162 results on '"Sarah Parisi"'
Search Results
2. A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes
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Sara Mongiorgi, Alessia De Stefano, Stefano Ratti, Valentina Indio, Annalisa Astolfi, Irene Casalin, Andrea Pellagatti, Stefania Paolini, Sarah Parisi, Michele Cavo, Andrea Pession, James A. McCubrey, Pann-Ghill Suh, Lucia Manzoli, Jacqueline Boultwood, Carlo Finelli, Lucio Cocco, and Matilde Y. Follo
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miRNA profiling ,Myelodysplastic syndromes ,BCL2 ,Azacitidine ,Lenalidomide ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.
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- 2023
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3. Donor selection for adoptive immunotherapy with NK cells in AML patients: Comparison between analysis of lytic NK cell clones and phenotypical identification of alloreactive NK cell repertoire
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Raffaella Meazza, Loredana Ruggeri, Fabio Guolo, Paola Minetto, Paolo Canevali, Fabrizio Loiacono, Sara Ciardelli, Alessandra Bo, Silvia Luchetti, Alberto Serio, Letizia Zannoni, Christelle Retière, Natalia Colomar-Carando, Sarah Parisi, Antonio Curti, Roberto M. Lemoli, and Daniela Pende
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natural killer cells (NK cells) ,donor selection ,NK alloreactivity ,killer immunoglobulin-like receptors (KIR) ,human leucocyte antigen (HLA) ,adoptive immunotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Natural killer (NK) cell-based adoptive immunotherapy in leukemia patients is an emerging field of interest based on clinical evidence of efficacy and safety. Elderly acute myeloid leukemia (AML) patients have been successfully treated with NK cells from HLA-haploidentical donors, especially when high amounts of alloreactive NK cells were infused. The aim of this study was comparing two approaches to define the size of alloreactive NK cells in haploidentical donors for AML patients recruited in two clinical trials with the acronym “NK-AML” (NCT03955848), and “MRD-NK”. The standard methodology was based on the frequency of NK cell clones capable of lysing the related patient-derived cells. The alternative approach consisted of the phenotypic identification of freshly derived NK cells expressing, as inhibitory receptors, only the inhibitory KIR(s) specific for the mismatched KIR-Ligand(s) (HLA-C1, HLA-C2, HLA-Bw4). However, in KIR2DS2+ donors and HLA-C1+ patients, the unavailability of reagents staining only the inhibitory counterpart (KIR2DL2/L3) may lead to an underestimated identification of the alloreactive NK cell subset. Conversely, in the case of HLA-C1 mismatch, the alloreactive NK cell subset could be overestimated due to the ability of KIR2DL2/L3 to recognize with low-affinity also HLA-C2. Especially in this context, the additional exclusion of LIR1-expressing cells might be relevant to refine the size of the alloreactive NK cell subset. We could also associate degranulation assays, using as effector cells IL-2 activated donor peripheral blood mononuclear cells (PBMC) or NK cells upon co-culture with the related patient target cells. The donor alloreactive NK cell subset always displayed the highest functional activity, confirming its identification accuracy by flow cytometry. Despite the phenotypic limitations and considering the proposed corrective actions, a good correlation was shown by the comparison of the two investigated approaches. In addition, the characterization of receptor expression on a fraction of NK cell clones revealed expected but also few unexpected patterns. Thus, in most instances, the quantification of phenotypically defined alloreactive NK cells from PBMC can provide data similar to the analysis of lytic clones, with several advantages, such as a shorter time to achieve the results and, perhaps, higher reproducibility/feasibility in many laboratories.
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- 2023
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4. Assessment of liver stiffness measurement and ultrasound findings change during inotuzumab ozogamicin cycles for relapsed or refractory acute lymphoblastic leukemia
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Federico Ravaioli, Giovanni Marconi, Giovanni Martinelli, Elton Dajti, Chiara Sartor, Maria Chiara Abbenante, Luigina Vanessa Alemanni, Jacopo Nanni, Benedetta Rossini, Sarah Parisi, Luigi Colecchia, Gianluca Cristiano, Giovanni Marasco, Amanda Vestito, Stefania Paolini, Francesca Bonifazi, Antonio Curti, Davide Festi, Michele Cavo, Antonio Colecchia, and Cristina Papayannidis
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clinical cancer research ,clinical management ,elastography ,leukemia ,liver stiffness ,risk assessment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno‐occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver‐related complications during clinical trials and real‐life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow‐up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate‐severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver‐related changes, especially with the severity of portal hypertension (PH)‐related complications. Pre‐transplant LSM was higher in patients receiving IO when compared with a control cohort. PH‐related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations.
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- 2022
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5. Long-Term Outcome After Adoptive Immunotherapy With Natural Killer Cells: Alloreactive NK Cell Dose Still Matters
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Sarah Parisi, Loredana Ruggeri, Elisa Dan, Simonetta Rizzi, Barbara Sinigaglia, Darina Ocadlikova, Andrea Bontadini, Valeria Giudice, Elena Urbani, Sara Ciardelli, Chiara Sartor, Gianluca Cristiano, Jacopo Nanni, Letizia Zannoni, Gabriella Chirumbolo, Mario Arpinati, Russell E. Lewis, Francesca Bonifazi, Giovanni Marconi, Giovanni Martinelli, Cristina Papayannidis, Stefania Paolini, Andrea Velardi, Michele Cavo, Roberto M. Lemoli, and Antonio Curti
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acute myeloid leukemia ,natural killer cells ,adoptive immune therapies ,alloreactivity ,cell dose ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Recently, many reports were published supporting the clinical use of adoptively transferred natural killer (NK) cells as a therapeutic tool against cancer, including acute myeloid leukemia (AML). Our group demonstrated promising clinical response using adoptive immunotherapy with donor-derived alloreactive KIR-ligand-mismatched NK cells in AML patients. Moreover, the antileukemic effect was correlated with the dose of infused alloreactive NK cells (“functional NK cell dose”). Herein, we update the results of our previous study on a cohort of adult AML patients (median age at enrollment 64) in first morphological complete remission (CR), not eligible for allogeneic stem cell transplantation. After an extended median follow-up of 55.5 months, 8/16 evaluable patients (50%) are still off-therapy and alive disease-free. Overall survival (OS) and disease-free survival (DFS) are related with the dose of infused alloreactive NK cells (≥2 × 105/kg).
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- 2022
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6. Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival
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Giulia Corradi, Carmen Baldazzi, Darina Očadlíková, Giovanni Marconi, Sarah Parisi, Nicoletta Testoni, Carlo Finelli, Michele Cavo, Antonio Curti, and Marilena Ciciarello
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Mesenchymal stromal cells ,Acute myeloid leukemia ,Myelodysplastic syndrome ,Leukemic microenvironment ,Medicine (General) ,R5-920 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Mesenchymal stromal cells (MSCs) are an essential element of the bone marrow (BM) microenvironment, playing a crucial function in regulating hematopoietic stem cell proliferation and differentiation. Recent findings have outlined a putative role for MSCs in hematological malignancy development. So far, conflicting results have been collected concerning MSC abnormalities in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In particular, a considerable amount of evidence has been accumulated strongly supporting a permissive role of MSCs in malignancy evolution to MDS, while a potentially causative or promoting function performed by MSCs in AML has not yet been fully clarified. Here, we compared MSCs isolated from healthy, MDS, and AML subjects to investigate MSC alterations and to emphasize putative common and/or diverse features. Methods We isolated and expanded MSCs from AML patients (AML-MSCs) and MDS patients (MDS-MSCs), and we analyzed and compared their phenotypic and functional properties with respect to each other and versus healthy donor-derived MSCs (HD-MSCs). Results We found that stable MSC cultures could be easily established from HD and MDS mononuclear BM-derived cells, while a substantial fraction (25%) of AML patients failed to yield MSCs. Nevertheless, isolated MDS-MSCs and AML-MSCs, as well as HD-MSCs, contained the basic features of MSCs. Indeed, they displayed similar surface marker expression and efficient capacity to differentiate versus osteogenic and adipogenic lineage in vitro. We also proved that MDS-MSCs and AML-MSCs, analyzed by fluorescence in-situ hybridization, did not harbor leukemic cell cytogenetic abnormalities. Moreover, MDS-MSCs and AML-MSCs were similar in terms of ability to sustain AML cell viability and immune-regulatory capacity. However, we were also able to detect some differences between AML-MSCs and MDS-MSCs. Indeed, we found that the frequency of rescued MSCs was lower in the AML group than in the HD and MDS groups, suggesting that a reduced number of MSC precursors could inhabit AML BM. Instead, MDS-MSCs showed the lowest proliferative capacity, reflecting some intrinsic and particular defect. Conclusions Overall, our results elucidated that MDS-MSCs and AML-MSCs did not show macroscopic and/or tumor-related defects, but both displayed functional features potentially contributing to favor a leukemia-protective milieu.
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- 2018
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7. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
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Andrea Ghelli Luserna Di Rorà, Neil Beeharry, Enrica Imbrogno, Anna Ferrari, Valentina Robustelli, Simona Righi, Elena Sabattini, Maria Vittoria Verga Falzacappa, Chiara Ronchini, Nicoletta Testoni, Carmen Baldazzi, Cristina Papayannidis, Maria Chiara Abbenante, Giovanni Marconi, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Fontana, Serena De Matteis, Ilaria Iacobucci, Pier Giuseppe Pelicci, Michele Cavo, Timothy J. Yen, and Giovanni Martinelli
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Acute lymphoblastic leukemia ,WEE1 inhibitor ,Chemo-sensitizer agent ,G2/M checkpoint ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Conclusions Our data suggest that WEE1 plays a role in ALL blast’s survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
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- 2018
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8. The clonal evolution of two distinct T315I-positive BCR-ABL1 subclones in a Philadelphia-positive acute lymphoblastic leukemia failing multiple lines of therapy: a case report
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Caterina De Benedittis, Cristina Papayannidis, Claudia Venturi, Maria Chiara Abbenante, Stefania Paolini, Sarah Parisi, Chiara Sartor, Michele Cavo, Giovanni Martinelli, and Simona Soverini
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BCR-ABL1 mutation ,T315I mutation ,Ph+ Acute Lymphoblastic Leukemia ,Resistance ,Case Report ,Relapse ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The treatment of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients who harbor the T315I BCR-ABL1 mutation or who have two or more mutations in the same BCR-ABL1 molecule is particularly challenging since first and second-generation Tyrosine Kinase Inhibitors (TKIs) are ineffective. Ponatinib, blinatumomab, chemotherapy and transplant are the currently available options in these cases. Case presentation We here report the case of a young Ph+ ALL patient who relapsed on front-line dasatinib therapy because of two independent T315I-positive subclones, resulting from different nucleotide substitutions -one of whom never reported previously- and where additional mutant clones outgrew and persisted despite ponatinib, transplant, blinatumomab and conventional chemotherapy. Deep Sequencing (DS) was used to dissect the complexity of BCR-ABL1 kinase domain (KD) mutation status and follow the kinetics of different mutant clones across the sequential therapeutic approaches. Conclusions This case presents several peculiar and remarkable aspects: i) distinct clones may acquire the same amino acid substitution via different nucleotide changes; ii) the T315I mutation may arise also from an ‘act’ to ‘atc’ codon change; iii) the strategy of temporarily replacing TKI therapy with chemo or immunotherapy, in order to remove the selective pressure and deselect aggressive mutant clones, cannot always be expected to be effective; iv) BCR-ABL1-mutated sub-clones may persist at very low levels (undetectable even by Deep Sequencing) for long time and then outcompete BCR-ABL1-unmutated ones becoming dominant even in the absence of any TKI selective pressure.
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- 2017
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9. Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia
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Sarah Parisi, Carlo Finelli, Antonietta Fazio, Alessia De Stefano, Sara Mongiorgi, Stefano Ratti, Alessandra Cappellini, Anna Maria Billi, Lucio Cocco, Matilde Y. Follo, and Lucia Manzoli
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erythropoiesis ,signal transduction ,myelodysplastic syndromes ,β-thalassemia ,inositides ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
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- 2021
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10. The More, The Better: 'Do the Right Thing' For Natural Killer Immunotherapy in Acute Myeloid Leukemia
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Sarah Parisi, Mariangela Lecciso, Darina Ocadlikova, Valentina Salvestrini, Marilena Ciciarello, Dorian Forte, Giulia Corradi, Michele Cavo, and Antonio Curti
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natural killer cells ,acute myeloid leukemia ,immunotherapy ,biomarkers ,cell dose ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Natural killer (NK) cells are circulating CD3− lymphocytes, which express CD56 or CD16 and an array of inhibitory receptors, called killer-immunoglobulin-like receptors (KIRs). Alloreactive KIR-ligand mismatched NK cells crucially mediate the innate immune response and have a well-recognized antitumor activity. Adoptive immunotherapy with alloreactive NK cells determined promising clinical results in terms of response in acute myeloid leukemia (AML) patients and several data demonstrated that response can be influenced by the composition of NK graft. Several data show that there is a correlation between NK alloreactivity and clinical outcome: in a cohort of AML patients who received NK infusion with active disease, more alloreactive NK cell clones were found in the donor repertoire of responders than in non-responders. These findings demonstrate that the frequency of alloreactive NK cell clones influence clinical response in AML patients undergoing NK cell immunotherapy. In this work, we will review the most recent preclinical and clinical data about the impact of alloreactive NK cells features other than frequency of alloreactive clones and cytokine network status on their anti-leukemic activity. A better knowledge of these aspects is critical to maximize the effects of this therapy in AML patients.
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- 2017
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11. Acute Myeloid Leukemia Mutations: Therapeutic Implications
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Cristina Papayannidis, Chiara Sartor, Giovanni Marconi, Maria Chiara Fontana, Jacopo Nanni, Gianluca Cristiano, Sarah Parisi, Stefania Paolini, and Antonio Curti
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acute myeloid leukemia ,mutations ,FLT3 ,IDH1-2 ,resistance ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Acute Myeloid Leukemia (AML) is an extremely heterogeneous group of hematological neoplasms, for which allogeneic stem cell transplantation (HSCT) still represents the only potentially curative option in the majority of cases. However, elderly age and clinically severe comorbidities may often exclude a wide amount of patients from this therapeutic approach, underlying the urgent need for alternative strategies. Thanks to the introduction of advanced high-throughput techniques, light is being shed on the pathogenesis of AML, identifying molecular recurrent mutations as responsible for the onset, as well as progression, of disease. As a consequence, and in parallel, many new compounds, including targeted therapies (FMS-like tyrosine kinase 3 (FLT3) and Isocitrate dehydrogenase 1-2 (IDH1-2) inhibitors), have found a wide room of application in this setting, and are now available in daily practice, or in late phases of clinical development. Moreover, several further innovative molecules are currently under investigation, and promising results for many of them have already been reported. In this review, we will present an update on the most relevant molecular alterations of AML, focusing on the most frequent genomic mutations of the disease, for which compounds have been approved or are still currently under investigation.
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- 2019
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12. Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach
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Alessandro Isidori, Federica Loscocco, Marilena Ciciarello, Giulia Corradi, Mariangela Lecciso, Darina Ocadlikova, Sarah Parisi, Valentina Salvestrini, Sergio Amadori, Giuseppe Visani, and Antonio Curti
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acute myeloid leukemia ,tumor immunity ,immunotherapy ,immunosenescence ,new drugs ,cell therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute myeloid leukemia (AML) is a disease, which mainly affects the elderly population. Unfortunately, the prognosis of patients aged >65 years is dismal, with 1-year overall survival approaching 10% with conventional therapies. The hypothesis of harnessing the immune system against cancer, including leukemia, has been postulated for a long time, and several clinical attempts have been made in this field. In the last years, we increased our knowledge about the interplay between AML and immune cells, but no major improvement has been translated, up to now, from bench to bedside. However, the outstanding results coming from the modern immuno-oncology trials with new drugs have granted a new interest for immunotherapy in AML. Accordingly, the elderly population represents an ideal target, given the low percentage of patients eligible for allogeneic stem cell transplant. With that in mind, in the era of immunotherapy, we consider immunosenescence as the optimal background to start investigating a biology-driven approach to AML therapy in the elderly. By taking into account the physiological age-related changes of immune response, more personalized and tailored use of the new drugs and strategies harnessing the immune system against AML, has the potential to increase their efficacy and impact on clinical outcomes.
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- 2018
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13. P558: ABSOLUTE LYMPHOCYTE COUNT IS AN INDEPENDENT SURVIVAL PREDICTOR COMPARED TO MINIMAL RESIDUAL DISEASE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA TREATED WITH INTENSIVE CHEMOTHERAPY
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Cristiano, Gianluca, primary, Nanni, Jacopo, additional, Zannoni, Letizia, additional, Zingarelli, Federico, additional, Sartor, Chiara, additional, Sarah, Parisi, additional, Paolini, Stefania, additional, Papayannidis, Cristina, additional, Cavo, Michele, additional, and Curti, Antonio, additional
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- 2023
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14. Exploring the rationale for red cell transfusion in myelodysplastic syndrome patients: emerging data and future insights
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Carlo Finelli, Sarah Parisi, and Stefania Paolini
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Iron Overload ,Myelodysplastic Syndromes ,Quality of Life ,Humans ,Anemia ,Prospective Studies ,Hematology ,Erythrocyte Transfusion ,Iron Chelating Agents ,Aged - Abstract
Anemia is often present in mostly elderly patients with myelodysplastic syndromes (MDS), and is associated with a poorer outcome. Although red blood cell (RBC) transfusions are the most immediate treatment, waiting for the response to disease-specific therapy, or in case of non-response, the choice of the optimal transfusion regimen is still controversial.The main objectives of RBC transfusion are the control of anemia-related symptoms and complications and the improvement of functional status and of health-related quality of life (HRQoL). However, RBC transfusions are associated with several negative clinical consequences, mainly adverse transfusion reactions and iron overload, which can be counteracted by iron chelation therapy. Recent few pilot prospective trials have shown a benefit, in terms of HRQoL, of more liberal transfusion regimens, with higher hemoglobin (Hb) targets, compared to conventional restrictive regimens, but these results need confirmation by larger studies.A patient-oriented RBC transfusion therapy in MDS patients must take into account several laboratory (Hb), clinical (age, comorbidities), psychological, family and social factors, and evaluation of HRQoL should become a fundamental parameter in assessing the clinical benefit of therapy. Many questions remain to be clarified, including why some patients report little benefit from transfusions.
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- 2022
15. Figure S1 from Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients
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Roberto M. Lemoli, Andrea Velardi, Michele Cavo, Russell E. Lewis, Francesca Bonifazi, Giuseppe Bandini, Giovanni Martinelli, Cristina Papayannidis, Elena Urbani, Fiorenza Fruet, Valeria Giudice, Mariangela Lecciso, Darina Ocadlikova, Sara Trabanelli, Simonetta Rizzi, Maria Rosa Motta, Elisa Dan, Andrea Bontadini, Sarah Parisi, Loredana Ruggeri, and Antonio Curti
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Figure S1. Hematologic recovery after NK cell infusion in all treated patients.
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- 2023
16. Supplementary Tables S1 and S2 from Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients
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Roberto M. Lemoli, Andrea Velardi, Michele Cavo, Russell E. Lewis, Francesca Bonifazi, Giuseppe Bandini, Giovanni Martinelli, Cristina Papayannidis, Elena Urbani, Fiorenza Fruet, Valeria Giudice, Mariangela Lecciso, Darina Ocadlikova, Sara Trabanelli, Simonetta Rizzi, Maria Rosa Motta, Elisa Dan, Andrea Bontadini, Sarah Parisi, Loredana Ruggeri, and Antonio Curti
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Table S1. Percentage and absolute number of alloreactive NK cells in responders (A) and non-responders (B) Table S2. Description of cell processing results in responders (A) and non-responders (B)
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- 2023
17. Data from Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients
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Roberto M. Lemoli, Andrea Velardi, Michele Cavo, Russell E. Lewis, Francesca Bonifazi, Giuseppe Bandini, Giovanni Martinelli, Cristina Papayannidis, Elena Urbani, Fiorenza Fruet, Valeria Giudice, Mariangela Lecciso, Darina Ocadlikova, Sara Trabanelli, Simonetta Rizzi, Maria Rosa Motta, Elisa Dan, Andrea Bontadini, Sarah Parisi, Loredana Ruggeri, and Antonio Curti
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Purpose: In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy.Experimental Design: Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53–73) received NK cells from haploidentical KIR-ligand–mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion.Results: Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6–68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3–51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively; P = 0.03).Conclusions: Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells. Clin Cancer Res; 22(8); 1914–21. ©2016 AACR.See related commentary by Muntasell and López-Botet, p. 1831
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- 2023
18. supplemental figure legend from Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients
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Roberto M. Lemoli, Andrea Velardi, Michele Cavo, Russell E. Lewis, Francesca Bonifazi, Giuseppe Bandini, Giovanni Martinelli, Cristina Papayannidis, Elena Urbani, Fiorenza Fruet, Valeria Giudice, Mariangela Lecciso, Darina Ocadlikova, Sara Trabanelli, Simonetta Rizzi, Maria Rosa Motta, Elisa Dan, Andrea Bontadini, Sarah Parisi, Loredana Ruggeri, and Antonio Curti
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supplemental figure legend
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- 2023
19. Impact of infectious comorbidity and overall time of hospitalization in total outpatient management of acute myeloid leukemia patients following venetoclax and hypomethylating agents
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Cristina Papayannidis, Jacopo Nanni, Gianluca Cristiano, Giovanni Marconi, Chiara Sartor, Sarah Parisi, Letizia Zannoni, Rashed Saed, Emanuela Ottaviani, Lorenza Bandini, Nicoletta Testoni, Carmen Baldazzi, Vincenza Solli, Paolo Ricci, Chiara Di Giovanni Bezzi, Rania Abd‐alatif, Marta Stanzani, Stefania Paolini, Michele Cavo, and Antonio Curti
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Hospitalization ,Leukemia, Myeloid, Acute ,Sulfonamides ,Antineoplastic Combined Chemotherapy Protocols ,Outpatients ,Humans ,Comorbidity ,Hematology ,General Medicine ,Bridged Bicyclo Compounds, Heterocyclic - Abstract
Venetoclax (VEN) and hypomethylating agent (HMAs) regimens are emerging as the standard of care for unfit for chemotherapy acute myeloid leukemia (AML) patients, but the safety and feasibility of a total outpatient management have not been fully investigated. Fifty-nine AML patients with active disease received VEN and HMAs. Nineteen out of 59 (32.2%) patients received the first cycle as inpatients, whereas 40/59 (67.8%) patients were treated in the outpatient setting. No significant differences were observed with regard to incidence of adverse events (AEs), including tumor lysis syndrome (TLS), and the 30-day and 60-day mortality was comparable. Notably, an infectious prophylaxis inspired to that adopted during intensive chemotherapy resulted in a low infection rate with a reduced bacterial infections incidence in out- versus hospitalized patients (p .0001). The overall time of hospitalization was significantly shorter in patients who received a total outpatient treatment as compared to those who received the first cycle as inpatients (5.9 vs. 39.7 days, p .0001). Despite the adopted differences in treatment management, the efficacy was similar. These data indicate that a total outpatient management of VEN and HMAs is feasible in AML patients without negatively impacting on treatment efficacy and may yield pharmacoeconomic and quality-of-life benefits.
- Published
- 2022
20. An IDO1-related immune gene signature predicts overall survival in acute myeloid leukemia
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Sarah Parisi, Chiara Sartor, Gianluca Cristiano, Antonio Curti, Annalisa Talami, Emanuela Ottaviani, Jayakumar Vadakekolathu, Matteo Olivi, Sarah Wagner, Simone Ragaini, Michele Cavo, Cristina Papayannidis, Giovanni Marconi, Stefania Paolini, Jacopo Nanni, Sergio Rutella, Darina Očadlíková, Giulia Corradi, and Marilena Ciciarello
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Inflammation ,Immune tolerance ,Transcriptome ,Immune system ,Semaphorin ,Interferon ,hemic and lymphatic diseases ,medicine ,Immune Tolerance ,Tumor Microenvironment ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,neoplasms ,Myeloid Neoplasia ,business.industry ,Myeloid leukemia ,Hematology ,Prognosis ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Cancer research ,Bone marrow ,medicine.symptom ,business ,medicine.drug - Abstract
Key Points The semaphorin receptor PLXNC1 is an IDO1-interacting gene and a strong predictor of survival in AML.An IDO1-related immune gene signature, including PLXNC1, predicts survival in AML., Visual Abstract, The contribution of the bone marrow (BM) immune microenvironment to acute myeloid leukemia (AML) development is well-known, but its prognostic significance is still elusive. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is an interferon-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 982 patients with newly diagnosed, nonpromyelocytic AML were retrieved from public datasets and analyzed using established computational pipelines. Targeted transcriptomic profiles of 24 diagnostic BM samples were analyzed using the NanoString’s nCounter platform. BIN1 and IDO1 were inversely correlated and individually predicted overall survival. PLXNC1, a semaphorin receptor involved in inflammation and immune response, was the IDO1-interacting gene retaining the strongest prognostic value. The incorporation of PLXNC1 into the 2-gene IDO1-BIN1 score gave rise to a powerful immune gene signature predicting survival, especially in patients receiving chemotherapy. The top differentially expressed genes between IDO1low and IDO-1high and between PLXNC1low and PLXNC1high cases further improved the prognostic value of IDO1 providing a 7- and 10-gene immune signature, highly predictive of survival and correlating with AML mutational status at diagnosis. Taken together, our data indicate that IDO1 is pivotal for the construction of an immune gene signature predictive of survival in AML patients. Given the emerging role of immunotherapies for AML, our findings support the incorporation of immune biomarkers into current AML classification and prognostication algorithms.
- Published
- 2022
21. Prognostic Factors and Clinical Considerations for Iron Chelation Therapy in Myelodysplastic Syndrome Patients
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Sarah Parisi and Carlo Finelli
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Oncology ,medicine.medical_specialty ,business.industry ,iron chelation therapy ,Hematology ,Iron chelation therapy ,Review ,myelodysplastic syndrome ,Internal medicine ,hemic and lymphatic diseases ,parasitic diseases ,medicine ,hepcidin ,iron overload ,business - Abstract
Iron chelation therapy (ICT) is an important tool in the treatment of transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients. ICT is effective in decreasing iron overload and consequently in limiting its detrimental effects on several organs, such as the heart, liver, and endocrine glands. Besides this effect, ICT also proved to be effective in improving peripheral cytopenia in a significant number of MDS patients, thus further increasing the clinical interest of this therapeutic tool. In the first part of the review, we will analyze the toxic effect of iron overload and its mechanism. Subsequently, we will revise the clinical role of ICT in various subsets of MDS patients (low, intermediate, and high risk MDS, patients who are candidates for allogeneic stem cell transplantation).
- Published
- 2021
22. Inotuzumab ozogamicin and donor lymphocyte infusion is a safe and promising combination in relapsed acute lymphoblastic leukemia after allogeneic stem cell transplant
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Stefania Paolini, Francesco Barbato, Sarah Parisi, Chiara Sartor, Valentina Robustelli, Giovanni Marconi, Nicoletta Testoni, Antonio Curti, Mario Arpinati, Gianluca Cristiano, Michele Cavo, Simona Soverini, Jacopo Nanni, Elisabetta Zappone, Gabriella Chirumbolo, Cristina Papayannidis, Francesca Bonifazi, Carolina Terragna, Alida Dominietto, Papayannidis C., Sartor C., Dominietto A., Zappone E., Arpinati M., Marconi G., Cristiano G., Nanni J., Parisi S., Barbato F., Paolini S., Soverini S., Terragna C., Robustelli V., Testoni N., Chirumbolo G., Curti A., Cavo M., and Bonifazi F.
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Prognosi ,Lymphoblastic Leukemia ,donor lymphocyte infusion ,acute lymphoblastic leukemia ,Donor lymphocyte infusion ,Follow-Up Studie ,Young Adult ,Antineoplastic Agents, Immunological ,Retrospective Studie ,stem cell transplant ,medicine ,Humans ,Inotuzumab Ozogamicin ,Retrospective Studies ,Salvage Therapy ,Inotuzumab ozogamicin ,business.industry ,Hematology ,General Medicine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Combined Modality Therapy ,Survival Rate ,Oncology ,Lymphocyte Transfusion ,Cancer research ,Female ,Neoplasm Recurrence, Local ,Stem cell ,business ,Follow-Up Studies ,Human ,Stem Cell Transplantation ,medicine.drug - Abstract
NA
- Published
- 2021
23. Venetoclax Rapidly and Strongly Enhances the Phospholipase C Response to Azacitidine Therapy in Myelodysplastic Syndromes
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Matilde Y Follo, Alessia De Stefano, Sara Mongiorgi, Irene Casalin, Alessandra Cappellini, Stefano Ratti, Andrea Pellagatti, Miriam Fogli, Michele Cavo, Lucia Manzoli, Lucio Cocco, Jacqueline Boultwood, Sarah Parisi, Stefania Paolini, Antonio Curti, and Carlo Finelli
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. A Chemo-Free Bridge-to-Transplant Strategy with Venetoclax and Azacitidine for NPM1-Mutated Acute Myeloid Leukemia in Molecular Failure
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Chiara Sartor, Lorenzo Brunetti, Ernesta Audisio, Alessandro Cignetti, Letizia Zannoni, Gianluca Cristiano, Jacopo Nanni, Emanuela Ottaviani, Lorenza Bandini, Sarah Parisi, Stefania Paolini, Sofia Sciabolacci, Valeria Cardinali, Cristina Papayannidis, Michele Cavo, Maria Paola Martelli, and Antonio Curti
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
25. Absolute Lymphocyte Count Is an Independent Survival Predictor in Patients with Acute Myeloid Leukemia Treated with Intensive Chemotherapy
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Gianluca Cristiano, Jacopo Nanni, Letizia Zannoni, Federico Zingarelli, Chiara Sartor, Sarah Parisi, Stefania Paolini, Cristina Papayannidis, Michele Cavo, and Antonio Curti
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
26. Author response for 'Baseline CD22 fluorescent intensity correlates with patient outcome after Inotuzumab Ozogamicin treatment'
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null Chiara Sartor, null Mario Arpinati, null Gabriella Chirumbolo, null Luca Dozza, null Gianluca Cristiano, null Jacopo Nanni, null Giovanni Marconi, null Valentina Robustelli, null Ilaria Vigliotta, null Sarah Parisi, null Carolina Terragna, null Nicoletta Testoni, null Stefania Paolini, null Giovanni Martinelli, null Antonio Curti, null Michele Cavo, and null Cristina Papayannidis
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- 2022
27. Baseline cluster of differentiation 22 fluorescent intensity correlates with patient outcome after Inotuzumab Ozogamicin treatment
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Chiara Sartor, Mario Arpinati, Gabriella Chirumbolo, Luca Dozza, Gianluca Cristiano, Jacopo Nanni, Giovanni Marconi, Valentina Robustelli, Ilaria Vigliotta, Sarah Parisi, Carolina Terragna, Nicoletta Testoni, Stefania Paolini, Giovanni Martinelli, Antonio Curti, Michele Cavo, and Cristina Papayannidis
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Cancer Research ,Immunoconjugates ,Treatment Outcome ,Oncology ,Remission Induction ,Humans ,Inotuzumab Ozogamicin ,Hematology ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma - Abstract
Antigen-directed target therapy for B-cell acute lymphoblastic leukemia (B-ALL) is now the standard of care for relapsed/refractory (R/R) disease. A comprehensive determination of the target itself is mandatory to aid physician's choice. We determined baseline Cluster of differentiation 22 (CD22) expression percentage and fluorescent intensity on lymphoblasts of 30 patients with R/R B-ALL treated with anti-CD22 immunoconjugate drug Inotuzumab Ozogamicin (INO) and analyzed the impact of both parameters on patient outcome. Most patients (24/30, 80%) had a high leukemic blast CD22-positivity defined as ≥90%. We did not observe a benefit in terms of complete remission, overall survival (OS) and duration of response (DoR) for patients with CD22 ≥ 90% versus CD22 90%. Concerning CD22-FI quartile analysis we appreciated a trend for superior response rates in higher quartiles (Q
- Published
- 2022
28. Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement
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Jacopo Nanni, Cristina Papayannidis, Antonio Curti, Francesco Barbato, Stefania Paolini, Sarah Parisi, Michele Cavo, Francesca Bonifazi, Mario Arpinati, Gianluca Cristiano, Giovanni Marconi, Chiara Sartor, Cristiano G., Nanni J., Sartor C., Parisi S., Marconi G., Barbato F., Arpinati M., Bonifazi F., Curti A., Cavo M., Paolini S., and Papayannidis C.
- Subjects
Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Fusion Proteins, bcr-abl ,Protein Kinase Inhibitor ,Chromosomal translocation ,Hematopoietic stem cell transplantation ,Philadelphia chromosome ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,chemistry.chemical_compound ,Bone Marrow ,Positron Emission Tomography Computed Tomography ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Imidazole ,Chemotherapy ,Acute leukemia ,business.industry ,Ponatinib ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Treatment Outcome ,chemistry ,Nelarabine ,Pyridazine ,business ,T-cell acute lymphoblastic leukemia ,Human ,medicine.drug - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a rare entity in the adult acute leukemia setting. Translocation (9;22)(q34;q11) and BCR-ABL1 rearrangement are occasionally found in T-ALL and have been reported in no more than 100 cases in the literature (most of which are chronic myeloid leukemia blast crisis). Here, we report the remarkable effectiveness of third-generation tyrosine-kinase inhibitor ponatinib in obtaining hematological and metabolic remission, in a patient with Philadelphia chromosome-positive de novo T-ALL and outcomes of a therapeutic strategy containing chemotherapy intensification, nelarabine, and allogeneic hematopoietic stem cell transplantation.
- Published
- 2021
29. Assessment of liver stiffness measurement and ultrasound findings change during inotuzumab ozogamicin cycles for relapsed or refractory acute lymphoblastic leukemia
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Federico Ravaioli, Giovanni Marconi, Giovanni Martinelli, Elton Dajti, Chiara Sartor, Maria Chiara Abbenante, Luigina Vanessa Alemanni, Jacopo Nanni, Benedetta Rossini, Sarah Parisi, Luigi Colecchia, Gianluca Cristiano, Giovanni Marasco, Amanda Vestito, Stefania Paolini, Francesca Bonifazi, Antonio Curti, Davide Festi, Michele Cavo, Antonio Colecchia, Cristina Papayannidis, Ravaioli F., Marconi G., Martinelli G., Dajti E., Sartor C., Abbenante M.C., Alemanni L.V., Nanni J., Rossini B., Parisi S., Colecchia L., Cristiano G., Marasco G., Vestito A., Paolini S., Bonifazi F., Curti A., Festi D., Cavo M., Colecchia A., and Papayannidis C.
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Adult ,elastography ,Cancer Research ,ultrasound ,clinical cancer research ,clinical management ,leukemia ,liver stiffness ,risk assessment ,Humans ,Inotuzumab Ozogamicin ,Liver ,Prospective Studies ,Antineoplastic Combined Chemotherapy Protocols ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,liver stiffne ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,Radiology, Nuclear Medicine and imaging ,RC254-282 - Abstract
In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno‐occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver‐related complications during clinical trials and real‐life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow‐up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate‐severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver‐related changes, especially with the severity of portal hypertension (PH)‐related complications. Pre‐transplant LSM was higher in patients receiving IO when compared with a control cohort. PH‐related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations.
- Published
- 2021
30. Author response for 'Inotuzumab ozogamicin and donor lymphocyte infusion is a safe and promising combination in relapsed acute lymphoblastic leukemia after allogeneic stem cell transplant'
- Author
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Carolina Terragna, Francesco Barbato, F Bonifazi, Simona Soverini, Jacopo Nanni, Elisabetta Zappone, Sarah Parisi, Mario Arpinati, Gianluca Cristiano, Antonio Curti, Chiara Sartor, Gabriella Chirumbolo, Michele Cavo, Alida Dominietto, Valentina Robustelli, Giovanni Marconi, Cristina Papayannidis, Nicoletta Testoni, and Stefania Paolini
- Subjects
Inotuzumab ozogamicin ,business.industry ,Lymphoblastic Leukemia ,Cancer research ,Medicine ,Stem cell ,business ,Donor lymphocyte infusion ,medicine.drug - Published
- 2021
31. Safety profile and impact on survival of tyrosine kinase inhibitors versus conventional therapy in relapse or refractory FLT3 positive acute myeloid leukemia patients
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Maria Teresa Bochicchio, Michele Cavo, Sarah Parisi, Carmen Baldazzi, Chiara Sartor, Giovanni Martinelli, Jacopo Nanni, Simone Ragaini, Matteo Olivi, Nicoletta Testoni, Stefano De Polo, Antonio Curti, Maddalena Raffini, Maria Chiara Fontana, Cristina Papayannidis, Emanuela Ottaviani, Francesca Bonifazi, Annalisa Talami, Gianluca Cristiano, Stefania Paolini, Mariachiara Abbenante, Giovanni Marconi, Luca Bertamini, Marconi G., De Polo S., Martinelli G., Nanni J., Bertamini L., Talami A., Olivi M., Ragaini S., Abbenante M.C., Sartor C., Ottaviani E., Bochicchio M.T., Parisi S., Fontana M.C., Cristiano G., Raffini M., Baldazzi C., Testoni N., Bonifazi F., Paolini S., Curti A., Cavo M., and Papayannidis C.
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Survival ,Adolescent ,medicine.medical_treatment ,Antineoplastic Agents ,Disease ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,AML ,Internal medicine ,hemic and lymphatic diseases ,Medicine ,Chemotherapy ,Humans ,Adverse effect ,FLT3 ,Protein Kinase Inhibitors ,Aged ,business.industry ,Surrogate endpoint ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Middle Aged ,TKI ,respiratory tract diseases ,Survival Rate ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Mutation ,Quality of Life ,Neoplastic cell ,Female ,Safety ,business ,030215 immunology - Abstract
Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis, and new therapies are a major clinical need. When mutated, FLT3 drives neoplastic cell proliferation. New drugs (i.e., tyrosine kinase inhibitors, TKIs) showed effectiveness in FLT3-AML and promise to change disease history and outcome. We evaluated the benefit conferred by TKIs in terms of survival, burden of complications and surrogate endpoint of quality of life in a retrospective cohort of 49 FLT3 positive, R/R AML patients. Patients who received TKIs were compared to those treated with conventional chemotherapy. Treatment with TKIs conferred a better OS and wea associated with a lower burden and severity of adverse events. Importantly, patients who received TKIs showed reduced time of hospitalization. In conclusion, treatment with TKI in R/R FLT3-AML was related to a better survival, less and milder AEs, and shorter hospitalization.
- Published
- 2020
32. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
- Author
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Simona Righi, Valentina Robustelli, Sarah Parisi, Nicoletta Testoni, Maria Vittoria Verga Falzacappa, Chiara Sartor, Cristina Papayannidis, Maria Chiara Abbenante, Timothy J. Yen, Michele Cavo, Andrea Ghelli Luserna di Rorà, Chiara Ronchini, Serena De Matteis, Pier Giuseppe Pelicci, Enrica Imbrogno, Anna Maria Ferrari, Neil Beeharry, Giovanni Marconi, Maria Chiara Fontana, Giovanni Martinelli, Ilaria Iacobucci, Carmen Baldazzi, Elena Sabattini, Stefania Paolini, Ghelli Luserna Di Rorà, Andrea, Beeharry, Neil, Imbrogno, Enrica, Ferrari, Anna, Robustelli, Valentina, Righi, Simona, Sabattini, Elena, Verga Falzacappa, Maria Vittoria, Ronchini, Chiara, Testoni, Nicoletta, Baldazzi, Carmen, Papayannidis, Cristina, Abbenante, Maria Chiara, Marconi, Giovanni, Paolini, Stefania, Parisi, Sarah, Sartor, Chiara, Fontana, Maria Chiara, De Matteis, Serena, Iacobucci, Ilaria, Pelicci, Pier Giuseppe, Cavo, Michele, Yen, Timothy J, and Martinelli, Giovanni
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,T cell ,Cell Cycle Proteins ,Acute lymphoblastic leukemia ,Peripheral blood mononuclear cell ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Clofarabine ,Molecular Biology ,G2/M checkpoint ,Hematology ,business.industry ,lcsh:RC633-647.5 ,Research ,Ponatinib ,Nuclear Proteins ,lcsh:Diseases of the blood and blood-forming organs ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Protein-Tyrosine Kinases ,Chemo-sensitizer agent ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,WEE1 inhibitor ,business ,Bosutinib ,Tyrosine kinase ,medicine.drug - Abstract
Background Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Conclusions Our data suggest that WEE1 plays a role in ALL blast’s survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL. Electronic supplementary material The online version of this article (10.1186/s13045-018-0641-1) contains supplementary material, which is available to authorized users.
- Published
- 2018
33. Impact of Comorbidities on Prognosis of Elderly Patients with Acute Myeloid Leukemia Who Receive Hypomethylating Agents
- Author
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Sarah Parisi, Chiara Sartor, Renato Fanin, Davide Lazzarotto, Stefania Paolini, Maria Chiara Abbenante, Giovanni Martinelli, Maria Chiara Fontana, Nicoletta Testoni, Michele Cavo, Gianluca Cristiano, Maria Benedetta Giannini, Rania Abd-alatif, Cristina Papayannidis, Anna Candoni, Chiara Di Giovanni Bezzi, Antonio Curti, Carmen Baldazzi, Emanuela Ottaviani, Jacopo Nanni, Giovanni Marconi, Roberta di Nicola, and Lorenza Bandini
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
BACKGROUND: Many efforts have been made in the attempt to address the conundrum question of fitness definition ad prognosis prediction in elderly acute myeloid leukemia (AML) patients. Parametric definitions are expected to give an advantage in patient stratification; however, clinical examination remain de facto pivotal to formulate therapy decisions and frequently the comorbidities are empirically evaluated. METHODS: We conducted a multicenter study collecting baseline comorbidity, laboratory data, CTCAE 4.0.3 adverse events (AE), and outcome of elderly patients (>65 years old) with new onset AML who received hypomethylating agents as 1st line therapy. We tested the impact on prognosis of baseline clinical and biological risk factors. Furthermore, we evaluated a score - acute myeloid leukemia-composite model, AML-CM (Mukherjee et al, 2017) - developed in chemotherapy-eligible patients, that accounts for baseline comorbidities, laboratory parameters, age and cytogenetic-molecular risk. The study was approved by local Ethical Authority (316/2019/Oss/AOUBo). RESULTS: We collected data from 131 consecutive elderly patients who received 1 st line HMAs between January 2008 and January 2021. Patients had a median age of 76 years (IQR 72 -79). Seventy-seven out of 131 patients (58.8%) had de novo AML, 32/131 (32.8%) had secondary AML, and 11/131 (8.4%) had therapy-related AML. Out of 123 evaluable patients, 43 (34.9%) had complex karyotype, 1 (0.8%) inv(16), 59 (48.4) normal karyotype, 18 (14.7%) other alterations; 8/108 patients harbored FLT3 ITD mutation (7.4%, 23 not tested), 12/101 NPM1 mutation (11.9%, 30 not tested). Based on these data, 111 patients were evaluable for ELN2010 risk stratification; 9 over 111 patients (8.1%) were stratified in the low risk, 42/111 (37.8%) in intermediate-1 risk, 17/111(15.3%) in intermediate-2 risk, and 43/111 (38.7%) in high-risk class. As expected, most of the patients had at least one comorbidity. Particularly, baseline arrhythmia was present in 29/130 (22.1%, 1 no data), cardiovascular comorbidity in 20/130 (15.4%, 1 no data), diabetes in 20/131 (15.3%), cerebrovascular comorbidity in 11/131 (8.4%), kidney disease in 15/130 (11.5%, 1 no data), lung chronic disease 19/130 (14.6% 1 no data), hypoalbuminemia in 25/111 patients (22.5%, 20 no data). With a median follow up of 28.2 months, median overall survival (OS) of the entire cohort was 15.8 months (95% C.I. 11.2-19.4). We confirmed that patient who obtained a response (complete remission, partial response, hematological improvement) after 2 months of therapy had the best OS (figure A, median OS of 21 months for responders vs 7.4 months for non-responders, p To test the impact of comorbidities combined with cytogenetic and molecular risk, AML-CM was used. Our results indicate that AML-CM score was able to stratify prognosis in elderly patients receiving frontline HMAs (figure B, median OS in score group 1: 29.7 months, score group 2: 16.5 months, score group 3: 11.2 months, score group 4: 6.6 months, p=.038). The worse prognosis of patients with higher AML-CM score, which includes patients with increased baseline comorbidities, may be explained with a higher incidence of AEs (84.55, 116.01, 131.45, 229.3 events for 100 patients per year for score group 1,2,3, and 4, respectively) and infections (53.80, 55.10, 85.95, 140.13 events for 100 patients per year for score group 1,2,3, and 4, respectively), in patients with higher baseline comorbidities. CONCLUSION: In this study we found that baseline comorbidities, captured by AML-CM score, may define prognosis of elderly patients receiving 1st line HMAs; parametric comorbidity scores may improve our ability to predict outcome and tailor interventions. The impact of comorbidity on OS may be increased with novel and more aggressive therapy. For this reason, specific studies on functional fitness tests and geriatric assessments are highly warranted in patients receiving HMAs plus venetoclax. This work was supported by Bologna AIL. CP and AC shared last authorship. Figure 1 Figure 1. Disclosures Martinelli: Daichii Sankyo: Consultancy; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Cavo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Curti: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2021
34. An Outpatient Management for First Cycle of Venetoclax and Hypomethylating Agents Results in Reduced Infection Rate and Hospitalizations in Acute Myeloid Leukemia Patients
- Author
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Michele Cavo, Emanuela Ottaviani, Rania Abd-alatif, Lorenza Bandini, Jacopo Nanni, Gianluca Cristiano, Paolo Ricci, Nicoletta Testoni, Giovanni Marconi, Carmen Baldazzi, Chiara Di Giovanni Bezzi, Letizia Zannoni, Antonio Curti, Sarah Parisi, Chiara Sartor, Stefania Paolini, Rashed Saed, and Cristina Papayannidis
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medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Infection rate ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,business ,Outpatient management - Abstract
Introduction In the setting of clinical trials Venetoclax (VEN) combined with hypomethylating agents (HMAs) has shown fair activity in Relapsed/Refractory (R/R) AML and impressive results in newly diagnosed (ND) elderly AML patients. However, no clear guidelines are available on real-life management, especially in the outpatient setting. This study involving AML patients treated with VEN combined with HMAs aims to amelioratate physicians' knowledge about the administration of these regimens. Methods This is a single-center retrospective study involving AML patients treated with Venetoclax combined with HMAs. Data were collected in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results A total of 59 AML patients, 43 R/R and 16 ND, have been treated with VEN plus HMAs from March 2018 to June 2021 and completed at least 1 therapy course (range 1-9, median 2, IQR 1.0 - 4.0). The median age was 70 (range 22-88) years and 15.3 % had a documented ECOG score greater than 1. VEN was combined with azacitidine in 35/59 (59.3 %) patients and with decitabine in 22/59 (37.3 %) patients (Table 1: patient and disease characteristics). The majority of patients (40/59, 67.8 %) (28/43 R/R, 12/16 ND) received the first cycle as out-patients, 19 out of 59 (32.2 %) patients were hospitalized and used as control. No significant differences with regards to disease and patients' characteristics were observed between in- and out-patients. During the ramp-up phase only 2 cases of tumor lysis syndrome (TLS) and 5 AEs were documented. During the first course, a total of 54 AEs were recorded and experienced by 16 over 19 hospitalized patients (84.2 %) and 20 over 40 outpatients (50 %). The 30-day and 60-day mortality were 2.5% (1/40) and 20 % (8/40), respectively, among patients receiving first course as out-patents, comparable to those documented in hospitalized patients. Overall, we reported 118 AEs, of which 74 were grade III-IV and the most common were hematological 23/74 (31.1 %) or infective 41/74 (55.4 %). Regarding infections, at least one bacterial infection was experienced in 10/40 (25%) and 12/19 (63.1%) patients of the outpatient and hospitalized cohorts, respectively (p = 0.009, IC 1.37 - 19.74, OR 4.98). Pneumonia and sepsis (13 and 18 cases) were the most frequent infections. Sepsis incidence was higher among hospitalized patients (13/19, 68.4 %, vs 5/40, 12.5 %, p = 0.000029). No significant difference in infective risk was documented between R/R and ND patients (65.1 vs 50 %). Thirty-two out of 59 (54.2 %) patients experienced at least one VEN withdrawal due to treatment toxicity. Twenty out of 43 AEs requiring VEN suspensions occurred during the first cycle. Patients treated in-patient showed the tendency for a higher probability to suspend therapy due to treatment toxicity (10/19 IN vs 10/40 OUT, p = 0.04). While twenty-three out of 59 (38.9 %) patients were hospitalized for treatment complications at least once, the average number of days spent in hospital was significantly different between patients receiving the first course as outpatients as compared to those who were hospitalized (5.9 vs 39.7, respectively, p < 0.0001). With a median follow-up of 117 days (IQR 92 - 173.75) in ND patients the Overall Response Rate (ORR), defined as CR + CRi + HI, was 62.5 % (10/16), with a CR/CRi rate of 50 % (8/16) and a median OS of 247 days (95% C.I. 177.71- 316.58)(Fig 1a). In the R/R setting the ORR rate was 41.8 % (18/43), with a CR/CRi rate of 25.6 % (11/43) and a median OS of 219 days (95% C.I. 91.8 - 346.2) (Fig 2a). No differences in OS were documented between patients who underwent VEN plus HMAs outpatient and patients who underwent the first cycle hospitalized (p = 0,38) (Fig. 1b-2b). Conclusions With the limitations of a single-center retrospective study, our real-life data indicate that VEN plus HMAs is feasible in an outpatient management, with minimal TLS rate and no limiting toxicities. Of note, infections rate was acceptable, bacterial infections and sepsis risk were lower in outpatients than in hospitalized patients. There was no significant impact of the outpatient management on treatment effectiveness, with data in line with published AML cohorts. Further studies evaluating the clinical, social and economic impact of outpatient VEN-based treatments are highly warranted. Figure 1 Figure 1. Disclosures Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Cavo: Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.
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- 2021
35. Role of Mir-192-5p during Response to Azacitidine and Lenalidomide Therapy in Myelodysplastic Syndromes
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Miriam Fogli, Stefano Ratti, Annalisa Astolfi, Sarah Parisi, Jacqueline Boultwood, Matilde Y. Follo, Stefania Paolini, Andrea Pession, Lucio Cocco, Carlo Finelli, Sara Mongiorgi, Lucia Manzoli, Andrea Pellagatti, Valentina Indio, Michele Cavo, and Alessia De Stefano
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Oncology ,Lenalidomide therapy ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
Background and Rationale. miRNAs are small non-coding RNAs that regulate gene expression by acting on the epigenetic machinery and are themselves controlled by epigenetic mechanisms. The expression of miRNAs is linked to cancer development and miRNA profiles are studied as new prognostic factors or therapeutic new perspectives (Jiang X et al. Nat Commun 2016). High-risk MDS are now treated with hypomethylating agents, like Azacitidine (AZA), alone or in combination with other drugs, such as Lenalidomide (LEN). Recent data showed that the concurrent acquisition of specific point mutations on PI3KCD, PLCG2 and AKT3 genes is associated with loss of response to AZA+LEN therapy (Follo MY et al. Leukemia 2019). Inositide signalling regulated by Phospholipase C (PLC) and PI3K/AKT is indeed involved in epigenetic processes and in MDS progression to AML, through the regulation of proliferation, differentiation and apoptosis. Patients and Methods. This study included 26 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21 or 8-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR), any hematologic improvement (HI) or marrow CR+HI following IWG response criteria were considered as responders, while patients showing stable disease or disease progression were considered as non-responders. miRNAs expression was assessed using an Affymetrix miRNA 4.0 array on patients' cells extracted at baseline and during the therapy, at the 4th (T4) and 8th (T8) cycle of therapy. Results were then validated by Real-Time PCR and miRNA targets were studied by dual Luciferase assay. Real-Time PCR was also used to examine the expression of PLC genes. Results. All patients included in this study were considered evaluable for response. According to the revised IWG criteria (14), the overall response rate (ORR) was 76.9% (20/26 cases): CR (5/26, 19.2%), PR (1/26, 3.8%), marrow CR (mCR, 2/26, 7.7%), HI (6/26, 23.1%), mCR+HI (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. For our analyses, we considered 10 patients as responders (R, showing response within T4 and maintaining it at T8), 10 losing response (LR, showing response within T4 and losing it at T8) and 6 non-responders (NR, never showing a response). Paired analysis between R and NR patients showed a statistically significant up-regulation of miR-192-5p and miR-21-5p between T0 and T4, as well as a down-regulation of miR-224-5p between T4 and T8, hinting at a relevant role for these miRNAs during AZA+LEN response. Real-Time PCR analyses confirmed the modulation of miR-192-5p and an altered expression of PLC genes during AZA+LEN therapy in all patients' subgroups, as well as an involvement of BCL-2 (possible target of miR-192-5p) that was also proven in vitro by dual Luciferase assays. Furthermore, as miR-192-5p expression seemed to be correlated with response, we performed Kaplan-Meier analyses and found out an association between high levels of miR-192-5p at T4 and OS (p=0.08) or LFS (p=0.04) in our MDS cases. More interestingly, this correlation was stronger (p=0.03) in R, as compared with LR and NR. Conclusions. This study shows that AZA+LEN therapy in MDS affects the expression of miR-192-5p, whose high level at T4 is associated with higher OS and LFS in responder patients. Moreover, we showed that miR-192-5p specifically targets and inhibits BCL-2, hinting at a regulation of MDS proliferation and apoptosis. Additional studies, to be performed in a larger cohort of MDS patients, are needed to confirm these data, as well as better understand the molecular mechanisms and the prognostic relevance of miR-192-5p in AZA+LEN therapy. Disclosures Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Finelli: Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy; Novartis: Consultancy, Speakers Bureau.
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- 2021
36. Current therapy and new drugs: a road to personalized treatment of myelodysplastic syndromes
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Sarah Parisi, James A. McCubrey, Sara Mongiorgi, Lucia Manzoli, Stefano Ratti, Carlo Finelli, Matilde Y. Follo, Pann-Ghill Suh, and Lucio Cocco
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0301 basic medicine ,Pharmacology ,Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Azacitidine ,Personalized treatment ,Gene mutation ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Drug Discovery ,Genetics ,medicine ,Molecular Medicine ,business ,medicine.drug ,Lenalidomide - Abstract
Introduction: An accurate diagnostic and prognostic evaluation of patients with myelodysplastic syndromes (MDS) is essential: treatments are different for patients at lower or higher risk of evolut...
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- 2017
37. A Three-Gene Immune Signature Including IDO1, BIN1 and PLXNC1 Predicts Survival in Acute Myeloid Leukemia
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Antonio Curti, Matteo Olivi, Sarah Wagner, Darina Ocadlikova, Sarah Parisi, Marilena Ciciarello, Sergio Rutella, Giovanni Marconi, Chiara Sartor, Jayakumar Vadakekolathu, Emanuela Ottaviani, Gianluca Cristiano, Giulia Corradi, Cristina Papayannidis, Annalisa Talami, Stefania Paolini, Michele Cavo, Jacopo Nanni, and Simone Ragaini
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Immune system ,Immunology ,Cancer research ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,Signature (topology) ,Biochemistry ,Gene - Abstract
Introduction A large body of evidence has increasingly demonstrated that the immune tumor microenvironment (TME) critically contributes to acute myeloid leukemia (AML) development. However, current AML prognostic classifications only rely on leukemia cell-intrinsic alterations and do not incorporate immunological markers referring to TME. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is a central mediator of immune tolerance in the AML TME. This study aimed to identify IDO1-interacting genes in the AML TME and to develop a prognostic immune gene signature. Methods Biological and clinical data of 732 patients with de novo AML treated with curative intent were retrieved from public TCGA and HOVON datasets. Patients >= 65 years were excluded from survival analyses. Co-expression analysis was performed through cBioPortal on TCGA data aiming at discovering new IDO1-interacting genes. Cox regression analysis was used to identify most survival-predicting genes in order to generate a prognostic score. Differential expression (DE) analysis was performed using the nSolver software package (NanoString Technologies, Seattle, WA). Results BIN1 and IDO1 expression were negatively correlated in HOVON cases (P Conclusions Our data identify PLXNC1 as a novel IDO1-correlated gene. A three-gene immune signature that includes PLXCN1, IDO1 and BIN1 strongly predicted clinical outcome in large AML cohorts. Moreover, IDO1 and PLXNC1 expression-based DE analysis generated an immunological signature highly predictive of prognosis. In light of the emerging role of immunotherapies for AML, our findings support the incorporation of TME-associated immune biomarkers into current AML classification and prognostication algorithms. Figure Disclosures Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding; Kura Oncology: Research Funding.
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- 2020
38. Sequential Analysis of miRNA Profiling during Azacitidine and Lenalidomide Therapy in Myelodysplastic Syndromes
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Andrea Pellagatti, Lucio Cocco, Andrea Pession, Sarah Parisi, Matilde Y. Follo, Carlo Finelli, Alessia De Stefano, Lucia Manzoli, Valentina Indio, Sara Mongiorgi, Miriam Fogli, Annalisa Astolfi, Stefano Ratti, Michele Cavo, and Jacqueline Boultwood
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Oncology ,Lenalidomide therapy ,medicine.medical_specialty ,education.field_of_study ,Combination therapy ,business.industry ,Myelodysplastic syndromes ,education ,Immunology ,Azacitidine ,Population ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,medicine ,Mirna profiling ,Cancer development ,business ,medicine.drug ,Lenalidomide - Abstract
Background and Rationale. Inositide signalling regulated by Phospholipase C (PLC) and AKT is involved in epigenetic processes and in MDS progression to AML. miRNAs are small non-coding RNAs that regulate gene expression by acting on the epigenetic machinery and are themselves controlled by epigenetic mechanisms. The expression of miRNAs has been definitively linked to cancer development and miRNA profiles are studied as new prognostic factors or therapeutic new perspectives (Jiang X et al. Nat Commun 2016). Azacitidine (AZA) is a standard first-line therapy in high-risk MDS. Its combination with Lenalidomide (LEN) has been tested, but its molecular effect is still under investigation, although the concurrent acquisition of specific point mutations on PI3KCD, PLCG2 and AKT3 genes has recently been associated with loss of response to this combination therapy (Follo MY et al. Leukemia 2019). Here we further analyzed the effect of AZA+LEN therapy on epigenetic processes and inositide regulation, focusing on miRNA expression in MDS patients. Patients and Methods. This study included 12 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR) or any hematologic improvement were considered as responders, while patients showing stable disease or disease progression were considered as non responders. miRNAs expression was assessed using an Affymetrix miRNA 4.0 array on patients' cells extracted at baseline and during the therapy, at the 4th (T4) and 8th (T8) cycle of therapy. Results. All patients included in this study were considered evaluable for response. 2 patients never responded, while 10 patients showed a positive response within T4: 9 of them maintained it at T8, whereas the remaining patient lost response at T8. These clinical results do not mirror the expected clinical outcomes, but this is due to our small population. However, our analyses could be relevant to test the molecular effect of the therapy in a time course, as well as comparing different phases (baseline vs T4; baseline vs T8; T4 vs T8). Paired analysis within the same patients during treatment course showed 61 miRNAs up- or down-regulated (p Conclusions. This preliminary study shows that AZA+LEN therapy affects the expression of specific clusters of miRNAs that target the PI3K signalling and, more specifically, three inositide genes that are mutated and associated with loss of response to this combination therapy, i.e. PI3KCD, AKT3 and PLCG2. Additional studies are warranted to confirm these data and to further analyze the role of these clusters, especially to test their pathogenetic or therapeutic relevance in MDS. Disclosures Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria. Finelli:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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- 2020
39. Venetoclax Plus Hypomethylating Agents for Relapsed/Refractory Acute Myeloid Leukemia (AML) Is Safe and Manageable in the Outpatient Setting
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Cristina Papayannidis, Sarah Parisi, Michele Cavo, Emanuela Ottaviani, Nicoletta Testoni, Chiara Sartor, Chiara Di Giovanni Bezzi, Carmen Baldazzi, Jacopo Nanni, Antonio Curti, Stefania Paolini, L. Baldini, Rania Abd-alatif, Gianluca Cristiano, Paolo Ricci, and Giovanni Marconi
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medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Decitabine ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tumor lysis syndrome ,Clinical trial ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ven ,Medicine ,Population study ,business ,Adverse effect ,medicine.drug - Abstract
JN and CP equally contributed Introduction In the setting of clinical trials Venetoclax (VEN) combined with hypomethylating agents (HMAs) has shown fair activity in R/R AML and impressive results in treatment-naïve elderly AML patients. However, no clear guidelines are available on real-life management, especially in the outpatient setting. This study involving R/R AML patients treated with VEN combined with HMAs aims to amelioratate physicians' knowledge about the administration of these regimens. Methods This is a single-center retrospective study involving AML patients treated with Venetoclax combined with HMAs. Data were collected in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Thirty-one R/R AML patients have been treated with VEN plus HMAs from March 2018 to March 2020 and completed at least 1 therapy course (range 1-9, median 2, IQR 1.0 - 5.0) (Table 1: patients' characteristics). Seventeen out of 31 (54,8 %) had received intensive chemotherapy as induction therapy. Twenty-two patients (71 %) had already received HMAs therapy, of which 14/31 (45,2 %) as first and only previous line of therapy. VEN was combined with azacitidine in 13/31 (41,9%) and with decitabine in 18/31 patients (58.1 %). The majority of patients (22/31, 70,9%) received the first cycle as out-patients, special focus of our analysis. For clinical reasons, only 9 out of 31 (29,1 %) patients were hospitalized and were used as control. In the outpatients setting, VEN dose escalation was managed with at least a weekly laboratory and clinical monitoring and the drug was often increased more slowly to carefully prevent tumor lysis syndrome or other complications. Specifically, there has been a trend toward a ramp-up schedule different from that indicated in clinical trials in the outpatient setting in comparison with hospitalized patients (77,2 % vs 33,3 %). In term of safety, no cases of tumor lysis syndrome (TLS) and only 2 AEs were documented during ramp-up phase, both experienced by hospitalized patients. Seventeen AEs were documented during cycle 1, affecting more frequently hospitalized patients (77,9% vs 31,8 %). In the outpatient setting, the early 30-days and 60-days mortalities were 4,5 % (1/22) and 13,6 % (3/22), respectively, comparable to percentages documented in hospitalized subgroup (0% and 11,1%). Overall, with a median follow-up of 138 days (IQR 69 - 285), we reported 48 AEs, of which 28 were grade III-IV and the most common were hematological (13/28, 48,1 %) or infective (14/28, 51,8 %). Twenty out of 31 (64,5 %) patients reduced VEN dosage during treatment, of which 12/20 (60 %) due to occurring AEs, and remaining patients for azole coadministration. Eleven out of 31 (35,5 %) patients required hospitalization, specifically 3 out of 9 hospitalized patients (33,3 %) during the subsequent outpatient phase of treatment, and 8/22 (36,3 %) patients who underwent VEN therapy outpatient, of which only 2 during the first 28 days of treatment. Twenty-four and 5 AEs were followed by a VEN temporary (median duration 14 days, range 5-120) and permanent withdrawn, respectively. As for the rate of response, the Overall Response Rate (ORR) by VEN plus HMAs therapy in our R/R study population, defined as CR + CRi + HI, was 41,9 % (13/31), with a CR/CRi rate of 22,6 % (7/31). The median time to first response was 67.0 days (IQR 37.0 - 133.5) and the median duration of response was 131.0 days (IQR 89.0 - 151.0). Four out of 31 (12,9 %) patients received subsequent HSCT. The median OS was 285 days (95% C.I. 178 - 392), with no difference in OS between patients who underwent VEN plus HMAs outpatient and patients who underwent the first cycle hospitalized (p = 0,38). Conclusions With the limitations of a single-center retrospective study, our real-life data indicate that VEN plus HMAs is feasible in an outpatient management, without TLS or other limiting toxicities and with comparable early-mortality and toxicity profiles, even in the ramp-up phase and first therapeutic cycle. There was no significant impact of the outpatient management on treatment effectiveness, with data in line with published R/R AML cohorts. Further studies evaluating the clinical, social and economic impact of outpatient VEN-based treatments are highly warranted. Disclosures Papayannidis: Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive:Consultancy, Honoraria. OffLabel Disclosure: In R/R AML, available data regarding the combination of VEN plus HMAs come only from retrospective studies where VEN is administered as an off-label prescription due to its widespread approval for chronic lymphocytic leukemia due to promising results obtained in treatment-naive elderly AML patients
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- 2020
40. Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes
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Pann-Ghill Suh, Marco Gobbi, Jacqueline Boultwood, Matilde Y. Follo, Sara De Fanti, Giovanni Martinelli, Andrea Pellagatti, Sara Mongiorgi, Michele Cavo, Sarah Parisi, Lucio Cocco, Carlo Finelli, Richard N. Armstrong, Maurizio Miglino, Donata Luiselli, Domenico Russo, James A. McCubrey, Maria Teresa Bochicchio, Lucia Manzoli, Stefano Ratti, Follo M.Y., Pellagatti A., Armstrong R.N., Ratti S., Mongiorgi S., De Fanti S., Bochicchio M.T., Russo D., Gobbi M., Miglino M., Parisi S., Martinelli G., Cavo M., Luiselli D., McCubrey J.A., Suh P.-G., Manzoli L., Boultwood J., Finelli C., and Cocco L.
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Azacitidine ,Kaplan-Meier Estimate ,Gene mutation ,Disease cluster ,AKT3 ,Disease-Free Survival ,Article ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Targeted therapies ,Internal medicine ,medicine ,Humans ,MDS, INOSITIDE MUTATIONS, LENALIDOMIDE, AZACITIDINE ,Lenalidomide ,Aged ,Cell Proliferation ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Point mutation ,Cell Differentiation ,Hematology ,Middle Aged ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Mutation ,Female ,business ,Myelodysplastic syndrome ,Inositol ,medicine.drug ,Cell signalling - Abstract
Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan–Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.
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- 2019
41. Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses
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Sarah Parisi, Patrizia Tosi, Andrea Pellagatti, Jacqueline Boultwood, Miriam Fogli, Maria Benedetta Giannini, Barbara Castagnari, Lucio Cocco, Matilde Y. Follo, Anna Candoni, Monica Crugnola, Cristina Clissa, Sara Mongiorgi, Carlo Finelli, Michele Cavo, Domenico Russo, Isabella Capodanno, Giovanna Leonardi, Costanza Bosi, Gian Matteo Rigolin, and Maurizio Miglino
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Long lasting ,Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Long term results ,medicine.disease ,Biochemistry ,stomatognathic diseases ,Multicenter study ,Internal medicine ,medicine ,Mutational status ,business ,Lenalidomide ,medicine.drug - Abstract
Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently or sequentially, has proven effective in Myelodysplastic Syndromes (MDS), however the optimum dose and schedule remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the IWG criteria (Cheson, 2006). Moreover, the aim of this analysisis is to enucleate the clinical and biological features of pts who showed long-lasting (≥ 20 cycles) responses. Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS with IPSS risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles. For responder pts the same treatment was continued until disease progression or unacceptable toxicity. Results. From March 2013, 44 pts (27 males), median age: 72 (48-83 yrs) were enrolled, from 13 hematologic Centers. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-68) cycles; in ARM 1: 9 (1-68) cycles; in ARM 2: 8 (1-63) cycles, respectively. Median follow-up: 15 (2-77) months. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression, and were not considered evaluable for response. Among the 34/44 pts (77.3%) evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. Intention-to-treat (ITT) analysis: ORR: 59.1%. First response was observed after a median of 2 (1-8) cycles. The Best Response achieved was: CR: 8 pts (23.5%) (ITT: 18.1%), PR: 1 pt (2.9%) (ITT: 2.2%), mCR: 3 pts (8.8%) (ITT: 6.8%), HI: 8 pts (23.5%) (ITT: 18.1%), mCR+HI: 6 pts (17.6%) (ITT: 13.6%). Median duration of hematologic response: 10.5 months. 37 pts (84.1%) died , and 20 pts (45.4%) showed progression to AML. Grade >2 non haematological toxicity: 54.5%. Median OS: 15 months. OS was significantly longer in responder pts as compared to the other pts (28 vs 7 months, p2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 33.3%; ARM 2: 56.5%; p=0.2150) and OS (ARM 1: 14 months; ARM 2: 16 months). However, among responder pts, sequential treatment showed a longer clinical benefit, as compared to combined treatment. Responder pts of ARM 2 showed a significantly longer median duration of response (18 vs 6 months, p=0.0481), a longer median duration of therapy (28 vs 10 months, p=0.0870; 20 vs 10 cycles, p=0.1181), more long-lasting (≥ 20 cycles) responses (34.8% vs 9.5%, p=0.1017) and a longer OS (35 vs 26 months, p=0.3868), as compared to responder pts of ARM 1. Overall, 10/44 long-responder pts (22.7%) received ≥ 20 cycles; 5/10 pts (50%) achieved CR. IPSS risk: Intermediate-2 (8 pts); High (2 pts); IPSS-R risk: Intermediate (2 pts); High (6 pts); Very High (2 pts); IPSS cytogenetic risk: Good (5 pts); Intermediate (3 pts); Poor (2 pts); IPSS-R cytogenetic risk: Good (5 pts); Intermediate (4 pts); Very Poor (1 pt); 4/6 patients with altered karyotype achieved cytogenetic remission; it is noteworthy that the only 3 pts of the entire series who showed no gene mutations at baseline are included in this subset of long-responders pts, while 5/10 pts showed at baseline ≥ 1 prognostically unfavorable gene mutations (none with TP53 mutations), with variable VAFs during treatment. Moreover all long-responder pts showed a common gene mutation on SOD2 gene, and mutations on PLCG2 gene. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although sequential treatment was associated with a longer clinical benefit among responder pts. A subset of pts (22,7 %) with less unfavorable cytogenetic and molecular characteristics showed a long-lasting response to treatment. Disclosures Finelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria.
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- 2020
42. Alterations in phosphatidylinositol 3-phosphate (PI3P) pathway and cAMP pathway confirm poor prognosis and reduced overall survival (OS) in a series of 209 acute myeloid leukemia patients
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Mariachiara Abbenante, Mariachiara Fontana, Giovanni Marconi, Giorgia Simonetti, Antonella Padella, Elena Tenti, Eugenia Franchini, Anna Ferrari, Sarah Parisi, Emanuela Ottaviani, Nicoletta Testoni, Viviana Guadagnuolo, Chiara Sartor, Silvia Lo Monaco, Cristina Papayannidis, Giovanni Martinelli, and Mariachiara Abbenante, Mariachiara Fontana, Giovanni Marconi, Giorgia Simonetti, Antonella Padella, Elena Tenti, Eugenia Franchini, Anna Ferrari, Sarah Parisi, Emanuela Ottaviani, Nicoletta Testoni, Viviana Guadagnuolo, Chiara Sartor, Silvia Lo Monaco, Cristina Papayannidis, Giovanni Martinelli
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PI3P, Acute Myeloid Leukemia - Published
- 2017
43. Renewing the immunological approach to AML treatment: from novel pathways to innovative therapies
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Alessandro Isidori, Darina Ocadlikova, Sarah Parisi, Mariangela Lecciso, Giulia Corradi, Giuseppe Visani, Michele Cavo, Margherita Parolini, Dorian Forte, Federica Loscocco, Valentina Salvestrini, Marilena Ciciarello, and Antonio Curti
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Psychotherapist ,Innovative Therapies ,Psychoanalysis ,General Medicine ,Psychology - Published
- 2016
44. ALL-073: Inotuzumab Ozogamicin (IO) and Donor Lymphocyte Infusion (DLI) are a Safe and Promising Combination in Relapsed Acute Lymphoblastic Leukemia (ALL) After Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
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Alida Dominietto, Carolina Terragna, Maria Chiara Abbenante, Jacopo Nanni, Michele Cavo, Simona Soverini, Valentina Robustelli, Giovanni Marconi, Elisabetta Zappone, Giovanni Martinelli, Mario Arpinati, Gianluca Cristiano, Antonio Curti, Francesca Bonifazi, Sarah Parisi, Chiara Sartor, Stefania Paolini, and Cristina Papayannidis
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Inotuzumab ozogamicin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Lymphoblastic Leukemia ,Context (language use) ,Hematology ,Gastroenterology ,Donor lymphocyte infusion ,Oncology ,Internal medicine ,Allogeneic hsct ,Toxicity ,Medicine ,Blinatumomab ,Allogeneic hematopoietic stem cell transplant ,business ,medicine.drug - Abstract
Context Post-HSCT relapse of B-cell ALL is associated with a dismal outcome. IO allows, in the setting of R/R B-ALL patients, high response rates, but with limited duration. Objective To report the outcome of 8 B-ALL adult patients, relapsed after allogeneic HSCT, treated with IO and DLI. Design Retrospective analysis (first patient treated in April 2015, last patient in October 2019). Setting Multicenter (Italian centers). Patients or other participants Five Ph-negative and 3 Ph-positive B-ALL adult patients, with BM disease (6 morphological relapse and 2 MRD-positivity) were treated; 2 patients had additionally extramedullary (EM) disease. Three patients were in salvage 1, 5 patients in salvage ≥ 2; 50% of the patients had previously received Blinatumomab. Median time from transplant to relapse and from relapse to IO was 11 (range 2-21) and 2.5 (range 0-65) months, respectively. Interventions Patients received a median of 3 (range 2-6) IO courses. Four patients received IO and DLI in an alternate schedule and 4 patients sequentially after IO; a median of 3 (range 2-4) DLI at escalating dose was administered (1st dose ranging from 1 × 104/kg CD3+ to 5 × 106/kg CD3+; following doses from 1 × 105 to 5 × 107/kg CD3+). Main outcome measures CR and MRD rate, EM response, DFS, OS, toxicity. MRD was evaluated with BCR-ABL fusion transcript or V(D)J IgH/TCR disease-specific rearrangement on BM. DFS and OS were calculated from start of IO. Toxicity was graded according to CTCAE version. 4.03. Results All patients achieved CR after 1st IO cycle. Six of 8 patients obtained MRD negativity after 2nd IO cycle (4 of 6 patients after 1st cycle). Both PET+ patients achieved PET-negativity. With a median follow-up of 23.5 (range 3-58) months, 6 of 8 (75%) patients are alive. Four of 8 (50%) patients relapsed, of which 2 with CNS localization. Median DFS is 12 months (range 3-58) and median OS is 23.5 (3-58) months. Four out of 8 patients experienced G4 thrombocytopenia. Two patients experienced grade 1 GvHD and no VOD were reported. Conclusions IO and DLI are a safe combination in the post-HSCT setting that may ameliorate the dismal prognosis of this patient subset.
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- 2020
45. Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival
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Nicoletta Testoni, Giulia Corradi, Darina Ocadlikova, Sarah Parisi, Michele Cavo, Carlo Finelli, Giovanni Marconi, Antonio Curti, Marilena Ciciarello, Carmen Baldazzi, Corradi, Giulia, Baldazzi, Carmen, Očadlíková, Darina, Marconi, Giovanni, Parisi, Sarah, Testoni, Nicoletta, Finelli, Carlo, Cavo, Michele, Curti, Antonio, and Ciciarello, Marilena
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Male ,0301 basic medicine ,Cell ,Mesenchymal stromal cells ,Gene Expression ,Medicine (miscellaneous) ,0302 clinical medicine ,hemic and lymphatic diseases ,lcsh:QD415-436 ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,lcsh:R5-920 ,Mesenchymal stromal cell ,Myeloid leukemia ,Cell Differentiation ,Middle Aged ,Hematopoietic stem cell proliferation ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Molecular Medicine ,Female ,Stem cell ,lcsh:Medicine (General) ,Adult ,Risk ,Adolescent ,Cell Survival ,Primary Cell Culture ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,lcsh:Biochemistry ,03 medical and health sciences ,Biomarkers, Tumor ,medicine ,Humans ,Leukemic microenvironment ,Aged ,Cell Proliferation ,Acute myeloid leukemia ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,medicine.disease ,Molecular medicine ,030104 developmental biology ,Case-Control Studies ,Myelodysplastic Syndromes ,Cancer research ,Bone marrow ,Myelodysplastic syndrome ,030215 immunology - Abstract
Background Mesenchymal stromal cells (MSCs) are an essential element of the bone marrow (BM) microenvironment, playing a crucial function in regulating hematopoietic stem cell proliferation and differentiation. Recent findings have outlined a putative role for MSCs in hematological malignancy development. So far, conflicting results have been collected concerning MSC abnormalities in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In particular, a considerable amount of evidence has been accumulated strongly supporting a permissive role of MSCs in malignancy evolution to MDS, while a potentially causative or promoting function performed by MSCs in AML has not yet been fully clarified. Here, we compared MSCs isolated from healthy, MDS, and AML subjects to investigate MSC alterations and to emphasize putative common and/or diverse features. Methods We isolated and expanded MSCs from AML patients (AML-MSCs) and MDS patients (MDS-MSCs), and we analyzed and compared their phenotypic and functional properties with respect to each other and versus healthy donor-derived MSCs (HD-MSCs). Results We found that stable MSC cultures could be easily established from HD and MDS mononuclear BM-derived cells, while a substantial fraction (25%) of AML patients failed to yield MSCs. Nevertheless, isolated MDS-MSCs and AML-MSCs, as well as HD-MSCs, contained the basic features of MSCs. Indeed, they displayed similar surface marker expression and efficient capacity to differentiate versus osteogenic and adipogenic lineage in vitro. We also proved that MDS-MSCs and AML-MSCs, analyzed by fluorescence in-situ hybridization, did not harbor leukemic cell cytogenetic abnormalities. Moreover, MDS-MSCs and AML-MSCs were similar in terms of ability to sustain AML cell viability and immune-regulatory capacity. However, we were also able to detect some differences between AML-MSCs and MDS-MSCs. Indeed, we found that the frequency of rescued MSCs was lower in the AML group than in the HD and MDS groups, suggesting that a reduced number of MSC precursors could inhabit AML BM. Instead, MDS-MSCs showed the lowest proliferative capacity, reflecting some intrinsic and particular defect. Conclusions Overall, our results elucidated that MDS-MSCs and AML-MSCs did not show macroscopic and/or tumor-related defects, but both displayed functional features potentially contributing to favor a leukemia-protective milieu.
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- 2018
46. The Use of Venetoclax for Acute Myeloid Leukemia in a Real-Life Setting: A Multicenter National Experience
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L. Baldini, Pietro Grieco, Antonio Curti, Filippo Gherlinzoni, Sofia Pilerci, Marco Cerrano, Sarah Parisi, Chiara Sartor, Giacomo Gianfaldoni, Matteo Piccini, Stefania Paolini, Michele Cavo, Nicoletta Testoni, Gianluca Cristiano, Mario Boccadoro, Carmen Baldazzi, Giovanni Marconi, Emanuela Ottaviani, Cristina Papayannidis, Alberto Bosi, Jacopo Nanni, and Michele Gottardi
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medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Clinical trial ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Concomitant ,Medicine ,business ,Adverse effect ,Febrile neutropenia - Abstract
Background The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor venetoclax has shown strong activity in R/R AML in controlled clinical trials, and recently impressive results in treatment-naïve AML elderly patients with acute myeloid leukemia. However, limited data are available in the real-life setting. Methods This is a multi-center (n=4), retrospective study involving patients with treatment-naïve or Relapsed/Refractory (R/R) AML treated with Venetoclax in combination with HMAs. Data were collected after anonymous aggregation, in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results Forty-four patients have been prescribed Venetoclax from March 2018 to June 2019 and completed at least 1 course of venetoclax (range 1-8, median 2, IQR 2.0 - 4.0), being evaluable in this analysis. Patients's characteristics are summarized in Table 1. Five/44 (11.4%) patients had a low risk AML, 21/44 (47.7%) had an intermediate risk AML and 14/44 (31.8%) patients had a high risk AML, according to ELN 2017 risk stratification (4 patients had no available ELN risk at baseline). Six out of 44 (13.6%) patients received Venetoclax in combination with HMAs as first line of therapy, whereas 14/44 (31%) as first line rescue for resistant AML, 15/44 (34.1%) at first relapse, 9/44 (20.5%) for second or further R/R AML. Among R/R patients who received Venetoclax, 17/38 (44.7%) and 21/38 (55.2 %) had received chemotherapy or HMAs as induction therapy, respectively. Overall, Venetoclax was combined with azacitidine in 19/44 patients (43.2%), with decitabine in 19/44 patients (43.2%), with Low-dose of Cytarabine in 5/44 (11.4%), and was performed in monotherapy in 1/44 (2.3%) patient. Three out of 44 patients (6.8%) received a maximum dosage of 100 mg daily, 2/44 (4.5%) received 200 mg, 37/44 (84.1%) received 400mg and 2/44 (4.5%) received 600 mg. Fifteen out of 44 (34.1%) patients reduced the dosage of venetoclax for concomitant Azole administration. The median follow-up is 75.5 (IQR 45.2 - 178.5) days for patients who received upfront venetoclax therapy, while 143 (IQR 49.2 - 235.7) days for R/R patients. In the first-line setting, no patients reduced venetoclax dosage for concomitant adverse events; two neutropenia grade IV and two thrombocytopenia grade III have been documented. In the R/R setting, 14/38 (36.6%) patients reduced venetoclax dosage for concomitant adverse events. Specifically, we reported 22 adverse events, of which 10 were grade III-IV (5 neutropenia grade IV, 2 pancytopenia grade IV, 1 neutropenia grade III and 2 febrile neutropenia grade III). The overall CR rate is 16.7 % in newly-onset AML patients and 28.9 % in R/R patients, respectively. Two out of 6 treatment-naive patients had an evaluable response at 2 months after the beginning of Venetoclax treatment, and 2/6 had an evaluable 4-months response: 1 stable disease (SD) and 1 disease progression (PD) at 2 months,1 SD e 1 complete remission (CR )at 4 months. Thirty-one out of 38 R/R patients had an evaluable response at 2 months and 21/38 had an evaluable 4-month response: 10 CR, 1 complete response with incomplete hematologic recovery (CRi), 14 SD and 6 PD at 2 months; 6 CR, 10 SD and 3 PD at 4 months have been documented. After a short follow-up period (75.5 days), no patients who received Venetoclax as upfront therapy underwent an allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, after a longer follow-up period (143 days), 5 out of 38 patients (13.2%) received a HSCT after Venetoclax therapy among R/R patients. Median Overall Survival was not reached in the newly-onset cohort. In R/R setting, median OS was 253 days (95% C.I. 157-349). Interpretation These data extend to the real-life setting some previous evidence obtained from trials. In particular, our data confirm that venetoclax plus HMAs or LDAC has an acceptable toxicity profile and is safe and manageable. However, especially in the R/R setting, hematological toxicity represents the most frequent adverse event, arising some concerns about the optimal drugs management. Although our data suggest a similar clinical activity of venetoclax combinations to that reported in clinical trials, further studies from the real-life setting are highly warranted to confirm venetoclax efficacy under normal clinical practice. GG and JN equally contributed CP and AC equally contributed Disclosures Boccadoro: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Papayannidis:Shire: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Teva: Honoraria. OffLabel Disclosure: Venetoclax is not approved to treat Acute Myeloid Leukemia in Italy
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- 2019
47. AML-CM Score Predicts Prognosis in Hemato-Geriatric Patients with New-Onset Acute Myeloid Leukemia (AML) Who Receive Hypomethylating Agents (HMA)
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Roberta di Nicola, Giovanni Marconi, Gianluca Cristiano, Stefania Paolini, Michele Baccarani, Carmen Baldazzi, Antonio Curti, Sarah Parisi, Lorenza Bandini, Maria Chiara Abbenante, Nicoletta Testoni, Maria Chiara Fontana, Jacopo Nanni, Chiara Sartor, Giovanni Martinelli, Cristina Papayannidis, Emanuela Ottaviani, and Michele Cavo
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medicine.medical_specialty ,education.field_of_study ,Incidence (epidemiology) ,Immunology ,Population ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Comorbidity ,Log-rank test ,symbols.namesake ,Interquartile range ,Internal medicine ,Chi-square test ,medicine ,symbols ,education ,Survival analysis ,Fisher's exact test - Abstract
Background Although much efforts have been made to precisely define fitness of AML patients, in patients who are not candidate to chemotherapy, there is no prognostic model and the respective weight of AML biology and patient fitness are not well established. Here we test AML-CM score (Sorror, JAMA 2018), that is validated in fit population, in a set of old AML patients who received HMAs. Methods We retrospectively collected data of consecutive patients who received HMAs in our institution from 1st Jan 2008 with an age > 65 years at AML diagnosis. AML-CM score was applied to all the patients. Patients were divided in 4 groups (score 1-4: group 1, score 5-6: group 2; score 7-9: group 3, score > 9: group 4) and in 2 macro-groups (score 1-6: group A and score > 6 group B) for the analyses. Descriptive data are presented as median with interquartile ranges (IQR). Adverse events are graded according to CTCAE v4.03. Survival analysis was conducted with Kaplan-Meyer and are presented as 95% confidence intervals (C.I.) and differences in overall survival (OS) were tested with 2-side log rank test. Fisher exact test and Person's chi squared test were used whenever appropriate. Results At data cut-off, 1st Jan 2019, 60 consecutive patients received decitabine or azacytidine as 1st line therapy for AML. Median age of the population was 75.94 years (IQR 72.53-80.38). Most of the patients (37/62, 59.7%) had de novo AML, 19/62 (30.6%) had AML secondary to previous myeloid disorders and 6/62 (9.7%) had AML secondary to chemotherapy or radiotherapy. Most of the patients were smokers (19/33, 57.57%, 29 no data), and few were usual drinkers (4/16, 25.00%, 46 no data). In our set, out of 62 patients, 2 patients (3.2%) had inv(3), 1 (1.6%) a translocation involving 11q23, 1 (1.6%) del(5q), 4 (6.4%) mon(7) or del (7q), 1 (1.6%) del(17p), 15 (24.2%) complex karyotype, 27 (43.5%) normal karyotype, 4 (6.5%) other alterations and 5 were not evaluable; 3/17 (17.65%, 45 no data) harbored IDH2 mutation, 1/16 (6.25%) IDH2 mutation, 2/33 FLT3 mutation (6.06%, 29 no data), 1/24 (4.17%, 38 no data), 2/15 (13.33%, 47 no data) TP53 mutation. According to ELN 2017, 3/62 patients (4.83%) had low risk, 34/62 (54.84%) intermediate risk and 23/62 (37.10%) high risk AML. According to AML-CM score, 13/62 patients (20.97%) were in group A, 20/62 (32.36%) in group B, 21/62 (33.87%) in group C, 6/62 (9.68%) in group D, 2/62 (3.23%) were not allocated for incomplete AML-CM score. There was no difference in term of age, ELN risk, secondary AML prevalence, HMA administered, or response to HMA according to ELN criteria between group 1, 2, 3, 4 or between macro-group A and B. Cardiovascular comorbidity, diabetes mellitus, obesity, previous tumor, hypoalbuminemia, elevated LDH were prevalent in higher risk AML-CM groups (3-4) and in macro-group B. Median OS was 658 days (95% C.I. 316-1000) in group 1, 556 days (95% C.I. 463-649 in group 2, 243 days (95% C.I. 153-353) in group 3, 107 days (95% C.I. 47-167) in group 4 (p=.021, figure 1A). Furthermore, we observed a median OS of 589 days (95% C.I. 328-850) in macro-group A and 219 days (95% C.I. 96-342) in macro-group B (p=.003, figure 1B). Reduced survival was correlated with a non-statistical trend toward augmented incidence of infections and adverse events in higher risk AML-CM groups (3-4). Conclusions AML-CM is a useful indicator of prognosis in old patients that receive HMAs. Prognosis in our set is influenced by comorbidity (measured with AML-CM, a quantitative score) more than by disease biology. We identified a group of patients (macro-group A) that has median OS after HMAs outlying OS reported in literature. This brilliant result can be due to lower comorbidity. AML-CM could help in defining candidate patients for therapy intensification and care utilization or for team comorbidity management. GM and RDN equally contributed Figure 1 Disclosures Martinelli: Roche: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Papayannidis:Pfizer: Honoraria; Teva: Honoraria; Shire: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Incyte: Honoraria. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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- 2019
48. An IDO1-Related 3-Gene Signature Predicts Overall Survival in Intermediate-Risk Acute Myeloid Leukemia
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Simone Ragaini, Marilena Ciciarello, Stefania Paolini, Emanuela Ottaviani, Sarah Wagner, Antonio Curti, Jayakumar Vadakekolathu, Michele Cavo, Sergio Rutella, Matteo Olivi, Darina Očadlíková, Giulia Corradi, Jacopo Nanni, Gianluca Cristiano, Annalisa Talami, Cristina Papayannidis, Sarah Parisi, Chiara Sartor, and Giovanni Marconi
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medicine.medical_specialty ,business.industry ,Mrna expression ,Optimal treatment ,Immunology ,Cell Biology ,Hematology ,Gene signature ,Biochemistry ,Transplantation ,Family medicine ,Overall survival ,Medicine ,Negative correlation ,Intermediate risk ,business ,Patient stratification - Abstract
Introduction: ELN intermediate-risk AML poses considerable challenges to clinicians both in terms of accurate prognostication and optimal treatment. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a central role as a mediator of immune tolerance in AML through the increase of Treg cells. IDO1 activity is negatively regulated by the BIN1 proto-oncogene. Herein, we analyzed the correlation between BIN1 and IDO1 expression in AML, also focusing on IDO1-interacting genes, with the aim to identify a predictive gene signature for OS. Methods: Biological and clinical data of 732 patients with de novo AML were retrieved from public TCGA and HOVON datasets. Since details on chemotherapy regimens were not available in the HOVON dataset, we decided to exclude patients >= 65 years from survival analyses. IDO1-interacting genes were selected through a co-expression analysis performed on TCGA RNA-sequencing data accessed through cBioPortal. The best genes combination predicting overall survival was plotted in a gene expression score. Patients were split in three different groups using score quartiles as cut-off. Results: In the HOVON dataset, IDO1 and BIN1 mRNA expression were negatively correlated (r = -0.40, P Conclusions: Our study shows a negative correlation between IDO1 and BIN1 in AML, suggesting IDO1 inhibition by BIN1, and identifies for the first time PLXNC1, a receptor for semaphorines, as an IDO1-interacting gene potentially implicated in immune response regulation. This finding corroborates the role of IDO1 and its interacting genes in the promotion of a tolerogenic microenvironment in AML. Lastly, our gene expression score predicted OS in intermediate-risk AML patients not undergoing HSCT, a finding which has clinical implications for accurate patient stratification and for clinical decision making, i.e., bridging these patients to transplant. Figure Disclosures Papayannidis: Pfizer: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Shire: Honoraria; Teva: Honoraria. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rutella:MacroGenics, Inc.: Research Funding; NanoString Technologies, Inc.: Research Funding; Kura Oncology: Research Funding.
- Published
- 2019
49. Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia
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Elton Dajti, Luigina Vanessa Alemanni, Maria Chiara Abbenante, Federico Ravaioli, Gianluca Cristiano, Cristina Papayannidis, Stefania Paolini, Sarah Parisi, Giovanni Marasco, Giovanni Martinelli, Amanda Vestito, Chiara Sartor, Michele Cavo, Davide Festi, Francesca Bonifazi, Jacopo Nanni, Antonio Colecchia, Giovanni Marconi, and Antonio Curti
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Inotuzumab ozogamicin ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Refractory ,Liver biopsy ,Acute lymphocytic leukemia ,Internal medicine ,Ascites ,Medicine ,Portal hypertension ,medicine.symptom ,business ,medicine.drug - Abstract
Rationale: Inotuzumab ozagomicin (IO) has been linked to an increased incidence of veno-occlusive disease (VOD) and liver alterations. Most VOD events occurred during hematopoietic stem cell (HSCT) transplantation after IO therapy. We have previously described that the measurement of liver stiffness can anticipate the diagnosis of VOD in the context of HSCT. The mechanisms underlying the increased risk of VOD and liver damage in patients receiving IO are not well understood; in the pathogenesis endothelial damage, ozagomicin release and on-target off-tumor effects may be involved. Here, we aimed to assess the effects of IO on the changes of liver, vascular and biochemistry parameters. Methods: Intensive monitoring of the liver was incorporated into the standard of care of patients who received IO for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL). Upper abdomen ultrasound with Doppler was performed at baseline and at the end of therapy; liver stiffness measurement (LSM) by Fibroscan® (Echosens, Paris, France) at every IO course or at every IO infusion. With the exception of ursodeoxycholic acid, the patients did not receive prophylaxis for VOD. Data was collected after anonymous aggregation, in accordance with GCP and Helsinki declaration. Results are reported as median with interquartile ranges (IQR). Results: At data cut-off, 1st Apr 2019, 16 patient received baseline assessment and at least a post-IO assessment in our monitoring program. In our patent set, median age was 44.5 (IQR 30.7 - 64.0); 12/16 (75 %) patients relapsed after the last treatment and 4/16 (25 %) patients were refractory to the last treatment; patients received a median of 3 (IQR 2 - 3.7) lines before IO; 6/16 (37.5 %) patients undergone HSCT before IO, of which a patient had 1st and 2nd HSCT before IO; 5/16 (31.25 %) undergone HSCT after IO therapy (no patients had second HSCT after IO). Patients received a median of 2 (IQR 2.0 - 3.7) IO administration according to the schedule of the phase 3 trial. The median duration of the therapy was 61.5 days (IQR 43.2 - 114.0) and median progression-free survival in our population was 278.0 days (95% C.I. 264.0 - 292.0). In our patient set, we performed 113 biochemistry determination, 30 liver ultrasounds with Doppler and 116 LSM examination. One patient received a liver biopsy. Among the biochemical exams (AST, ALT, GGT and alkaline phosphatase) only the AST values significantly increased after 1st course of IO (from the median value of 21 U/L to 53 U/L after course 3). Liver ultrasound with Doppler revealed portal hypertension signs in half of the patients during IO monitoring program. Among these patients 7/16 (44%), 3/16 (17%), 5/16 (33.3%) and 3/16 (17%) showed splenomegaly, recanalization of the paraumbilical vein, dilatation of portal vein and ascites, respectively. Median LSM significantly increased from a baseline value of 6 kPa to 7.8 kPa after last post-IO assessment (p-value 7.1 kPa). With a median follow up of 387.5 days (IQR 182.8-524.5) we observed one VOD event (7%); the VOD was graded severe and occurred after HSCT post-IO. Conclusions: Our clinical experience represents the first step to better understand the IO-related liver alterations, as we described the frequency and relevance of quantitative markers. Most of the patients in our set developed ultrasound and/or elastography alteration during IO therapy. Furthermore, these alterations do not seem to correlate with biochemistry. Even if most of the patients had sub-clinical vascular and parenchymal alterations of the liver portal-hypertension related, VOD incidence in our set is comparable with literature. Long-term follow-up results are expected to test whether alterations return or evolve over time. Stratifying the tailored risk liver complications with prospective non-invasive and marker-driven strategies in term of IO dosing and HSCT timing could be a great benefit for patients. * FR and GM contributed to this manuscript equally # AC and CP contributed to this manuscript equally Figure Disclosures Martinelli: Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Papayannidis:Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Shire: Honoraria.
- Published
- 2019
50. New JAK2 heterozygous loss: A role in overall survival in acute myeloid leukemia patients
- Author
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Viviana Guadagnuolo, Maria Chiara Fontana, Cristina Papayannidis, Marco Manfrini, Antonella Padella, Giorgia Simonetti, Anna Ferrari, Giovanni Marconi, Andrea Ghelli Luserna di Rorà, Stefania Paolini, MariaChiara Abbenante, Sarah Parisi, Chiara Sartor, Emanuela Ottaviani, Giovanni Martinelli, and Viviana Guadagnuolo, Maria Chiara Fontana, Cristina Papayannidis, Marco Manfrini, Antonella Padella, Giorgia Simonetti, Anna Ferrari, Giovanni Marconi, Andrea Ghelli Luserna di Rorà, Stefania Paolini, MariaChiara Abbenante, Sarah Parisi, Chiara Sartor, Emanuela Ottaviani, Giovanni Martinelli
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JAK2, Acute Myeloid Leukemia - Published
- 2016
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