infiltration. However, the use of MFC to diagnose CNS involvement presents some pitfalls, due to the typical hypocellularity of cerebrospinal fluids (CSF), and low cell vitality. Furthermore, the threshold to be used for defining the MFC positivity is not universally defined. In this paper, a working group of the European Society for Clinical Cell Analysis-ESCCA-and the Italian Society for Clinical Cell Analysis-ISCCA-will discuss the critical aspects of CSF processing, highlighting difficulties in storage and processing of samples, interpretation and reporting of data., (© 2020 International Clinical Cytometry Society.)
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- 2021
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49. Use of Measurable Residual Disease to Evolve Transplant Policy in Acute Myeloid Leukemia: A 20-Year Monocentric Observation.
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Buccisano F, Palmieri R, Piciocchi A, Maurillo L, Del Principe MI, Paterno G, Soddu S, Cerretti R, De Angelis G, Mariotti B, Irno Consalvo MA, Conti C, Fraboni D, Divona M, Ottone T, Lavorgna S, Panetta P, Voso MT, Arcese W, and Venditti A
- Abstract
Measurable residual disease (MRD) is increasingly employed as a biomarker of quality of complete remission (CR) in intensively treated acute myeloid leukemia (AML) patients. We evaluated if a MRD-driven transplant policy improved outcome as compared to a policy solely relying on a familiar donor availability. High-risk patients (adverse karyotype, FLT3-ITD) received allogeneic hematopoietic cell transplant (alloHCT) whereas for intermediate and low risk ones (CBF-AML and NPM1-mutated), alloHCT or autologous SCT was delivered depending on the post-consolidation measurable residual disease (MRD) status, as assessed by flow cytometry. For comparison, we analyzed a matched historical cohort of patients in whom alloHCT was delivered based on the sole availability of a matched sibling donor. Ten-years overall and disease-free survival were longer in the MRD-driven cohort as compared to the historical cohort (47.7% vs. 28.7%, p = 0.012 and 42.0% vs. 19.5%, p = 0.0003). The favorable impact of this MRD-driven strategy was evident for the intermediate-risk category, particularly for MRD positive patients. In the low-risk category, the significantly lower CIR of the MRD-driven cohort did not translate into a survival advantage. In conclusion, a MRD-driven transplant allocation may play a better role than the one based on the simple donor availability. This approach determines a superior outcome of intermediate-risk patients whereat in low-risk ones a careful evaluation is needed for transplant allocation.
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- 2021
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50. A new focus on thyrosine kinases inhibitors in eosinophilic granulomatosis with polyangiitis.
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Triggianese P, D'Antonio A, Conigliaro P, Buccisano F, Fonti GL, Chimenti MS, and Perricone R
- Subjects
- Eosinophils, Humans, Immunosuppressive Agents, Churg-Strauss Syndrome diagnosis, Churg-Strauss Syndrome drug therapy, Granulomatosis with Polyangiitis diagnosis, Granulomatosis with Polyangiitis drug therapy
- Published
- 2021
- Full Text
- View/download PDF
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