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1. Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia

Author

Montanaro, A, Kitara, S, Cerretani, E, Marchesini, M, Rompietti, C, Pagliaro, L, Gherli, A, Su, A, Minchillo, Ml, Caputi, M, Fioretzaki, R, Lorusso, B, Ross, L, Alexe, G, Masselli, E, Marozzi, M, Rizzi, Fma, La Starza, R, Mecucci, C, Xiong, Y, Jin, J, Falco, A, Knoechel, B, Aversa, F, Candini, O, Quaini, F, Sportoletti, P, Stegmaier, K, 2022 Jun 17, Roti G. Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia. Cell Death Dis., PMID: 35710782, 13(6):551. doi: 10. 1038/s41419-022-05002-5., and Pmcid:, Pmc9203761.

Subjects
Cancer Research, Cellular and Molecular Neuroscience, Glycogen Synthase Kinase 3, Histocompatibility Antigens, T-Lymphocytes, Immunology, Humans, Nuclear Proteins, Cell Biology, Histone-Lysine N-Methyltransferase, DNA Methylation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Abstract

Genomic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in acute lymphoblastic leukemia (ALL), suggesting new opportunities for therapeutic interventions. In this study, we identified G9a/EHMT2 as a potential target in T-ALL through the intersection of epigenome-centered shRNA and chemical screens. We subsequently validated G9a with low-throughput CRISPR-Cas9-based studies targeting the catalytic G9a SET-domain and the testing of G9a chemical inhibitors in vitro, 3D, and in vivo T-ALL models. Mechanistically we determined that G9a repression promotes lysosomal biogenesis and autophagic degradation associated with the suppression of sestrin2 (SESN2) and inhibition of glycogen synthase kinase-3 (GSK-3), suggesting that in T-ALL glycolytic dependent pathways are at least in part under epigenetic control. Thus, targeting G9a represents a strategy to exhaust the metabolic requirement of T-ALL cells.

Published
2022

2. Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Author

Antic D, Milic N, Chatzikonstantinou T, Scarfò L, Otasevic V, Rajovic N, Allsup D, Alonso Cabrero A, Andres M, Baile Gonzales M, Capasso A, Collado R, Cordoba R, Cuéllar-García C, Correa JG, De Paoli L, De Paolis MR, Del Poeta G, Dimou M, Doubek M, Efstathopoulou M, El-Ashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Lopez-Garcia A, García-Marco JA, García-Serra R, Gentile M, Gimeno E, da Silva MG, Gutwein O, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Itchaki G, Jaksic O, Janssens A, Kalashnikova OB, Kalicińska E, Kater AP, Kersting S, Koren- Michowitz M, Labrador J, Lad D, Laurenti L, Fresa A, Levin MD, Mayor Bastida C, Malerba L, Marasca R, Marchetti M, Marquet J, Mihaljevic B, Milosevic I, Mirás F, Morawska M, Motta M, Munir T, Murru R, Nunes R, Olivieri J, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Reda G, Rigolin GM, Shrestha A, Šimkovič M, Smirnova S, Špaček M, Sportoletti P, Stanca O, Stavroyianni N, Te Raa D, Tomic K, Tonino S, Trentin L, Van Der Spek E, van Gelder M, Varettoni M, Visentin A, Vitale C, Vukovic V, Wasik-Szczepanek E, Wróbel T, Segundo LYS, Yassin M, Coscia M, Rambaldi A, Montserrat E, Foà R, Cuneo A, Carrier M, Ghia P, Stamatopoulos K.

Subjects
Age, Anticoagulation therapy, Bleeding, CLL, COVID-19, D-dimer, LMWH, Thromboprophylaxis, Thrombosis
Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment- related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS- CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C- reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Published
2022

3. Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group

Author

Rigolin, G. M., Cavazzini, F., Piciocchi, A., Arena, V., Visentin, A., Reda, G., Zamprogna, G., Cibien, F., Vitagliano, O., Coscia, M., Farina, L., Gaidano, G., Murru, R., Varettoni, M., Paolini, R., Sportoletti, P., Pietrasanta, D., Molinari, A. L., Quaglia, F. M., Laurenti, L., Marasca, R., Marchetti, M., Mauro, F. R., Crea, E., Vignetti, M., Gentile, M., Montillo, M., Foa, R., Cuneo, A., Chiarenza, A., Perbellini, O., Mannina, D., Sancetta, R., Olivieri, A., Molica, S., Pane, F., Patti, C., Iliariucci, F., Gozzetti, A., Califano, C., Galieni, P., Augello, A. F., Vallisa, D., Cura, F., Frustaci, A. M., Fazi, P., Trentin, L., and Ferrara, F.

Subjects
Male, Oncology, Cancer Research, idelalisib, law.invention, 0302 clinical medicine, Randomized controlled trial, Recurrence, law, Original Research Articles, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Original Research Article, Chronic, Aged, 80 and over, Leukemia, real‐world evidence, Hematology, General Medicine, Middle Aged, Lymphocytic, Survival Rate, 030220 oncology & carcinogenesis, Female, Rituximab, Refractory Chronic Lymphocytic Leukemia, Idelalisib, chronic lymphocytic leukemia, real-world evidence, Aged, Disease-Free Survival, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Purines, Quinazolinones, medicine.drug, medicine.medical_specialty, NO, 03 medical and health sciences, Internal medicine, medicine, Survival rate, Performance status, business.industry, B-Cell, Clinical trial, Settore MED/15 - MALATTIE DEL SANGUE, Regimen, business, 030215 immunology
Abstract

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real‐life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression‐free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0–1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p

Published
2021

5. Frontline treatment with the combination obinutuzumab±chlorambucil for chronic lymphocytic leukemia outside clinical trials: results of a multinational, multicenter study by ERIC and the Israeli CLL study group

Author

Herishanu Y, Shaulov A, Fineman R, BasiC-Kinda S, Aviv A, Wasik-Szczepanek E, Jaksic O, Zdrenghea M, Greenbaum U, Mandac I, Simkovic M, Morawska M, Benjamini O, Spacek M, Nemets A, Bairey O, Trentin L, Ruchlemer R, Laurenti L, Ciocan O, Doubek M, Shvidel L, Dali N, Miras F, De Meuter A, Dimou M, Mauro F, Coscia M, Bumbea H, Szasz R, Tadmor T, Gutwein O, Gentile M, Scarfo L, Tedeschi A, Sportoletti P, Vazquez E, Marquet J, Assouline S, Papaioannou M, Braester A, Levato L, Gregor M, Rigolin G, Loscertales J, Perez A, Nijziel M, Popov V, Collado R, Slavutsky I, Itchaki G, Ringelstein S, Goldschmidt N, Perry C, Levi S, Polliack A, and Ghia P

Abstract

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O±Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del(17p13.1)/TP53mutation were excluded. A total of 437 patients (median age, 75.9years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min)were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95%CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del(11q22.3) and/or IGHV-unmutated], lymph nodes of diameter >5cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del(11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease. This article is protected by copyright. All rights reserved.

Published
2020

8. Treatment of chronic lymphocytic leukemia in the new drugs era: the state of art in the Italian landscape

Author

Morelli, F, Innocenti, I, Autore, F, Fresa, F, Tomasso, A, Piciocchi, A, Frustaci, Am, Trentin, L, Mauro, Fr, Schiattone, L, Visentin, A, Del Poeta, G, Reda, G, Rigolin, Gm, Ibatici, A, Ciolli, S, Vitale, C, Sportoletti, P, Murru, R, Levato, L, Gentile, M, D’Arena, G, Coscia, M, Villa, Mr, Fontana, R, Efremov, D, Tedeschi, A, Scarfò, L, Cuneo, A, Foà, R, and Laurenti, L

Published
2020

12. Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein α activity: implications in myelodysplastic syndrome and acute myeloid leukemia

Author

Khanna Gupta, A, Abayasekara, N, Levine, M, Sun, H, Virgilio, M, Nia, N, Halene, S, Sportoletti, P, Jeong, Jy, PANDOLFI DE RINALDIS, Pier Paolo, and Berliner, N.

Subjects
Gene Expression Regulation, Leukemic, Nuclear Proteins, Molecular Bases of Disease, Haploinsufficiency, Mice, Mutant Strains, Neoplasm Proteins, Up-Regulation, Leukemia, Myeloid, Acute, Mice, Eukaryotic Initiation Factor-4E, HEK293 Cells, hemic and lymphatic diseases, Myelodysplastic Syndromes, CCAAT-Enhancer-Binding Proteins, Animals, Humans, Protein Isoforms, Nucleophosmin
Abstract

NPM1 is a ubiquitously expressed nucleolar phosphoprotein, the gene for which maps to chromosome 5q35 in close proximity to a commonly deleted region associated with (del)5q, a type of myelodysplastic syndrome (MDS). This region is also a frequent target of deletions in de novo and therapy-related MDS/acute myeloid leukemia. Previous studies have shown that Npm1(+/-) mice develop an MDS-like disease that transforms to acute myeloid leukemia over time. To better understand the mechanism by which NPM1 haploinsufficiency causes an MDS phenotype, we generated factor-dependent myeloid cell lines from the bone marrow of Npm1(+/+) and Npm1(+/-) mice and demonstrated compromised neutrophil-specific gene expression in the MNPM1(+/-) cells. We attribute these observations to increased levels of the shorter, dominant negative leukemogenic isoform (p30) of CCAAT enhancer-binding protein α (C/EBPα). We show that this increase is caused, in part, by elevated levels of the activated translation initiation factor eIF4E, overexpression of which also increases translation of C/EBPαp30 in HEK293 cells. In a positive feedback loop, eIF4E expression is further elevated both at the mRNA and protein levels by C/EBPαp30 but not by the full-length C/EBPαp42. Re-expression of C/EBPαp42 or NPM1 but not C/EBPαp30 in MNPM1(+/-) cells partially rescues the myeloid phenotype. Our observations suggest that the aberrant feed-forward pathway that keeps eIF4E and C/EBPαp30 elevated in NPM1(+/-) cells contributes to the MDS phenotype associated with NPM1 deficiency.

Published
2012

14. The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice

Author

Galuppo, M., Nocentini, G., Mazzon, E., Ronchetti, S., Esposito, Emanuela, Riccardi, L., Sportoletti, P., Paola, R. D., Bruscoli, S., Riccardi, C., Cuzzocrea, Salvatore, and DI PAOLA, Rosanna

Subjects
Male, Mice, 129 Strain, acute pancreatitis, etiology, Knockout, Recombinant Fusion Proteins, T-Lymphocytes, Interleukin-1beta, Nitric Oxide Synthase Type II, Apoptosis, Receptors, Nerve Growth Factor, 129 Strain, Ligands, Receptors, Tumor Necrosis Factor, Mice, NF-KappaB Inhibitor alpha, Glucocorticoid-Induced TNFR-Related Protein, Receptors, Nerve Growth Factor, Animals, Edema, GITR, administration /&/ dosage/deficiency/genetics/physiology, administration /&/ dosage/genetics, Mice, Knockout, Tumor Necrosis Factor-alpha, Animals, Apoptosis, Caerulein, toxicity, Edema, etiology, I-kappa B Proteins, metabolism, Intercellular Adhesion Molecule-1, metabolism, Interleukin-1beta, metabolism, Ligands, Male, Mice, Mice, 129 Strain, Mice, Knockout, Neutrophil Infiltration, Nitric Oxide Synthase Type II, metabolism, P-Selectin, metabolism, Pancreatitis, etiology/pathology/physiopathology/prevention /&/ control, Poly(ADP-ribose) Polymerases, metabolism, Receptors, administration /&/ dosage/deficiency/genetics/physiology, Receptors, Tumor Necrosis Factor, administration /&/ dosage/deficiency/genetics/physiology, Recombinant Fusion Proteins, administration /&/ dosage/genetics, T-Lymphocytes, physiology, Transcription Factor RelA, metabolism, Tumor Necrosis Factor-alpha, metabolism, Transcription Factor RelA, toxicity, Intercellular Adhesion Molecule-1, Research Papers, Caerulein, P-Selectin, Neutrophil Infiltration, Pancreatitis, physiology, I-kappa B Proteins, etiology/pathology/physiopathology/prevention /&/ control, Poly(ADP-ribose) Polymerases, Ceruletide
Abstract

Pancreatitis represents a life-threatening inflammatory condition where leucocytes, cytokines and vascular endothelium contribute to the development of the inflammatory disease. The glucocorticoid-induced tumour necrosis factor (TNF) receptor family-related protein (GITR) is a costimulatory molecule for T lymphocytes, modulates innate and adaptive immune system and has been found to participate in a variety of immune responses and inflammatory processes. Our purpose was to verify whether inhibition of GITR triggering results in a better outcome in experimental pancreatitis.In male GITR knock-out (GITR(-/-)) and GITR(+/+) mice on Sv129 background, acute pancreatitis was induced after i.p. administration of cerulein. Other experimental groups of GITR(+/+) mice were also treated with different doses of Fc-GITR fusion protein (up to 6.25 µg·mouse⁻¹), given by implanted mini-osmotic pump. Clinical score and pro-inflammatory parameters were evaluated.A less acute pancreatitis was found in GITR(-/-) mice than in GITR(+/+) mice, with marked differences in oedema, neutrophil infiltration, pancreatic dysfunction and injury. Co-treatment of GITR(+/+) mice with cerulein and Fc-GITR fusion protein (6.25 µg·mouse⁻¹) decreased the inflammatory response and tissue injury, compared with treatment with cerulein alone. Inhibition of GITR triggering was found to modulate activation of nuclear factor κB as well as the production of TNF-α, interleukin-1β, inducible nitric oxide synthase, nitrotyrosine, poly-ADP-ribose, intercellular adhesion molecule-1 and P-selectin.The GITR-GITR ligand system is crucial to the development of acute pancreatitis in mice. Our results also suggest that the Fc-GITR fusion protein could be useful in the treatment of acute pancreatitis.

Published
2011

27. VENETOCLAX AND RITUXIMAB (VENR) FOR THE FRONT-LINE TREATMENT OF YOUNG PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND AN UNFAVORABLE BIOLOGIC PROFILE. PRELIMINARY RESULTS OF THE GIMEMA VERITAS STUDY

Author

Mauro, F. R., Reda, G., Arena, V., Visentin, A., Coscia, M., Sportoletti, P., Laurenti, L., Gaidano, G., Marasca, R., Orsucci, L., Murru, R., Stelitano, C., Ilariucci, F., Mannina, D., Massaia, M., Gian Matteo Rigolin, Scarfo, L., Marchetti, M., Levato, L., Tani, M., Arcari, A., Musuraca, G., Deodato, M., Galieni, P., Patrizi, V. Belsito, Gottardi, D., Liberati, A. M., Pietrasanta, D., Molica, S., Cassin, R., Vitale, C., Ielo, C., Propris, M. S., Della Starza, I., Raponi, S., Nanni, M., Del Giudice, I., Paoloni, F., Fazi, P., Albano, F., Neri, A., Piciocchi, A., Trentin, L., Cuneo, A., Guarini, A., and Foa, R.

29. MUTATIONS OF THE EXPORTIN 1 (XPO1) GENE PREDICT SHORTER TIME TO FIRST TREATMENT IN 1092 EARLY STAGE CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. TRAINING/VALIDATION STUDY

Author

Favini, C., Moia, R., Ferri, V., Riccardo Bomben, Sagiraju, S., Bittolo, T., Scarfo, L., Bonfiglio, S., Maffei, R., Baldoni, S., Raponi, S., Spina, V., Bruscaggin, A., Di Bergamo, L. Terzi, Paoli, L., Casaluci, G. Margiotta, Deambrogi, C., Rasi, S., Condoluci, A., Schipani, M., Talotta, D., Al Essa, W., Adhinaveni, R., Patriarca, A., Zucchetto, A., Rossi, F. M., Del Giudice, I., Sportoletti, P., Marasca, R., Ghia, P., Foa, R., Rossi, D., Gattei, V., and Gaidano, G.

32. OBINUTUZUMAB PLUS CHLORAMBUCIL VERSUS IBRUTINIB IN PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA WITHOUT TP53 DISRUPTIONS. A CAMPUS CLL STUDY

Author

Visentin, A., Pravato, S., Mauro, F. R., Pietrasanta, D., Fresa, A., Vitale, C., Ciolli, S., Cassin, R., Cibien, F., Sportoletti, P., Gentile, M., Gian Matteo Rigolin, Quaglia, F. M., Murru, R., Gozzetti, A., Molica, S., Marchetti, M., Scarfo, L., Guardalben, E., Avitabile, A., Reda, G., Coscia, M., Laurenti, L., Pizzolo, G., Semenzato, G., Foa, R., Cuneo, A., and Trentin, L.

34. COVID-19 infection in chronic myeloid leukaemia after oneyear of the pandemic in Italy. A Campus CML report

Author

Elisabetta Abruzzese, Sabina Russo, Carmen Fava, Francesca Lunghi, Sabrina Leonetti Crescenzi, Chiara Elena, Vincenzo Accurso, Fausto Castagnetti, Debora Luzi, Giovanni Caocci, Elena Crisà, Maria Cristina Miggiano, Massimo Breccia, Antonella Gozzini, Giuseppina Loglisci, Giovanna Rege-Cambrin, Monica Bocchia, Immacolata Attolico, Massimiliano Bonifacio, Luigiana Luciano, Gaetano La Barba, Gianantonio Rosti, Maria Stella De Candia, Roberto Latagliata, Gabriele Gugliotta, Francesco Cavazzini, Rosaria Sancetta, Micaela Bergamaschi, Anna Rita Scortechini, Sara Galimberti, Tamara Intermesoli, Federica Sorà, Luciano Levato, Paolo Sportoletti, Monica Crugnola, Mario Tiribelli, Isabella Capodanno, Giuseppe Saglio, Davide Rapezzi, Robin Foà, Alessandra Iurlo, Alessandro Lucchesi, Michele Pizzuti, Sara Barulli, Fabio Stagno, Patrizia Pregno, Alessandra Malato, Gianni Binotto, Agostino Tafuri, Breccia M., Abruzzese E., Accurso V., Attolico I., Barulli S., Bergamaschi M., Binotto G., Bocchia M., Bonifacio M., Caocci G., Capodanno I., Castagnetti F., Cavazzini F., Crisa E., Crugnola M., Stella De Candia M., Elena C., Fava C., Galimberti S., Gozzini A., Gugliotta G., Intermesoli T., Iurlo A., La Barba G., Latagliata R., Leonetti Crescenzi S., Levato L., Loglisci G., Lucchesi A., Luciano L., Lunghi F., Luzi D., Malato A., Cristina Miggiano M., Pizzuti M., Pregno P., Rapezzi D., Rege-Cambrin G., Rosti G., Russo S., Sancetta R., Rita Scortechini A., Sora F., Sportoletti P., Stagno F., Tafuri A., Tiribelli M., Foa R., and Saglio G.

Subjects
Male, Tyrosine-kinase inhibitor, law.invention, law, Retrospective Studie, Pandemic, Chronic, Covid‐19, Leukemia, Mortality rate, Hematology, Middle Aged, Intensive care unit, Research Papers, Survival Rate, Italy, covid-19, Hematologic Neoplasms, Cohort, Female, prognosi, Human, Research Paper, chronic myeloid leukemia, Covid-19, prognosis, mortality, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), medicine.drug_class, chronic myeloid leukemia, prognosis, mortality, Chronic myeloid leukaemia, Disease-Free Survival, NO, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Covid-19, mortality, prognosis, Aged, Humans, Retrospective Studies, COVID-19, Pandemics, SARS-CoV-2, medicine, business.industry, Concomitant, Commentary, BCR-ABL Positive, business, Myelogenous
Abstract

Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18years). Twenty-one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.

Published
2022

35. Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Author

Anna Maria Frustaci, Giovanni Del Poeta, Andrea Visentin, Paolo Sportoletti, Alberto Fresa, Candida Vitale, Roberta Murru, Annalisa Chiarenza, Alessandro Sanna, Francesca Romana Mauro, Gianluigi Reda, Massimo Gentile, Marzia Varettoni, Claudia Baratè, Chiara Borella, Antonino Greco, Marina Deodato, Giulia Zamprogna, Roberta Laureana, Alessandra Cipiciani, Andrea Galitzia, Angelo Curto Pelle, Francesca Morelli, Lucio Malvisi, Marta Coscia, Luca Laurenti, Livio Trentin, Marco Montillo, Roberto Cairoli, Alessandra Tedeschi, Frustaci, A, Del Poeta, G, Visentin, A, Sportoletti, P, Fresa, A, Vitale, C, Murru, R, Chiarenza, A, Sanna, A, Mauro, F, Reda, G, Gentile, M, Varettoni, M, Barate, C, Borella, C, Greco, A, Deodato, M, Zamprogna, G, Laureana, R, Cipiciani, A, Galitzia, A, Curto Pelle, A, Morelli, F, Malvisi, L, Coscia, M, Laurenti, L, Trentin, L, Montillo, M, Cairoli, R, and Tedeschi, A

Subjects
CIRS, comorbiditie, discontinuations, fitne, venetoclax, CLL, ECOG, comorbidities, fitness, reduction, targeted therapies, Hematology, Settore MED/15 - MALATTIE DEL SANGUE, MED/15 - MALATTIE DEL SANGUE, targeted therapie, discontinuation
Abstract

Background: The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia (CLL) is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events. Objectives: This study was aimed to evaluate whether age, fitness status, patients’/disease characteristics, or concomitant medications may predict outcomes in CLL patients receiving venetoclax. Design: Retrospective observational study. Methods: Impact of age, presence of Cumulative Illness Rating Scale (CIRS) >6 or severe organ impairment (CIRS3+), Eastern Cooperative Oncology Group–Performance Status (ECOG-PS), renal function, and concomitant medications were retrospectively analyzed on treatment management (definitive discontinuation due to toxicity, discontinuation due to toxicity, Tox-DTD; permanent dose reduction, PDR) and survival [progression free survival (PFS), event free survival (EFS), overall survival (OS)] in unselected patients receiving venetoclax monotherapy in common practice. Results: A total of 221 relapsed/refractory patients were included. Tox-DTD and PDR were reported in 5.9% and 21.7%, respectively, and were not influenced by any fitness parameter, age, number or type of concomitant medication, baseline neutropenia, or impaired renal function. None of these factors were associated with tumor lysis syndrome (TLS) development. Age and coexisting conditions had no influence on PFS and EFS. At univariate analysis, OS was significantly shorter only in patients with ECOG-PS >1 ( p 6 ( p = 0.014) or CIRS3+ ( p = 0.031). ECOG-PS >1 retained an independent role only for EFS and OS. While Tox-DTD affected all survival outcomes, no differences in PFS were reported among patients permanently reducing dose or interrupting venetoclax for > 7 days. Conclusion: Clinical outcome with venetoclax is not influenced by comorbidities, patients’ clinical characteristics, or concomitant medications. Differently from other targeted therapies, this demonstrates that, except ECOG-PS, none of the parameters generally considered for treatment choice, including baseline neutropenia or impaired renal function, should rule the decision process with this agent. Anyway, if clinically needed, a correct drug management does not compromise treatment efficacy and may avoid toxicity-driven discontinuations. Plain Language Summary Chapter 1: Why was this study done? Chapter 2: Which are the main findings of the study? Chapter 3: How these findings may impact on clinical practice? Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia • The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events (e.g. compromised renal function or baseline neutropenia). • In our large series of patients treated outside of clinical trials, we demonstrated that neither age, fitness, comorbidities nor concomitant medications impact on venetoclax management and survival. Importantly, patients presenting with baseline neutropenia or impaired renal function did not have a higher rate of dose reductions or toxicity-driven discontinuations, thus further underlining that venetoclax may be safely administered even in those categories with no preclusions. • Differently from other targeted agents, our data demonstrate that none of the baseline factors commonly considered in treatment decision process retains a role with venetoclax. Finally, permanent dose reductions and temporary interruptions did not adversely impact PFS suggesting that, if clinically needed, a correct drug management should be adopted with no risk of compromising venetoclax efficacy.

Published
2022

36. Continuous treatment with Ibrutinib in 100 untreated patients with TP 53 disrupted chronic lymphocytic leukemia: A real‐life campus CLL study

Author

Andrea Visentin, Francesca Romana Mauro, Francesca Cibien, Candida Vitale, Gianluigi Reda, Alberto Fresa, Stefania Ciolli, Daniela Pietrasanta, Monia Marchetti, Roberta Murru, Massimo Gentile, Gian Matteo Rigolin, Francesca Maria Quaglia, Lydia Scarfò, Paolo Sportoletti, Stefano Pravato, Francesco Piazza, Marta Coscia, Luca Laurenti, Stefano Molica, Robin Foà, Antonio Cuneo, Livio Trentin, Visentin, A., Mauro, F. R., Cibien, F., Vitale, C., Reda, G., Fresa, A., Ciolli, S., Pietrasanta, D., Marchetti, M., Murru, R., Gentile, M., Rigolin, G. M., Quaglia, F. M., Scarfo', L., Sportoletti, P., Pravato, S., Piazza, F., Coscia, M., Laurenti, L., Molica, S., Foa, R., Cuneo, A., and Trentin, L.

Subjects
Settore MED/15 - MALATTIE DEL SANGUE, Ibrutinib, Chronic Lymphocytic Leukemia, TP53, Hematology, NO
Published
2021

37. COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Author

Ellen van der Spek, Emili Montserrat, Talha Munir, Paolo Ghia, Shaimaa El-Ashwah, Andreas Glenthøj, Viola Maria Popov, Sanne H. Tonino, Ann Janssens, Michel van Gelder, Lara Malerba, Rocío García-Serra, Alberto Lopez-Garcia, Juan-Gonzalo Correa, Christos Demosthenous, Idanna Innocenti, Maria Papaioannou, Lydia Scarfò, Antonio Cuneo, Francesca Romana Mauro, Sabina Kersting, Robin Foà, David Donaldson, Livio Trentin, Roberta Murru, Panagiotis Baliakas, Marina Motta, Deepesh Lad, Yervand K Hakobyan, Paolo Sportoletti, Lucrecia Yáñez San Segundo, Alicia Enrico, Elżbieta Kalicińska, Ewa Wasik-Szczepanek, Martin Spacek, Tamar Tadmor, Enrico Lista, Roel van Kampen, Lorella Orsucci, Michael Doubek, Yair Herishanu, Blanca Espinet, Jose Angel Hernandez-Rivas, Inga Piskunova, Ozren Jakšić, Georgios Karakatsoulis, Tomasz Wróbel, Oana Stanca, Luca Laurenti, Martin Andres, Roberto Marasca, Mark-David Levin, Giovanni Del Poeta, Miguel Arturo Pavlovsky, Maria Dimou, Monia Marchetti, Ivana Milosevic, Gianluigi Reda, Tobias Herold, David Allsup, Raul Cordoba, Andrea Visentin, Maria Gomes da Silva, Angela Ferrari, Antonella Capasso, Juan Marquet, Francesca Maria Quaglia, Candida Vitale, Mattias Mattsson, Marta Coscia, Moritz Fürstenau, Lucia Farina, Niki Stavroyianni, Marta Morawska, Arnon P. Kater, Mónica Baile, Gevorg Saghumyan, Carolina Cuéllar-García, Jacopo Olivieri, Darko Antic, Raquel Nunes Rodrigues, Alejandro Alonso Cabrero, Henrik Frederiksen, Alessandro Rambaldi, Marzia Varettoni, Amit Shrestha, Оlga B Kalashnikova, Thomas Chatzikonstantinou, José A. García-Marco, Martin Simkovic, Linda Katharina Karlsson, Odit Gutwein, Mohamed A. Yassin, Rosa Ruchlemer, Eva Gimeno, Kristian Qvist, Fatima Miras, Gilad Itchaki, Maria Rosaria De Paolis, Maria Efstathopoulou, Doreen te Raa, Barbara Eichhorst, Dominique Bron, Jorge Labrador, Gian Matteo Rigolin, Myriam Foglietta, Massimo Gentile, Sofia Chatzileontiadou, Carsten Utoft Niemann, Anargyros Kapetanakis, Kostas Stamatopoulos, Lorenzo De Paoli, Giulia Quaresmini, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), Chatzikonstantinou, T., Kapetanakis, A., Scarfo, L., Karakatsoulis, G., Allsup, D., Cabrero, A. A., Andres, M., Antic, D., Baile, M., Baliakas, P., Bron, D., Capasso, A., Chatzileontiadou, S., Cordoba, R., Correa, J. -G., Cuellar-Garcia, C., De Paoli, L., De Paolis, M. R., Del Poeta, G., Demosthenous, C., Dimou, M., Donaldson, D., Doubek, M., Efstathopoulou, M., Eichhorst, B., El-Ashwah, S., Enrico, A., Espinet, B., Farina, L., Ferrari, A., Foglietta, M., Frederiksen, H., Furstenau, M., Garcia-Marco, J. A., Garcia-Serra, R., Gentile, M., Gimeno, E., Glenthoj, A., Gomes da Silva, M., Gutwein, O., Hakobyan, Y. K., Herishanu, Y., Hernandez-Rivas, J. A., Herold, T., Innocenti, I., Itchaki, G., Jaksic, O., Janssens, A., Kalashnikova, Оb., Kalicinska, E., Karlsson, L. K., Kater, A. P., Kersting, S., Labrador, J., Lad, D., Laurenti, L., Levin, M. -D., Lista, E., Lopez-Garcia, A., Malerba, L., Marasca, R., Marchetti, M., Marquet, J., Mattsson, M., Mauro, F. R., Milosevic, I., Miras, F., Morawska, M., Motta, M., Munir, T., Murru, R., Niemann, C. U., Rodrigues, R. N., Olivieri, J., Orsucci, L., Papaioannou, M., Pavlovsky, M. A., Piskunova, I., Popov, V. M., Quaglia, F. M., Quaresmini, G., Qvist, K., Reda, G., Rigolin, G. M., Ruchlemer, R., Saghumyan, G., Shrestha, A., Simkovic, M., Spacek, M., Sportoletti, P., Stanca, O., Stavroyianni, N., Tadmor, T., Te Raa, D., Tonino, S. H., Trentin, L., Van Der Spek, E., van Gelder, M., van Kampen, R., Varettoni, M., Visentin, A., Vitale, C., Wasik-Szczepanek, E., Wrobel, T., San Segundo, L. Y., Yassin, M., Coscia, M., Rambaldi, A., Montserrat, E., Foa, R., Cuneo, A., Stamatopoulos, K., Ghia, P., Experimental Immunology, Clinical Haematology, AII - Cancer immunology, and CCA - Cancer Treatment and Quality of Life

Subjects
Chronic lymphocytic leukaemia, Cancer Research, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Epidemiology, medicine.medical_treatment, Chronic lymphocytic leukemia, CLL, COVID-19, 610 Medicine & health, Disease, Lower risk, COVID-19 (Malaltia), Severity of Illness Index, Article, NO, law.invention, Risk Factors, law, Internal medicine, Case fatality rate, Mortalitat, medicine, Humans, Hematologi, Chronic, Mortality, Science & Technology, Leukemia, SARS-CoV-2, business.industry, Vaccination, B-Cell, Leucèmia, COVID-19, Immunosuppression, Hematology, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, Intensive care unit, Lymphocytic, Oncology, business, Life Sciences & Biomedicine
Abstract

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p

Published
2021

38. Perspectives and Emotional Experiences of Patients With Chronic Myeloid Leukemia During ENESTPath Clinical Trial and Treatment-Free Remission: Rationale and Protocol of the Italian Substudy

Author

Elena Vegni, Chiara Elena, Gianantonio Rosti, Eros Di Bona, Simona Sica, Claudia Minotto, Gaetano La Barba, Sharon Supekar, Flavia Rivellini, Massimo Breccia, Luca Arcaini, Fabio Ciceri, I Capodanno, Sara Galimberti, Luigi Di Caprio, Antonio Cuneo, Alessandro Maggi, Paolo Sportoletti, Alessandra Iurlo, Giovanna Rege Cambrin, Enrico Capochiani, Francesco Albano, Lidia Borghi, Michele Baccarani, Massimiliano Bonifacio, Monica Crugnola, Borghi, L., Rosti, G., Maggi, A., Breccia, M., Di Bona, E., Iurlo, A., La Barba, G., Sportoletti, P., Albano, F., Galimberti, S., Rivellini, F., Cambrin, G. R., Capodanno, I., Cuneo, A., Bonifacio, M., Sica, S., Arcaini, L., Capochiani, E., Minotto, C., Ciceri, F., Crugnola, M., Di Caprio, L., Supekar, S., Elena, C., Baccarani, M., and Vegni, E.

Subjects
0301 basic medicine, Cancer Research, Pediatrics, medicine.medical_specialty, Randomization, Chronic myeloid leukemia, ENESTPath, emotional experience, mixed methods, nilotinib, psychological distress, quality of life, study protocol, Dysfunctional family, NO, 03 medical and health sciences, 0302 clinical medicine, Quality of life, medicine, Methods, RC254-282, business.industry, Myeloid leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Imatinib, Clinical trial, Distress, 030104 developmental biology, Nilotinib, Oncology, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian ‘patient’s voice CML’ substudy was to evaluate patients’ psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive BCR-ABL1+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed via patients’ emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination.NCT number: NCT01743989, EudraCT number: 2012-005124-15

Published
2021

39. Survival risk score for real-life relapsed/refractory chronic lymphocytic leukemia patients receiving ibrutinib. A campus CLL study

Author

Valter Gattei, Gian Matteo Rigolin, Yair Herishanu, Aaron Polliack, Annalisa Chiarenza, Francesca Rossi, Fortunato Morabito, Marzia Varettoni, Paolo Sportoletti, Roberta Murru, Riccardo Bomben, Gianluigi Reda, Giovanni Tripepi, Giacomo Loseto, Luca Laurenti, Graziella D’. Arrigo, Annalisa Biagi, Antonella Zucchetto, Adalgisa Condoluci, Ugo Consoli, Antonio Cuneo, Ilaria Del Giudice, Davide Rossi, Anna Grazia Recchia, Francesco Di Raimondo, Riccardo Moia, Giovanni Del Poeta, Robin Foà, Gianluca Gaidano, Ilaria Scortechini, Vincenzo Fraticelli, Ilaria Angeletti, Daniela Pietrasanta, Angela Rago, Cirino Botta, Marta Coscia, Ernesto Vigna, Francesca Romana Mauro, Massimo Gentile, Gentile M., Morabito F., Del Poeta G., Mauro F.R., Reda G., Sportoletti P., Laurenti L., Coscia M., Herishanu Y., Recchia A.G., Varettoni M., Murru R., Chiarenza A., Condoluci A., Moia R., Pietrasanta D., Loseto G., Consoli U., Scortechini I., Rossi F.M., Zucchetto A., Fraticelli V., Vigna E., Botta C., Tripepi G., Arrigo G.D., Rago A., Angeletti I., Biagi A., Del Giudice I., Bomben R., Rigolin G.M., Rossi D., Di Raimondo F., Gaidano G., Polliack A., Cuneo A., Foa R., and Gattei V.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Survival risk score, Chronic lymphocytic leukemia, Treatment outcome, Antineoplastic Agents, risk score, NO, chemistry.chemical_compound, relapsed/refractory chronic lymphocytic leukemia, Antineoplastic Agents, Immunological, Piperidines, ibrutinib, Internal medicine, medicine, Humans, real-life, Molecular Targeted Therapy, Chronic, Protein Kinase Inhibitors, Framingham Risk Score, Leukemia, chronic lymphocytic leukemia, prognosis, business.industry, Adenine, B-Cell, Hematology, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, prognostic score, Lymphocytic, Survival risk score, real-life, relapsed/refractory chronic lymphocytic leukemia, ibrutinib, Settore MED/15 - MALATTIE DEL SANGUE, Immunological, Treatment Outcome, chemistry, Ibrutinib, Relapsed refractory, business
Published
2021

40. Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Author

Claudia Baratè, Marta Coscia, Francesca Morelli, Paolo Sportoletti, Claudia Ielo, Chiara Cavalloni, Massimiliano Postorino, Annalisa Chiarenza, Alessandra Tedeschi, Marco Montillo, Roberto Cairoli, Alberto Fresa, Annalisa Biagi, Valentina Rossi, Giovanni Del Poeta, Roberta Murru, Stefania Ciolli, Giulia Zamprogna, Antonino Greco, Ramona Cassin, Anna Maria Frustaci, Angelo Curto Pelle, Francesco Di Raimondo, Gianfranco Lapietra, Luca Laurenti, Gianluigi Reda, Chiara Borella, Marzia Varettoni, Candida Vitale, Francesca Romana Mauro, Marina Deodato, Tedeschi, A, Frustaci, A, Mauro, F, Chiarenza, A, Coscia, M, Ciolli, S, Reda, G, Laurenti, L, Varettoni, M, Murru, R, Barate, C, Sportoletti, P, Greco, A, Borella, C, Rossi, V, Deodato, M, Biagi, A, Zamprogna, G, Pelle, A, Lapietra, G, Vitale, C, Morelli, F, Cassin, R, Fresa, A, Cavalloni, C, Postorino, M, Ielo, C, Cairoli, R, Di Raimondo, F, Montillo, M, and Del Poeta, G

Subjects
Oncology, drug safety, medicine.medical_treatment, retrospective study, chemistry.chemical_compound, Piperidines, hemic and lymphatic diseases, Prospective Studies, event free survival, Prospective cohort study, progression free survival, Lymphoid Neoplasia, fitne, Hematology, aged, comorbidity, Cumulative Illness Rating Scale, ECOG Performance Statu, female, Pharmaceutical Preparations, risk factor, Ibrutinib, disease severity, chronic lymphatic leukemia, medicine.medical_specialty, overall survival, Neutropenia, Article, cancer chemotherapy, male, Internal medicine, drug tolerance, medicine, Humans, neutropenia, human, drug dose reduction, neoplasms, Retrospective Studies, Chemotherapy, business.industry, Proportional hazards model, Adenine, aging, medicine.disease, Settore MED/15, Comorbidity, Leukemia, Lymphocytic, Chronic, B-Cell, major clinical study, predictor variable, Clinical trial, chemistry, Concomitant, treatment outcome, business
Abstract

Key points Age per se does not influence outcome in CLL patients on ibrutinib, whereas CIRS score is predictive of treatment management, PFS, and EFS.ECOG-PS and neutropenia resulted as the only baseline parameters affecting overall survival., Visual Abstract, Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Published
2021

41. Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study

Author

Ilaria Scortechini, Riccardo Moia, Marzia Varettoni, Francesca Romana Mauro, Sara Galimberti, Giovanni Del Poeta, Graziella D'Arrigo, Marta Coscia, Luca Laurenti, Ernesto Vigna, Davide Rossi, Annalisa Biagi, Gianluca Gaidano, Daniele Caracciolo, Riccardo Bomben, Ilaria Angeletti, Gianluigi Reda, Giovanna Cutrona, Daniela Pietrasanta, Gilberto Fronza, Ramona Cassin, Antonino Neri, Aaron Polliack, Annalisa Chiarenza, Yair Herishanu, Fortunato Morabito, Ilaria Del Giudice, Valter Gattei, Francesca Rossi, Roberta Murru, Giovanni Tripepi, Andrea Visentin, Livio Trentin, Antonio Cuneo, Angela Rago, Antonella Zucchetto, Adalgisa Condoluci, Giacomo Loseto, Ugo Consoli, Enrica Antonia Martino, Manlio Ferrarini, Massimo Gentile, Francesco Di Raimondo, Francesco Mendicino, Paolo Sportoletti, Robin Foà, Cirino Botta, Morabito F., Tripepi G., Del Poeta G., Mauro F.R., Reda G., Sportoletti P., Laurenti L., Coscia M., Herishanu Y., Varettoni M., Murru R., Chiarenza A., Visentin A., Condoluci A., Moia R., Pietrasanta D., Loseto G., Consoli U., Scortechini I., Rossi F.M., Zucchetto A., Vigna E., Martino E.A., Mendicino F., Botta C., Caracciolo D., Cassin R., D'Arrigo G., Galimberti S., Rago A., Angeletti I., Biagi A., Del Giudice I., Bomben R., Neri A., Fronza G., Cutrona G., Rossi D., Di Raimondo F., Cuneo A., Gaidano G., Polliack A., Trentin L., Foa R., Ferrarini M., Gattei V., and Gentile M.

Subjects
Oncology, Male, chronic B cell leukemia, chronic lymphocytic leukemia, ibrutinib, 4-factor score, prognosis, Datasets as Topic, Severity of Illness Index, chemistry.chemical_compound, Piperidines, Retrospective analysis, Multicenter Studies as Topic, Chronic, Leukemia, Hematology, Middle Aged, Prognosis, Lymphocytic, Progression-Free Survival, Ibrutinib, Female, medicine.medical_specialty, real-word study, Factor score, Antineoplastic Agents, Adenine, Aged, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Proportional Hazards Models, Protein Kinase Inhibitors, Reproducibility of Results, Retrospective Studies, Risk Assessment, Survival Analysis, NO, Internal medicine, Severity of illness, medicine, Progression-free survival, Survival analysis, business.industry, Proportional hazards model, B-Cell, Retrospective cohort study, Settore MED/15 - MALATTIE DEL SANGUE, chemistry, business, chronic lymphocytic leukaemia
Abstract

Not Available

Published
2021

42. Management of chronic lymphocytic leukemia in Italy during a one year of the COVID-19 pandemic and at the start of the vaccination program. A Campus CLL report

Author

Marina Motta, Daniela Gottardi, Vittorio Stefoni, Daniela Pietrasanta, Gianluigi Reda, Lydia Scarfò, Gian Matteo Rigolin, Annalisa Chiarenza, Francesca Maria Quaglia, Maria Chiara Tisi, Alessandro Sanna, Luciano Levato, Robin Foà, Monica Leone, Livio Trentin, Massimo Gentile, Monia Marchetti, Adalberto Ibatici, Enrico Derenzini, Roberta Murru, Antonio Cuneo, Angela Ferrari, Giulia Quaresmini, Francesca Romana Mauro, Annamaria Giordano, Lucia Farina, Myriam Foglietta, Paolo Sportoletti, Lara Malerba, Alessandro Gozzetti, Roberto Marasca, Federico Chiurazzi, Lorenzo De Paoli, Francesca Re, Giovanni Del Poeta, Andrea Ferrario, Marta Coscia, Luca Laurenti, Lorella Orsucci, Marzia Varettoni, Claudia Baratè, Giuseppa Penna, Valter Gattei, Jacopo Olivieri, Cuneo, A., Rigolin, G. M., Coscia, M., Quaresmini, G., Scarfo', L., Mauro, F. R., Motta, M., Quaglia, F. M., Trentin, L., Ferrario, A., Laurenti, L., Reda, G., Ferrari, A., Pietrasanta, D., Sportoletti, P., Re, F., De Paoli, L., Foglietta, M., Giordano, A., Marchetti, M., Farina, L., Del Poeta, G., Varettoni, M., Chiurazzi, F., Marasca, R., Malerba, L., Ibatici, A., Tisi, M. C., Stefoni, V., Leone, M., Barate, C., Olivieri, J., Murru, R., Gentile, M., Sanna, A., Gozzetti, A., Gattei, V., Gottardi, D., Derenzini, E., Levato, L., Orsucci, L., Penna, G., Chiarenza, A., and Foa, R.

Subjects
Male, Cancer Research, 2019-20 coronavirus outbreak, Time Factors, targeted agents, Coronavirus disease 2019 (COVID-19), Chronic lymphocytic leukemia, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), NO, COVID‐19, Pandemic, medicine, Humans, Chronic, chronic lymphocytic leukemia, COVID-19, vaccination, Letter to the Editor, Aged, Leukemia, business.industry, SARS-CoV-2, Vaccination, B-Cell, Disease Management, Hematology, General Medicine, Middle Aged, medicine.disease, Prognosis, Virology, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Settore MED/15 - MALATTIE DEL SANGUE, Oncology, Italy, Female, business
Published
2021

43. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

Author

Tobias Herold, Martin Andres, Gimena Dos Santos, Livio Trentin, Monia Marchetti, Antonio Cuneo, Robin Foà, Vladimir Strugov, Sunil Iyengar, Ozren Jakšić, Mark-David Levin, Angela Ferrari, Francesca Romana Mauro, Candida Vitale, Martin Spacek, Olga Kalashnikova, Eugene Nikitin, Ann Janssens, Constantine S. Tam, Julio Delgado, Maria Papaioannou, Barbara Pocali, Davide Rossi, Marina Motta, Niki Stavroyianni, Myriam Foglietta, Alicia Enrico, Carolina Cuéllar-García, Lara Malerba, Mónica Baile, Lydia Scarfò, Ellen van der Spek, Paolo Sportoletti, Maria Rosaria De Paolis, Mihnea Zdrenghea, Macarena Ortiz Pareja, Annalisa Chiarenza, Sabina Kersting, Fatima Miras, Yair Herishanu, Emili Montserrat, Marta Coscia, Giuseppe Rossi, Jose Angel Hernandez-Rivas, Carsten Utoft Niemann, Alessandro Rambaldi, Amit Shrestha, Roberto Marasca, Rosa Ruchlemer, Marzia Varettoni, Dominique Bron, Juan Marquet, Eva Gimeno, Viola Maria Popov, Massimo Gentile, Mohamed A. Yassin, Kostas Stamatopoulos, Lorenzo De Paoli, Thomas Chatzikonstantinou, Giulia Quaresmini, Luca Laurenti, Lucia Farina, Arnon P. Kater, Nimish Shah, Elisabeth Vandenberghe, José A. García-Marco, Oana Stanca, Giovanni Del Poeta, Martin Simkovic, Yervand K Hakobyan, Enrico Lista, Michael Doubek, Gilad Itchaki, Talha Munir, Paolo Ghia, Ewa Wasik-Szczepanek, Gianluigi Reda, Francesca Maria Quaglia, Maria Dimou, Gábor Barna, Lorella Orsucci, Gian Matteo Rigolin, Scarfo', L., Chatzikonstantinou, T., Rigolin, G. M., Quaresmini, G., Motta, M., Vitale, C., Garcia-Marco, J. A., Hernandez-Rivas, J. A., Miras, F., Baile, M., Marquet, J., Niemann, C. U., Reda, G., Munir, T., Gimeno, E., Marchetti, M., Quaglia, F. M., Varettoni, M., Delgado, J., Iyengar, S., Janssens, A., Marasca, R., Ferrari, A., Cuellar-Garcia, C., Itchaki, G., Spacek, M., De Paoli, L., Laurenti, L., Levin, M. -D., Lista, E., Mauro, F. R., Simkovic, M., Van Der Spek, E., Vandenberghe, E., Trentin, L., Wasik-Szczepanek, E., Ruchlemer, R., Bron, D., De Paolis, M. R., Del Poeta, G., Farina, L., Foglietta, M., Gentile, M., Herishanu, Y., Herold, T., Jaksic, O., Kater, A. P., Kersting, S., Malerba, L., Orsucci, L., Popov, V. M., Sportoletti, P., Yassin, M., Pocali, B., Barna, G., Chiarenza, A., dos Santos, G., Nikitin, E., Andres, M., Dimou, M., Doubek, M., Enrico, A., Hakobyan, Y., Kalashnikova, O., Ortiz Pareja, M., Papaioannou, M., Rossi, D., Shah, N., Shrestha, A., Stanca, O., Stavroyianni, N., Strugov, V., Tam, C., Zdrenghea, M., Coscia, M., Stamatopoulos, K., Rossi, G., Rambaldi, A., Montserrat, E., Foa, R., Cuneo, A., Ghia, P., Experimental Immunology, Clinical Haematology, and CCA - Cancer Treatment and Quality of Life

Subjects
0301 basic medicine, Male, Chronic lymphocytic leukaemia, Cancer Research, Chronic Lymphocytic Leukemia, COVID-19, Chronic lymphocytic leukemia, Comorbidity, Severity of Illness Index, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Obinutuzumab, Surveys and Questionnaires, hemic and lymphatic diseases, 80 and over, Viral, Chronic, 610 Medicine & health, Immunodeficiency, Aged, 80 and over, Leukemia, Mortality rate, Age Factors, Hematology, Middle Aged, Prognosis, Lymphocytic, Oncology, 030220 oncology & carcinogenesis, Infectious diseases, Female, Coronavirus Infections, medicine.drug, Bendamustine, medicine.medical_specialty, Pneumonia, Viral, Antineoplastic Agents, Article, NO, 03 medical and health sciences, Betacoronavirus, Internal medicine, Severity of illness, medicine, Humans, Chronic Lymphocytic Leukemia, Pandemics, Protein Kinase Inhibitors, Aged, Retrospective Studies, SARS-CoV-2, Venetoclax, business.industry, Adenine, B-Cell, COVID-19, Odds ratio, Pneumonia, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Settore MED/15 - MALATTIE DEL SANGUE, 030104 developmental biology, Pyrazoles, Pyrimidines, chemistry, business
Abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Published
2020

44. Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group

Author

Rosa Ruchlemer, Angeles Medina Perez, Ariel Aviv, Alessandra Tedeschi, Sandra Bašić-Kinda, Sarit Assouline, Marta Morawska, Mihnea Zdrenghea, Maria Papaioannou, Gilad Itchaki, Viola Maria Popov, Odit Gutwein, Rosa Collado, Michael Gregor, Horia Bumbea, Inga Mandac, Livio Trentin, Neta Goldschmidt, Paolo Sportoletti, Adir Shaulov, Marta Coscia, Gian Matteo Rigolin, Anatoly Nemets, Francesca Romana Mauro, Róbert Szász, Nagib Dali, Fatima Miras, Massimo Gentile, Shimrit Ringelstein, Martin Simkovic, Martin Spacek, Uri Greenbaum, Aaron Polliack, Lydia Scarfò, Michael Doubek, Riva Fineman, Andrei Braester, Lev Shvidel, M.R. Nijziel, Irma Slavutsky, Tamar Tadmor, Eva Gimeno Vázquez, Yair Herishanu, Juan Marquet, Ozren Jakšić, Shai Levi, Ohad Benjamini, Javier Loscertales, Oana Stanca Ciocan, Paolo Ghia, Luciano Levato, Chava Perry, Maria Dimou, Anne De Meûter, Ewa Wasik-Szczepanek, Luca Laurenti, Osnat Bairey, Herishanu, Y., Shaulov, A., Fineman, R., Basic-Kinda, S., Aviv, A., Wasik-Szczepanek, E., Jaksic, O., Zdrenghea, M., Greenbaum, U., Mandac, I., Simkovic, M., Morawska, M., Benjamini, O., Spacek, M., Nemets, A., Bairey, O., Trentin, L., Ruchlemer, R., Laurenti, L., Stanca Ciocan, O., Doubek, M., Shvidel, L., Dali, N., Miras, F., De Meuter, A., Dimou, M., Mauro, F. R., Coscia, M., Bumbea, H., Szasz, R., Tadmor, T., Gutwein, O., Gentile, M., Scarfo', L., Tedeschi, A., Sportoletti, P., Gimeno Vazquez, E., Marquet, J., Assouline, S., Papaioannou, M., Braester, A., Levato, L., Gregor, M., Rigolin, G. M., Loscertales, J., Medina Perez, A., Nijziel, M. R., Popov, V. M., Collado, R., Slavutsky, I., Itchaki, G., Ringelstein, S., Goldschmidt, N., Perry, C., Levi, S., Polliack, A., and Ghia, P.

Subjects
obinutuzumab, Oncology, Male, chemistry.chemical_compound, 0302 clinical medicine, Obinutuzumab, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Chronic, Humanized, chronic lymphocytic leukemia, obinutuzumab, chlorambucil, Aged, 80 and over, Leukemia, Hematology, Lymphocytic, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Ibrutinib, Female, Aged, Antibodies, Monoclonal, Humanized, Chlorambucil, Chromosomes, Human, Pair 17, Disease-Free Survival, Humans, Retrospective Studies, Tumor Suppressor Protein p53, Chromosome Deletion, Leukemia, Lymphocytic, Chronic, B-Cell, IGHV@, medicine.drug, Human, medicine.medical_specialty, chronic lymphocytic leukemia, chlorambucil, Antibodies, Chromosomes, NO, 03 medical and health sciences, Internal medicine, medicine, Progression-free survival, Survival rate, Venetoclax, business.industry, Pair 17, B-Cell, Clinical trial, Settore MED/15 - MALATTIE DEL SANGUE, chemistry, business, 030215 immunology
Abstract

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Published
2020

45. Venetoclax in CLL patients who progress after B-cell Receptor inhibitor treatment: a retrospective multi-centre Italian experience

Author

Gianluigi Reda, Luana Schiattone, Giovanni Del Poeta, Dimitar G. Efremov, Antonio Cuneo, Marta Coscia, Francesca Morelli, Alfonso Piciocchi, Adalberto Ibatici, Lydia Scarfò, Paolo Sportoletti, Luca Laurenti, Livio Trentin, Luciano Levato, Stefania Ciolli, Idanna Innocenti, Giovanni D'Arena, Gian Matteo Rigolin, Francesco Autore, Robin Foà, Massimo Gentile, Alessandra Tedeschi, Roberta Murru, Francesca Romana Mauro, Annamaria Frustaci, Innocenti, I., Morelli, F., Autore, F., Piciocchi, A., Frustaci, A., Mauro, F. R., Schiattone, L., Trentin, L., Del Poeta, G., Reda, G., Rigolin, G. M., Ibatici, A., Ciolli, S., Coscia, M., Sportoletti, P., Murru, R., Levato, L., Gentile, M., D'Arena, G., Efremov, D. G., Tedeschi, A., Scarfo', L., Cuneo, A., Foa, R., and Laurenti, L.

Subjects
Oncology, Kaplan-Meier Estimate, B-Cell receptor, chronic lymphocytic leukaemia, ibrutinib, idelalisib, venetoclax, Antineoplastic Combined Chemotherapy Protocols, Bridged Bicyclo Compounds, Heterocyclic, Disease Progression, Drug Administration Schedule, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Purines, Pyrazoles, Pyrimidines, Quinazolinones, Receptors, Antigen, B-Cell, Retrospective Studies, Sulfonamides, chemistry.chemical_compound, Piperidines, Receptors, Multi centre, Chronic, Leukemia, Heterocyclic, Hematology, Lymphocytic, Ibrutinib, Antigen, Idelalisib, medicine.medical_specialty, B-cell receptor, NO, Bridged Bicyclo Compounds, chronic lymphocytic leukaemia, venetoclax, ibrutinib, idelalisib, B-Cell receptor, Internal medicine, medicine, Progression-free survival, business.industry, Venetoclax, Adenine, B-Cell, Retrospective cohort study, medicine.disease, Settore MED/15, Settore MED/15 - MALATTIE DEL SANGUE, chemistry, business
Published
2019

46. Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita

Author

Maria Paola Martelli, Modi Safra, Aldo Mele, Daphna Nachmani, Olivier Bluteau, Ke Cheng, Tom Vulliamy, Dietmar Bothmer, Silvia Grisendi, Assaf C. Bester, Jonathan D. Lee, John G. Clohessy, Olga Pozdnyakova, Emanuele Monteleone, Inderjeet Dokal, Lucio Luzzatto, Keisuke Ito, Robert B. Darnell, Brunangelo Falini, Schraga Schwartz, Caitlin A. Mitchell, Alison Guzzetti, Lourdes M. Mendez, Jean Soulier, Yang Zhang, Anne Bothmer, Paolo Sportoletti, Pier Paolo Pandolfi, Nachmani, D., Bothmer, A. H., Grisendi, S., Mele, A., Bothmer, D., Lee, J. D., Monteleone, E., Cheng, K., Zhang, Y., Bester, A. C., Guzzetti, A., Mitchell, C. A., Mendez, L. M., Pozdnyakova, O., Sportoletti, P., Martelli, M. -P., Vulliamy, T. J., Safra, M., Schwartz, S., Luzzatto, L., Bluteau, O., Soulier, J., Darnell, R. B., Falini, B., Dokal, I., Ito, K., Clohessy, J. G., and Pandolfi, P. P.

Subjects
Epigenomics, Male, RNA Processing, Knockout, Messenger, Post-Transcriptional, Biology, Inbred C57BL, Methylation, Article, Germline, Dyskeratosis Congenita, 03 medical and health sciences, Mice, 0302 clinical medicine, Germline mutation, Genetics, medicine, Animals, RNA, Small Nucleolar, RNA, Messenger, Small nucleolar RNA, RNA Processing, Post-Transcriptional, Germ-Line Mutation, Small Nucleolar, 030304 developmental biology, Ribosomal, Mice, Knockout, 0303 health sciences, Gene Expression Profiling, RRNA 2'-O-methylation, Bone marrow failure, RNA, Hematopoietic stem cell, Nuclear Proteins, medicine.disease, Hematopoietic Stem Cells, 3. Good health, Mice, Inbred C57BL, medicine.anatomical_structure, RNA, Ribosomal, Cancer research, Transcriptome, Nucleophosmin, 030217 neurology & neurosurgery, Dyskeratosis congenita
Abstract

RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2'-O-methylation (2'-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2'-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2'-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2'-O-Me can be etiological to human disease.

Published
2019

47. BRAF mutations in hairy-cell leukemia

Author

Pellegrino Musto, Antony B. Holmes, Victoria A. Wells, Livio Trentin, Stefano Pileri, Robin Foà, Gianpietro Semenzato, Claudia Haferlach, Roberta Pacini, Brunangelo Falini, Oliver Elliott, Maria Paola Martelli, Susanne Schnittger, Laura Pasqualucci, Arcangelo Liso, Vladimir Trifonov, Valentina Pettirossi, Raul Rabadan, Gianluca Schiavoni, Wolfgang Kern, Alessandro Pulsoni, Enrico Tiacci, Luca Arcaini, Achille Ambrosetti, Giovanni Pizzolo, Monia Capponi, Torsten Haferlach, Roberta Mannucci, Caterina Patti, Laurent Farinelli, Francesco Forconi, Giorgio Inghirami, Alessandra Pucciarini, Francesco Di Raimondo, Paolo Sportoletti, Barbara Bigerna, Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, and Falini B.

Subjects
Male, Lymphoma, Hairy Cell, genetics/metabolism/pathology, Hypereosinophilic Syndrome, Medicine, Missense mutation, genetics, Extracellular Signal-Regulated MAP Kinases, Exome, Hairy Cell Leukemia Variant, Sanger sequencing, Leukemia, Hairy Cell, Leukemia, Massive parallel sequencing, protein kinase, General Medicine, Middle Aged, MAP Kinase Kinase Kinases, Leukemia, Myeloid, symbols, Female, Sequence Analysis, Mastocytosis, Adult, Proto-Oncogene Proteins B-raf, Lymphoma, B-Cell, Genomics, Article, symbols.namesake, Humans, Adult, Aged, Extracellular Signal-Regulated MAP Kinases, metabolism, Female, Humans, Leukemia, genetics/metabolism/pathology, Lymphoma, B-Cell, genetics/pathology, MAP Kinase Kinase Kinases, metabolism, Male, Middle Aged, Mutation, Proto-Oncogene Proteins B-raf, genetics, Sequence Analysis, DNA, Hairy cell leukemia, Aged, business.industry, genetics/pathology, Sequence Analysis, DNA, medicine.disease, hairy cell leukemia", braf", BRAF MUTATIONS, Myelodysplastic Syndromes, Mutation, Cancer research, business, metabolism
Abstract

BACKGROUND: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. METHODS: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. RESULTS: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

Published
2011

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