Publications by authors named "Stefania Paolini"

84 Publications

Case Report: A Novel Activating FLT3 Mutation in Acute Myeloid Leukemia.

Front Oncol 2021 30;11:728613. Epub 2021 Sep 30.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, studies demonstrated that this novel mutation is sensitive to midostaurin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.728613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514815PMC
September 2021

INCB84344-201: Ponatinib and steroids in frontline therapy of unfit patients with Ph+ acute lymphoblastic leukemia.

Blood Adv 2021 Oct 14. Epub 2021 Oct 14.

Incyte Corporation, Wilmington, Delaware, United States.

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL aged ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/day for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/day from days -14 to 29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) was reached in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of April 24, 2020, median event-free survival was 14.31 months (95% CI 9.30, 22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increased (15.9%), erythema (15.9%), and gamma-glutamyltransferase increased (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%) of patients, respectively. Dose reductions/interruptions/discontinuations due to TEAEs occurred in 43.2%/43.2%/27.3% of patients; 5 patients had fatal TEAEs. Ponatinib and prednisone had efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. (This trial is registered at www.clinicaltrials.gov as NCT01641107).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004821DOI Listing
October 2021

An IDO1-related immune gene signature predicts overall survival in acute myeloid leukemia.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Institute of Hematology, Bologna, Italy.

The contribution of the bone marrow (BM) immune microenvironment (TME) 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 (IFN)-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 732 patients with newly diagnosed, non-promyelocytic 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 PLXNC1 high 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004878DOI Listing
September 2021

Seeking and avoiding contact with Muslims at a Hijab Stall: Evidence for multilayer, multi-determined solidarity, courage, apathy, and moral outrage.

Br J Soc Psychol 2021 Jun 22. Epub 2021 Jun 22.

Department of Experimental Psychology, University of Oxford, UK.

Intergroup contact is key to social cohesion, yet psychological barriers block engagement with diversity even when contact opportunities are abundant. We lack an advanced understanding of contact seeking because intergroup contact is often an independent variable in research, and studies on contact seeking have favoured experimental probing of selected factors or measured only broad behavioural intentions. This research carried out the first ecological tests of a novel multilayer-multivariate framework to contact seeking/avoiding. These tests were centred on a Muslim-led community contact-based initiative with visible support from local authorities following a terrorist attack. Non-Muslim Australian women (N = 1,347) contributed field data on their situated contact motivations, choices, and attendance at an intercultural educational stall; many (N = 559) completed a profiling test battery. Among those who responded to the initiative invite, the rate of taking up the high-salience contact opportunity in this heated setting was high and reflected multiple approach/avoidance motivations. Contact seeking/avoiding was not just allophilia/prejudice; it presented as new typologies of politicized solidarity, courage, apathy, and moral outrage. While intergroup predictors were significant across all profiling analyses, intrapersonal and interpersonal predictors also regularly contributed to explain variance in non-Muslims' contact motivations and choices, confirming their multilayer-multivariate nature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjso.12477DOI Listing
June 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Emotions in Intergroup Contact: Incidental and Integral Emotions' Effects on Interethnic Bias Are Moderated by Emotion Applicability and Subjective Agency.

Front Psychol 2021 28;12:588944. Epub 2021 May 28.

School of Psychology, the University of Newcastle, Callaghan, NSW, Australia.

This research draws from three distinct lines of research on the link between emotions and intergroup bias as springboard to integrative, new hypotheses. Past research suggests that emotions extrinsic to the outgroup (or "incidental"), and intrinsic to the outgroup (or "integral"), produce valence-congruent effects on intergroup bias when relevant or "applicable" to the outgroup (e.g., incidental/integral anger and ethnic outgroups). These emotions produce valence congruent effects when irrelevant or "non-applicable" to the outgroup (e.g., incidental/integral sadness and happiness, and ethnic outgroups). Internally valid and ecologically sound tests of these contrasting effects are missing; hence we examined them experimentally in meaningful settings of interethnic contact. To this end, we hybridized established research paradigms in mood and intergroup contact research; this approach enabled us to use same materials and induction methods to instigate incidental and integral emotions in a single research design. In Experiment 1, White Australian students ( = 93) in real face-to-face contact with an ethnic tutor in their classroom displayed less interethnic bias when incidentally sad (vs. happy) or integrally happy (vs. sad). In Experiment 2, White American males' ( = 492) anti-Arab bias displayed divergent effects under incidental vs. integral (non-applicable) sadness/happiness and similar effects under incidental vs. integral (applicable) anger. The role of perceptions of agency in the emotion-inducing situation is also explored, tested, and explained drawing from mainstream emotion theory. As expected, integral and incidental emotions caused valence congruent effects, at the opposite sides of the subjective agency spectrum, by encouraging the generalization of dislike from the outgroup contact partner to the outgroup as a whole. On the other hand, incidental-non-applicable emotions caused valence-incongruent effects on bias, under high agency conditions, by encouraging (non-partner-centered) heuristic processing. Because of the improved methodology, these effects can be regarded as genuine and not the byproduct of methodological artifacts. This theory-driven and empirically sound analysis of the interplay between emotion source, emotion applicability and subjective agency in intergroup contact can increase the precision of emotion-based bias reduction strategies by deepening understanding of the emotion conditions that lead to intergroup bias attenuation vs. exacerbation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2021.588944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193362PMC
May 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.
View Article and Find Full Text PDF

Download full-text PDF

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

Ceftolozane-Tazobactam Treatment of Hypervirulent Multidrug Resistant Infections in Neutropenic Patients.

Microorganisms 2020 Dec 21;8(12). Epub 2020 Dec 21.

Institute of Hematology "Seràgnoli", IRCCS-Azienda Ospedaliero Policlinico Sant'Orsola-Universitaria di Bologna, 40138 Bologna, Italy.

The effectiveness of ceftolozane/tazobactam for the treatment of infections in neutropenic patients caused by hypervirulent multidrug-resistant (MDR) has not been previously reported. We identified seven cases of MDR infection in neutropenic patients over a four-month period within the same hematology ward. Four cases were associated with rapid progression despite piperacillin-tazobactam or meropenem therapy, and three patients developed sepsis or extensive skin/soft tissue necrosis. In three of the four cases, patients were empirically switched from meropenem to ceftolozane/avibactam before carbapenem susceptibility test results were available, and all four patients underwent extensive surgical debridement or amputation of affected tissues and survived. Further investigation revealed a common bathroom source of MDR clonal subtypes ST175 and ST235 that harbored genes for type III secretion system expression and elaboration of ExoU or ExoS exotoxin. We conclude that ceftolozane/tazobactam plus early source control was critical for control of rapidly progressing skin and soft infection in these neutropenic patients caused by highly virulent ST175 and ST235 clones of MDR .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8122055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767535PMC
December 2020

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Blood 2021 02;137(6):751-762

Notable Labs, Foster City, CA.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885824PMC
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13406DOI Listing
July 2020

A Western Case of Intravascular Large B-Cell Lymphoma as Unusual Cause of Persistent Fever.

Case Rep Hematol 2019 16;2019:1480710. Epub 2019 Nov 16.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Fever of unknown origin (FUO) is a common and challenging clinical condition that can be referred, among others, to infections, drug's effects, various inflammatory disorders, and cancers. Among the latter, lymphomas can indeed cause fever, which is therefore accounted as a lymphoma-related sign in patients' staging. Intravascular large B-cell lymphoma (IVLBCL) is a very rare tumor, characterized by lymphoma cell accumulation within sinusoids and, despite a very aggressive course, the evidence of this disease is scarce. Two variants are currently recognized, respectively, occurring in either Western (mainly characterized by neurological symptoms and skin involvement) or Eastern countries (with hemophagocytic syndrome, bone marrow, spleen, and liver involvement). We describe an atypical and unprecedented IVLBCL patient, presenting with pronounced features of Eastern cases as well as skin involvement. Due to the scant amount of neoplastic cells, the diagnosis was very challenging, with FUO being the first and for a certain time unique clinical sign. Although lymphoma was suspected, the lack of evidence for neoplastic cells delayed the final diagnosis. Eventually, only autopsy revealed the extensive involvement of different organs and tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/1480710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881760PMC
November 2019

Synergism Through WEE1 and CHK1 Inhibition in Acute Lymphoblastic Leukemia.

Cancers (Basel) 2019 Oct 25;11(11). Epub 2019 Oct 25.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Introduction: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia.

Methods: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays.

Results: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson = 0.5770, = 0.0001) and relapse (Pearson = 0.8919; = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells.

Conclusion: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11111654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895917PMC
October 2019

Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML.

N Engl J Med 2019 10;381(18):1728-1740

From the Abramson Cancer Center, University of Pennsylvania (A.E.P.), and Thomas Jefferson University (M.K.) - both in Philadelphia; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Meldola (G.M.), L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna (S.P.), Ospedali Riuniti Villa Sofia-Cervello, Palermo (F.F.), and IRCCS San Raffaele Scientific Institute, Milan (F.C.) - all in Italy; University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Universitätsklinikum Giessen und Marburg, Marburg, Germany (A.N.); Memorial Sloan Kettering Cancer Center, New York (E. Berman); Hospital Universitari i Politècnic La Fe, Valencia, and Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto Carlos III, Madrid - both in Spain (P.M.); University of Maryland Greenebaum Comprehensive Cancer Center (M.R.B.) and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (M.J.L.) - both in Baltimore; University of Chicago, Chicago (R.A.L.), and Astellas Pharma, Northbrook (C.L., N. Hasabou, X.L., E. Bahceci) - both in Illinois; University of Minnesota, Minneapolis (C.U.); University of Alabama at Birmingham, Birmingham (H.P.E., A.D.S.); Hollings Cancer Center, Medical University of South Carolina, Charleston (R.S.); University of California, San Francisco, San Francisco (R.O.); National Taiwan University, Taipei City, Taiwan (W.-C.C.); Yale University School of Medicine, New Haven, CT (N.P.); Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France (C.R.); Sendai Medical Center, National Hospital Organization, Sendai (H.Y.), and University of Fukui, Fukui (N. Hosono) - both in Japan; Seoul National University (S.-S.Y.) and Asan Medical Center, University of Ulsan College of Medicine (J.-H.L.) - both in Seoul, South Korea; Wake Forest Baptist Medical Center, Winston-Salem, NC (T.P.); and Massachusetts General Hospital, Harvard Medical School, Boston (A.T.F.).

Background: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene () infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory -mutated AML.

Methods: In a phase 3 trial, we randomly assigned adults with relapsed or refractory -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.

Results: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

Conclusions: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1902688DOI Listing
October 2019

Saprochaete clavata infections in patients undergoing treatment for haematological malignancies: A report of a monocentric outbreak and review of the literature.

Mycoses 2019 Dec 21;62(12):1100-1107. Epub 2019 Oct 21.

Unit of Infectious Diseases, Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Saprochaete clavata is a rare cause of fungaemia with deep organ involvement in patients with haematological malignancies with reported mortality rates of 60%-80%. We describe four cases of S clavata infection in a haematology unit over several months that were treated with voriconazole-based regimens. We also review the literature on factors that could contribute to earlier recognition and effective treatment of S clavata. We included all cases of culture-positive S clavata from sterile sites with associated signs of infection in patients undergoing treatment for a haematological malignancy. Isolates were identified by MALDI-TOF MS, and spectrum profiles were used to prepare clustering analysis of isolates. Susceptibility testing was performed using a commercial microtitre methods. Saprochaete clavata was isolated from the bloodstream in three cases and bronchial alveolar lavage (BAL) fluid in one case. Clustering analysis suggested strains of S clavata were clonal without evidence of divergence although a common source was not identified. Susceptibility testing yielded elevated MICs to fluconazole (8 mg/L) and echinocandins (>1-8 mg/L). All patients were treated with voriconazole-based regimens resulting in survival of 3/4 patients, who continued chemotherapy for their underlying malignancy without evidence of relapse. Saprochaete clavata is a rare but aggressive cause of breakthrough yeast infection in patients undergoing treatment for haematological malignancies, particularly patients with a prior history of echinocandin treatment. Timely initiation of appropriate treatment, aided by more rapid identification in microbiology laboratory, can reduce the risk of deep organ dissemination and patient death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/myc.12978DOI Listing
December 2019

Phase II trial with sequential clofarabine and cyclophosphamide for refractory and relapsed philadelphia-negative adult acute lymphoblastic leukemia. Results of the GIMEMA LAL 1610 protocol.

Leuk Lymphoma 2019 12 12;60(14):3482-3492. Epub 2019 Jul 12.

Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Università "Sapienza" Roma, Italy.

Clofarabine (CLO) and cyclophosphamide (CY) combinations were tested in late stage refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) with disappointing results and high-grade toxicity. We designed a sequential 5-day combination of CLO 40 mg/m/d plus CY 400 mg/m/d as first salvage for Philadelphia-negative ALL patients refractory or relapsed until 24 months from complete remission (CR). Primary endpoint was an overall response rate (ORR) ≥ 40%. Among 26 study patients (median age 40.5 years) ORR was 57.6% (CR with complete [ = 8] or incomplete [ = 7] hematologic recovery). Despite severe myelotoxicity, no dose-limiting toxicity suggested de-intensification of CLO schedule. With a median follow-up of 17.0 months, median and 1-year overall and disease-free survival were 6.5 months and 28.6%, and 3.7 months and 28.1%, respectively. This association was tolerable and more effective in patients younger than 40 years with B-precursor ALL, longer first CR, not previously transplanted and achieving CR with full hematological recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1639170DOI Listing
December 2019

Mediating Effects of the 'eCoFit' Physical Activity Intervention for Adults at Risk of, or Diagnosed with, Type 2 Diabetes.

Int J Behav Med 2019 Oct;26(5):512-521

Priority Research Centre for Physical Activity and Nutrition, Advanced Technology Center, The University of Newcastle, Level 3, University Drive, Callaghan, NSW, 2308, Australia.

Background: The study aim was to examine the mechanisms of physical activity behaviour change in the multi-component eCoFit randomised controlled trial (RCT) among adults diagnosed with, or at risk of, T2D.

Method: The RCT included two phases: phase 1 (weeks 1-10) integrated group sessions (outdoor physical activity and cognitive mentoring) and the use of the eCoFit smartphone application (app), and phase 2 (weeks 11-20), which included the use of the eCoFit smartphone application only. Participants (n = 84) were assessed at baseline and 10 and 20 weeks from baseline. Physical activity was assessed using pedometers, and the following mediators were tested: action self-efficacy, barrier self-efficacy, recovery self-efficacy, implementation intentions, intention to have regular physical activity, outcome expectations, risk perception and implicit associations related to physical activity. The PROCESS INDIRECT Macro was used to perform mediation analyses.

Results: Significant mediation pathways were found for implementation intention measured at 10 weeks, AB (95% CI = 486.04 [128.19, 1073.42]). No significant pathways were found for the other social-cognitive and implicit attitudinal mediators.

Conclusion: Increased daily steps among the intervention participants were explained by increased implementation intentions. The eCoFit study successfully operationalised implementation intentions in the smartphone app designed to promote outdoor physical activity.

Trial Registration: The trial was approved by a University Human Research Committee and is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12615000990527).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12529-019-09800-8DOI Listing
October 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Increased angiogenesis seems to correlate with inferior overall survival in myeloid sarcoma patients.

Pol J Pathol 2018;69(3):254-265

Myeloid sarcomas (MS) are tumors composed by myeloid elements and developing outside bone marrow. The prognosis is overall poor, only stem cell transplantation being consistently reposted as a potentially curative approach. In this study we explored whether microvessel density, a biomarker of angiogenesis, might be relevant in MS. We studied 60 MS, 24 acute myeloid leukemia, 5 normal bone marrow samples and 2 cases of extramedullary hemopoiesis in patients without evidence of hematological malignancy. We used immunohistochemistry (anti-CD34) to identify and quantify micro-vessel density (MVD) and micro-vessel grading (MVG). We found that MS had significantly higher MVD and MVG than normal bone marrow (p = 0.0002 and p < 0.001, respectively). We then found that cases with monocytic morphology had significantly higher MVD than myelo-monocytic and blastic ones (p = 0.005), while no differences were recorded based on extramedullary site. Finally, we found that higher MVD and higher MVG were associated with inferior outcome in terms of overall survival in multivariate analysis (p = 0.05 and p = 0.02, respectively), when censoring for stem cell transplantation was undertaken. In conclusion, we documented for the first time that increased angiogenesis is characteristic of MS and correlates with survival, suggesting that anti-angiogenic approaches might deserve a clinical evaluation in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5114/pjp.2018.79545DOI Listing
May 2019

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.

Cancer 2019 03 27;125(5):712-725. Epub 2018 Nov 27.

Munich Leukemia Laboratory, Munich, Germany.

Background: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis.

Methods: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases.

Results: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression.

Conclusions: These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587451PMC
March 2019

Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia.

BMC Cancer 2018 Nov 15;18(1):1117. Epub 2018 Nov 15.

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

Background: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin.

Case Presentation: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response.

Conclusions: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-5026-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238377PMC
November 2018

Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

Haematologica 2019 02 6;104(2):312-318. Epub 2018 Sep 6.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome

To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with deletions outnumbering gains (88% 12%). The most common deletions were those targeting , and , which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of plus and/or had a significantly lower disease-free survival rate (24.9% 43.3%; =0.026). The only isoform affecting prognosis was the dominant negative one (=0.003). Analysis of copy number aberrations showed that 18% of patients harbored deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (=0.05) and had a favorable impact on disease-free survival (64.3% 32.1% at 36 months; =0.031). These findings retained statistical significance also in multivariate analysis (=0.057). deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (=0.009). These results indicate that in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including , , , and - has prognostic implications and should be incorporated in the design of more personalized treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.196055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355475PMC
February 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

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

Bad Is Stronger Than Good for Stigmatized, but Not Admired Outgroups: Meta-Analytical Tests of Intergroup Valence Asymmetry in Individual-to-Group Generalization Experiments.

Pers Soc Psychol Rev 2019 02 23;23(1):3-47. Epub 2018 Feb 23.

1 The University of Newcastle, Australia.

Theories of risk aversion, epistemic defense, and ingroup enhancement converge in predicting greater impact of negative (vs. positive) experiences with outgroup members on generalized evaluations of stigmatized outgroups. However, they diverge in predictions for admired outgroups. Past tests have focused on negative outgroups using correlational designs without a control group. Consequently, they have not distinguished between alternative explanations or ascertained the direction of causality/generalization, and they have suffered from self-selection biases. These limitations were redressed by a meta-analysis of experimental research on individual-to-group generalization with positive and negative outgroups (59 tests; 3,012 participants). Controlling for modest confounds, the meta-analysis found a generalization advantage of negative experiences for stigmatized outgroups and a generalization advantage of positive experiences for admired outgroups. These results highlight the centrality of valenced expectations about outgroups, consistent with epistemic defense and ingroup enhancement and inconsistent with risk aversion. Implications for positive changes in intergroup dynamics are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1088868317753504DOI Listing
February 2019

Chromothripsis in acute myeloid leukemia: biological features and impact on survival.

Leukemia 2018 07 23;32(7):1609-1620. Epub 2018 Feb 23.

Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.

Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-018-0035-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035145PMC
July 2018

Low-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: Final result of a phase II study.

Leuk Res 2017 11 25;62:77-83. Epub 2017 Sep 25.

Hematology and Hematopoietic Stem Cell Transplant Center, AORMN, Pesaro, Italy.

Outcome for elderly patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. Sixty-six newly diagnosed AML patients (median age: 76years), ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10mg/day orally, days 1-21) plus 10mg/m low-dose cytarabine, subcutaneously, twice a day (days 1-15) every six weeks, up to 6 cycles. Complete remission (CR) rate was 36.3% according to intention-to-treat. Responding patients had a longer median overall survival than non-responders (517 vs. 70days, P<0.001). The achievement of CR was not predicted by bone marrow blast count, cytogenetics, molecular markers, prior MDS, white blood cell count. Conversely, by studying the global gene expression profile, we identified a molecular signature, including 309 genes associated with clinical response (CR versus no CR). Based on the expression of a minimal set of 16 genes, we developed an algorithm to predict treatment response, that was successfully validated by showing an overall accuracy of 88%. We met the primary endpoint of the study, by beating the estimated successful CR rate (P1) fixed at 30%. Moreover, CR induced by this 2-drug combo was efficiently predicted by genetic profiling, identifying a biomarker that warrants validation in independent series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2017.09.019DOI Listing
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2016.1258056DOI Listing
December 2016

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.10535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288194PMC
August 2016

FGFR1 and KAT6A rearrangements in patients with hematological malignancies and chromosome 8p11 abnormalities: biological and clinical features.

Am J Hematol 2016 Mar;91(3):E14-6

Institute of Hematology and Medical Oncology "Lorenzo E Ariosto Seràgnoli", Sant'Orsola-Malpighi Hospital-University of Bologna, Bologna, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.24276DOI Listing
March 2016
-->