Publications by authors named "Sarah Parisi"

31 Publications

Clinical Efficacy of Ponatinib in Philadelphia-Positive T-Cell Acute Lymphoblastic Leukemia with Extramedullary Involvement.

Acta Haematol 2021 Jun 15:1-5. Epub 2021 Jun 15.

Istituto di Ematologia "Seràgnoli" IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.1159/000516003DOI Listing
June 2021

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.

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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http://dx.doi.org/10.3390/ijms22020827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830211PMC
January 2021

Safety profile and impact on survival of tyrosine kinase inhibitors versus conventional therapy in relapse or refractory FLT3 positive acute myeloid leukemia patients.

Leuk Res 2021 02 25;101:106497. Epub 2020 Dec 25.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.leukres.2020.106497DOI Listing
February 2021

The clinical impact of COVID-19 epidemic in the hematologic setting.

Adv Biol Regul 2020 08 16;77:100742. Epub 2020 Jul 16.

Institute of Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy.

The rapid onset and worldwide spread of the COVID-19 epidemic (caused by SARS-CoV-2 coronavirus) has been associated with a profound impact in clinical practice also in the hematologic setting. First of all, given the immunosuppressive effect of many therapies that are normally administered to patients with hematological diseases, with a consequent increased risk of contracting a more severe viral infection, it has been necessary to reconsider in each individual patient the urgency and priority of the treatments foreseen by the normal standards of care. In particular, as regards allogeneic (and to a lesser extent autologous) hematopoietic cell transplantation and CAR T-cell therapy, specific recommendations have been issued by the transplant community on the criteria to be used to decide whether or not to postpone these procedures and on the clinical management of recipients and donors exposed to COVID-19. As to cytotoxic chemotherapy and other antineoplastic therapies, criteria have been proposed to decide, in the various clinical situations, which treatments were not deferrable and which instead could be postponed or replaced by less aggressive therapies. In the outpatient clinics, various organizational solutions for telemedicine have been adopted, resorting to telephone interviews and/or Information Technology, with the aim of reducing the influx of patients while maintaining an adequate control of their clinical condition. The collection of blood by the transfusion centers has been the subject of organizational measures, in order to avoid the transmission of COVID 19 while maintaining a sufficient blood collection for clinical needs. Finally, some hematologic laboratory alterations have been identified, such as thrombocytopenia, lymphopenia and coagulation abnormalities, useful for the prognostic evaluation of infected patients.
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http://dx.doi.org/10.1016/j.jbior.2020.100742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364141PMC
August 2020

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

Eur J Haematol 2020 Jul 7;105(1):47-55. Epub 2020 Apr 7.

Department of Hematology and Oncology, Institute of Hematology L. e A. Seràgnoli, Azienda Ospedaliero-Universitaria S. Orsola Malpighi, Bologna, Italy.

Introduction: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen.

Methods And Patients: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification.

Results: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000).

Conclusion: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.
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http://dx.doi.org/10.1111/ejh.13406DOI Listing
July 2020

Acute Myeloid Leukemia Mutations: Therapeutic Implications.

Int J Mol Sci 2019 Jun 3;20(11). Epub 2019 Jun 3.

Istituto di Ematologia e Oncologia Medica "L. e A. Seràgnoli", S.Orsola-Malpighi Hospital, 40138 Bologna, Italy.

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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http://dx.doi.org/10.3390/ijms20112721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600275PMC
June 2019

Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes.

Leukemia 2019 09 20;33(9):2276-2290. Epub 2019 Feb 20.

Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

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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http://dx.doi.org/10.1038/s41375-019-0416-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733710PMC
September 2019

Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival.

Stem Cell Res Ther 2018 10 25;9(1):271. Epub 2018 Oct 25.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. & A. Seràgnoli", University of Bologna, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi Bologna, Via Massarenti 9, 40138, Bologna, Italy.

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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http://dx.doi.org/10.1186/s13287-018-1013-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202844PMC
October 2018

Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia.

J Hematol Oncol 2018 08 1;11(1):99. Epub 2018 Aug 1.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

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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http://dx.doi.org/10.1186/s13045-018-0641-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090987PMC
August 2018

Immunosenescence and Immunotherapy in Elderly Acute Myeloid Leukemia Patients: Time for a Biology-Driven Approach.

Cancers (Basel) 2018 Jun 22;10(7). Epub 2018 Jun 22.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy.

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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http://dx.doi.org/10.3390/cancers10070211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071222PMC
June 2018

The More, The Better: "Do the Right Thing" For Natural Killer Immunotherapy in Acute Myeloid Leukemia.

Front Immunol 2017 19;8:1330. Epub 2017 Oct 19.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

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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http://dx.doi.org/10.3389/fimmu.2017.01330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653691PMC
October 2017

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.

BMC Cancer 2017 Aug 5;17(1):523. Epub 2017 Aug 5.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Via Massarenti, 9-40138, Bologna, Italy.

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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http://dx.doi.org/10.1186/s12885-017-3511-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545087PMC
August 2017

Efficacy of Azacitidine in the treatment of adult patients aged 65 years or older with AML.

Expert Opin Pharmacother 2016 Dec 21;17(18):2479-2486. Epub 2016 Nov 21.

a Institute of Hematology L. e A. Seràgnoli , Universita degli Studi di Bologna Azienda Ospedaliera Sant\'Orsola-Malpighi Ringgold standard institution , Bologna , Italy.

Introduction: Therapy for acute myeloid leukemia (AML) in elderly populations (>65 years) is still a challenge for scientists and hematologists worldwide, and represents an urgent medical need. Notably, the identification and the recognition of molecular and epigenetic mechanisms involved in the pathogenesis of such a heterogeneous disease, are providing new tools for a more successful and 'targeted' approach. Azacitidine is a hypomethylating agent (HMA) with relevant activity in patients affected by myelodysplastic syndrome (MDS) and AML with low blast cells percentage (>30%), in terms of reduction of transfusion dependence, and improvement of quality of life. Areas covered: This review summarizes the mechanism of action, safety profile and efficacy of azacitidine in the field of elderly AML populations, providing up-to-date references on this subset of high-risk patients. Expert opinion: HMAs are the first successful treatment for elderly patients with high-risk MDS and are effective for some AML subtypes. Translational studies based on gene expression profiling and molecular sequencing, would be able to identify, in the near future, patients with a favorable profile of response to these compounds suggesting new potential treatment combinations also.
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http://dx.doi.org/10.1080/14656566.2016.1258056DOI Listing
December 2016

Novel strategies of adoptive immunotherapy: How natural killer cells may change the treatment of elderly patients with acute myeloblastic leukemia.

Exp Hematol 2017 Jan 5;45:10-16. Epub 2016 Nov 5.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. Electronic address:

Although many attempts have been made to identify novel molecular-targeted therapies for patients with acute myeloid leukemia, their translation into the clinic have had limited impact. In particular, the question of effective and curative treatments for elderly patients, who are not eligible for stem cell transplantation, remains an unmet medical need. To answer this question, a wide range of immunologic therapeutic strategies, mostly T cell based, have been proposed and investigated. At present, however, the clinical results have been largely unsatisfactory. Natural killer cells have recently been used as a means of adoptive immunotherapy with promising clinical results. On the basis of recent clinical reports and moving from the basic immunobiology of natural killer cells, here we discuss some open issues in the clinical translation of natural killer-based adoptive immunotherapy for the management of elderly patients with acute myeloid leukemia.
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http://dx.doi.org/10.1016/j.exphem.2016.10.007DOI Listing
January 2017

Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia.

Oncotarget 2016 Aug;7(33):53377-53391

Institute of Hematology "L. e A. Seragnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A.X protein expression and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). Furthermore, the inhibition of Chk1 changed the cell cycle profile. In order to evaluate the chemo-sensitizer activity of the compound, different cell lines were treated for 24 and 48 hours with prexasertib in combination with other drugs (imatinib, dasatinib and clofarabine). The results from cell line models were strengthened in primary leukemic blasts isolated from peripheral blood of adult acute lymphoblastic leukemia patients. In this study we highlighted the mechanism of action and the effectiveness of prexasertib as single agent or in combination with other conventional drugs like imatinib, dasatinib and clofarabine in the treatment of B-/T-ALL.
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http://dx.doi.org/10.18632/oncotarget.10535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288194PMC
August 2016

Clinical Impact of Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes.

Curr Pharm Des 2016 ;22(16):2349-57

Institute of Hematology "L e A Seràgnoli", S. Orsola-Malpighi Hospital, via Albertoni 15, 40138 Bologna, Italy.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic diseases, mainly affecting the elderly, characterized by unilinear or multilinear peripheral cytopenia, bone marrow ineffective haemopoiesis, and a varying risk of progression to acute myeloid leukemia (AML). On the basis of the prognostic score systems currently used, MDS patients are generally classified as having higher risk (HR) or lower risk (LR) MDS. Two drugs, azacitidine (AZA) and decitabine (DAC), defined, because of their proven mechanism of action, as DNA methyltransferase inhibitors (DNMTIs), or hypomethylating agents (HMAs), have proven effective in improving peripheral cytopenias and quality of life, reducing or eliminating transfusion need, delaying leukemic evolution, and (only for AZA) prolonging overall survival (OS). HMAs are currently the first therapeutic choice for MDS patients who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). HMAs have also been used before and after allo-HSCT, but their role in this setting needs to be confirmed by larger studies. Although data from several clinical and biological studies might help to identify patients with a higher probability to respond to HMAs, to date this treatment should not be denied to any HR MDS patient. Several attempts have been made to combine HMAs with other therapeutic agents, and these results await confirmation by further studies.
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http://dx.doi.org/10.2174/1381612822666160310145040DOI Listing
November 2017

Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients.

Clin Cancer Res 2016 Apr 19;22(8):1914-21. Epub 2016 Jan 19.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, IRCCS Azienda Ospedaliera Universitaria S. Martino-IST, Genoa, Italy.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1604DOI Listing
April 2016

Alloreactive Natural Killer Cells for the Treatment of Acute Myeloid Leukemia: From Stem Cell Transplantation to Adoptive Immunotherapy.

Front Immunol 2015 15;6:479. Epub 2015 Oct 15.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, University of Bologna , Bologna , Italy.

Natural killer (NK) cells express activating and inhibitory receptors, which recognize MHC class-I alleles, termed "Killer cell Immunoglobulin-like Receptors" (KIRs). Preclinical and clinical data from haploidentical T-cell-depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched NK cells play a major role as effectors against acute myeloid leukemia (AML). Outside the transplantation setting, several reports have proven the safety and feasibility of NK cell infusion in AML patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. The aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts at exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against AML. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of AML.
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http://dx.doi.org/10.3389/fimmu.2015.00479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606119PMC
November 2015

Revealing very small FLT3 ITD mutated clones by ultra-deep sequencing analysis has important clinical implications in AML patients.

Oncotarget 2015 Oct;6(31):31284-94

"Seràgnoli" Institute of Hematology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

FLT3 internal tandem duplication (ITD), one of the most frequent mutations in Acute Myeloid Leukemia (AML), is reported to be an unstable marker, as it can evolve from FLT3 ITD- to ITD+ during the disease course. A single-gene sensitive mutational screening approach may be helpful for better clarifying the exact timing of mutation occurrence, especially when FLT3 ITD appears to occur late, at disease progression. We developed an amplicon-based ultra-deep-sequencing (UDS) approach for FLT3 mutational screening. We exploited this highly sensitive technology for the retrospective screening of diagnosis, relapse and follow-up samples of 5 out of 256 cytogenetically normal (CN-) AML who were FLT3 wild-type at presentation, but tested ITD+ at relapse or disease progression. Our study revealed that all patients carried a small ITD+ clone at diagnosis, which was undetectable by routine analysis (0,2-2% abundance). The dynamics of ITD+ clones from diagnosis to disease progression, assessed by UDS, reflected clonal evolution under treatment pressure. UDS appears as a valuable tool for FLT3 mutational screening and for the assessment of minimal residual disease (MRD) during follow-up, by detecting small ITD+ clones that may survive chemotherapy, evolve over time and definitely worsen the prognosis of CN-AML patients.
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http://dx.doi.org/10.18632/oncotarget.5161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741605PMC
October 2015

An increased expression of PI-PLCβ1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes.

J Leukoc Biol 2015 Nov 14;98(5):769-80. Epub 2015 May 14.

*Cellular Signalling Laboratory, Institute of Human Anatomy, Dipartimento di Scienze Biomediche e NeuroMotorie, University of Bologna, Italy; Institute of Hematology "L. e A. Seràgnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy; Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy; Unit of Blood Disease and Stem Cell Transplantation, University of Brescia, Italy; and Hematology Unit, Ospedale Civile di Piacenza, Italy

This study tested the hypothesis that PI-PLCβ1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCβ1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCβ1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCβ1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCβ1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCβ1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.
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http://dx.doi.org/10.1189/jlb.2MA1114-541RDOI Listing
November 2015

The role of the immunosuppressive microenvironment in acute myeloid leukemia development and treatment.

Expert Rev Hematol 2014 Dec 16;7(6):807-18. Epub 2014 Sep 16.

Haematology and Haematopoietic Stem Cell Transplant Center, AORMN Hospital, Via Lombroso, 1, 61122, Pesaro, Italy.

Functional interplay between acute myeloid leukemia (AML) cells and the bone marrow microenvironment is a distinctive characteristic of this hematological cancer. Indeed, a large body of evidence suggests that proliferation, survival and drug resistance of AML are sustained and modulated by the bone marrow immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated. Furthermore, the presence of a number of different immunosuppressive mechanisms results in massive immune deregulation, which causes the eventual escape from natural immune control. Modulating the immune system, as documented by 40 years of stem cell transplantation, may improve survival of AML patients, as the immune system is clearly able to recognize and attack leukemic cells. The understanding of the factors responsible for the escape from immune destruction in AML, which becomes more prominent with disease progression, is necessary for the development of innovative immunotherapeutic treatment modalities in AML.
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http://dx.doi.org/10.1586/17474086.2014.958464DOI Listing
December 2014

The cumulative effect of different childhood trauma types on self-reported symptoms of adult male depression and PTSD, substance abuse and health-related quality of life in a large active-duty military cohort.

J Psychiatr Res 2014 Nov 4;58:46-54. Epub 2014 Aug 4.

VA Center of Excellence for Stress and Mental Health, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA. Electronic address:

History of childhood trauma (CT) is highly prevalent and may lead to long-term consequences on physical and mental health. This study investigated the independent association of CT with symptoms of adult depression and posttraumatic stress disorder (PTSD), mental and physical health-related quality of life (HRQoL), as well as current tobacco consumption and alcohol abuse in a large homogenous cohort of 1254 never-deployed, young male Marines enrolled in the Marine Resiliency Study. Independent effects of CT history, number and type of CT on outcomes were analyzed using hierarchical multivariate logistic regression models. Our results suggested dose-dependent negative effect of an increasing number of trauma types of CT on depression, PTSD and HRQoL. Experience of single CT type demonstrated overall weak effects, while history of multiple CT types distinctively increased the likelihood of adult PTSD symptomology (OR: 3.1, 95% CI: 1.5-6.2), poor mental (OR: 2.3, 95% CI: 1.7-3.1) and physical HRQoL (OR: 1.4, 95% CI: 1.1-1.9). Risk for depression symptoms was similar for both single and multiple CT (OR: 2.2, 95% CI: 1.3-3.8 and OR: 2.1, 95% CI: 1.2-3.5 respectively). CT history had no effects on current tobacco use and alcohol abuse. Our study thus provides evidence for substantial additive effect of different CT types on adult mental and physical health with increasing levels of exposure.
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http://dx.doi.org/10.1016/j.jpsychires.2014.07.014DOI Listing
November 2014

Use of a high sensitive nanofluidic array for the detection of rare copies of BCR-ABL1 transcript in patients with Philadelphia-positive acute lymphoblastic leukemia in complete response.

Leuk Res 2014 May 18;38(5):581-5. Epub 2014 Feb 18.

Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. Electronic address:

Monitoring of minimal residual disease (MRD) by quantification of BCR-ABL1 transcript levels has become a main part of the management of patients with BCR-ABL1-positive acute lymphoblastic leukemia (ALL) in treatment with tyrosine kinase inhibitors (TKIs). The failure to achieve molecular negativity shortly after starting TKI has been demonstrated to be predictive of relapse, suggesting that an accurate measurement of low BCR-ABL1 levels may have a role in preventing hematological relapse. Despite the big efforts made by many European laboratories within the European Study Group, at the time of writing a standardized procedure to quantify and express results is still missing for BCR-ABL1-positive ALL. In this study, in order to detect with high sensitivity low levels of BCR-ABL1 transcripts, we used a new technology and a new molecular approach based on microfluidic digital polymerase chain reaction (dPCR) using Taqman chemistry and we compared obtained results with those generated by the conventional method based on reverse transcriptase PCR reaction (RQ-PCR) for BCR-ABL1 and total ABL1, with TaqMan chemistry and with Applied Biosystems instrument. We demonstrated the dPCR is high-sensitive (able to detect a single copy of BCR-ABL1) and reliable (results are comparable to those obtained by BCR-ABL1 quantification with conventional technology), allowing an accurate monitoring of BCR-ABL1-positive ALL patients in complete remission.
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http://dx.doi.org/10.1016/j.leukres.2014.02.005DOI Listing
May 2014

Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients.

Blood 2011 Sep 25;118(12):3273-9. Epub 2011 Jul 25.

Institute of Hematology, Department of Hematology and Oncological Sciences L. and A. Seràgnoli, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.

Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56(+)CD3(-) natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor-ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 10(6)/Kg. T cells were < 10(5)/Kg. No NK cell-related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799.
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http://dx.doi.org/10.1182/blood-2011-01-329508DOI Listing
September 2011

Complete paraplegia after nelarabine treatment in a T-cell acute lymphoblastic leukemia adult patient.

Am J Hematol 2010 Aug;85(8):608

Institute of Hematology/Oncology "L. and A. Seràgnoli," S.Orsola-Malpighi Hospital, University of Bologna, Italy.

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http://dx.doi.org/10.1002/ajh.21719DOI Listing
August 2010

Functional mobility and postural control in essential tremor.

Arch Phys Med Rehabil 2006 Oct;87(10):1357-64

School of Rehabilitation Therapy, Queen's University, Kingston, ON, Canada.

Objective: To evaluate functional mobility and postural control in participants with essential tremor (ET).

Design: Cross-sectional cohort study.

Setting: Motor performance research laboratory.

Participants: Sixteen participants with ET including head tremor (age, 59.4+/-12.0 y), 14 participants with ET and no head tremor (age, 57.1+/-15.9 y), and 28 healthy controls (age, 58.4+/-12.4 y).

Interventions: Not applicable.

Main Outcome Measures: We assessed the Timed Up & Go, time to ascend and descend stairs, Dynamic Gait Index, and Berg Balance Scale (BBS). Participants completed the Activities-specific Balance Confidence Scale and the Human Activity Profile. We assessed postural control using center-of-pressure measures from force platform recordings of quiet standing in 5 conditions.

Results: Participants with ET including head tremor performed worse than controls on all functional mobility performance and self-report measures (P<.05) except the BBS and stair descent time. Mean performance of ET participants without head tremor was intermediate between the other 2 groups. Sway speed measures of postural control showed similar patterns, but no significant group differences in post hoc analysis. There were no statistically significant or clinically important correlations between measures of tremor status and functional mobility status.

Conclusions: Participants with ET show reduced functional mobility, especially those with head tremor.
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http://dx.doi.org/10.1016/j.apmr.2006.07.255DOI Listing
October 2006
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