Publications by authors named "Giuseppe Carli"

32 Publications

Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic.

Mediterr J Hematol Infect Dis 2021 1;13(1):e2021032. Epub 2021 May 1.

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

The current COVID-19 pandemic requires revisiting our current approach to major blood disorders, including ITP (Immune Thrombocytopenia), stirring up the production of several disease-specific practical guidelines. This report describes an updated version of consensus-based practical guidelines on the management of ITP, adapted to the Italian health system and social context. It highlights the role of the hematologist in offering guidance for choosing differentiated approaches in relation to specific circumstances and is intended to provide them with a useful tool for sharing the decision-making process with their patients. Probably, the greatest risk to avoid for a patient with suspected, ongoing or relapsed ITP - that is not severe enough to place him or her at risk for major bleeding - is to be infected in non-hospital and hospital healthcare settings. This risk must be carefully considered when adapting the diagnostic and therapeutic approach. More in detail, the document first addresses the appropriate management for COVID-19 negative patients with newly diagnosed ITP or who experience a relapse of previous ITP, according to first and second lines of treatment and then the management of COVID-19 positive patients according to their severity, from paucisymptomatic to those requiring admission to Intensive Cure Units (ICU). The pros and cons of the different treatments required to correct platelet count are discussed, as are some specific situations, including chronic ITP, splenectomy, thromboembolic complication and anti COVID-19 vaccination.
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http://dx.doi.org/10.4084/MJHID.2021.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114883PMC
May 2021

Real-world use of thrombopoietin receptor agonists in elderly patients with primary immune thrombocytopenia.

Blood 2021 Apr 22. Epub 2021 Apr 22.

(Institute of Hematology, Bologna, Italy.

The efficacy and safety of thrombopoietin-receptor agonists (TRAs) in elderly patients with primary immune thrombocytopenia (ITP) is uncertain. In 384 ITP patients treated with TRAs when aged ≥60 years, we investigated TRAs response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROT). After 3 months, 82.5% and 74.3% of eltrombopag and romiplostim-treated patients achieved a response, respectively (p=0.09); 66.7% maintained the response (median follow-up: 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; while no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. During TRA, 34 major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, and were associated with thrombosis history (SHR: 2.04, p=0.05) and platelet count <20x109/L at TRA start (SHR: 1.69, p=0.04), respectively. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but one during persisting TRA treatment (incidence rate: 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRA; 53 (13.8%) patients maintained SROT, which was associated with TRA discontinuation in complete response (p<0.001). Very old age (≥75, 41.1%) was associated with more frequent TRAs start in persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in elderly ITP patients, with no fatal haemorrhages and with SROT in a significant portion of patients; in patients with thrombosis history caution is warranted and a careful risk/benefit balance should be carried out.
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http://dx.doi.org/10.1182/blood.2021010735DOI Listing
April 2021

Deep vein thrombosis (DVT) occurring shortly after the second dose of mRNA SARS-CoV-2 vaccine.

Intern Emerg Med 2021 04 9;16(3):803-804. Epub 2021 Mar 9.

Hematology Department, S. Bortolo Hospital, ULSS 8 Berica, Viale Rodolfi 37, 36100, Vicenza, Italy.

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http://dx.doi.org/10.1007/s11739-021-02685-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940863PMC
April 2021

Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study.

Br J Haematol 2021 Apr 22;193(2):386-396. Epub 2021 Feb 22.

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.
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http://dx.doi.org/10.1111/bjh.17334DOI Listing
April 2021

Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19.

Blood Cancer J 2021 02 4;11(2):21. Epub 2021 Feb 4.

Hospital Moncloa, Madrid, Spain.

In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (-23.3%, p < 0.0001) than in PV (-16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.
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http://dx.doi.org/10.1038/s41408-021-00417-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871138PMC
February 2021

Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial.

Lancet Haematol 2021 Mar 18;8(3):e175-e184. Epub 2021 Jan 18.

Unità Operativa di Ematologia e Trapianto Midollo Osseo, IRCCS Ospedale San Raffaele, Milan, Italy.

Background: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone.

Methods: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325.

Findings: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred.

Interpretation: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera.

Funding: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
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http://dx.doi.org/10.1016/S2352-3026(20)30373-2DOI Listing
March 2021

A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.

Blood 2020 07;136(2):171-182

Hematology Project Foundation, Vicenza, Italy.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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http://dx.doi.org/10.1182/blood.2019004596DOI Listing
July 2020

The prognostic role of speckle tracking echocardiography in clinical practice: evidence and reference values from the literature.

Heart Fail Rev 2020 Mar 26. Epub 2020 Mar 26.

Department of Cardiovascular Diseases, University of Siena, Viale Bracci 1, Siena, Italy.

Speckle tracking echocardiography (STE) is a second-level echocardiographic technique which has gradually gained relevance in the last years. It allows semi-automatic quantification of myocardial deformation and function, overcoming most of the limitations characterizing basic echocardiography and providing an early detection of cardiac impairment. Today, its feasibility and usefulness are highly supported by literature. In particular, several studies demonstrated that STE could provide additional prognostic information beyond conventional echocardiographic and traditional clinical parameters. Moreover, a recent standardization of speckle tracking analysis regarding all cardiac chambers paved the way for the integration of STE in diagnostic and prognostic protocols for particular clinical settings. The aim of this review is to describe the prognostic role of STE in different clinical scenarios basing on currently available evidence.
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http://dx.doi.org/10.1007/s10741-020-09945-9DOI Listing
March 2020

Mantle Cell Lymphoma of Mucosa-Associated Lymphoid Tissue: A European Mantle Cell Lymphoma Network Study.

Hemasphere 2020 Feb 16;4(1):e302. Epub 2019 Dec 16.

Division of Hematology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6-182), 5-year progression-free survival (PFS) was 45% (95% CI: 35-54) and 5-year overall survival (OS) was 71% (95% CI: 62-79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.
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http://dx.doi.org/10.1097/HS9.0000000000000302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000480PMC
February 2020

Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study.

Blood 2020 01;135(5):381-386

Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
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http://dx.doi.org/10.1182/blood.2019002614DOI Listing
January 2020

Second cancers in MPN: Survival analysis from an international study.

Am J Hematol 2020 03 22;95(3):295-301. Epub 2019 Dec 22.

Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy.

One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.
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http://dx.doi.org/10.1002/ajh.25700DOI Listing
March 2020

Management of elderly patients with immune thrombocytopenia: Real-world evidence from 451 patients older than 60 years.

Thromb Res 2020 01 21;185:88-95. Epub 2019 Nov 21.

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

Introduction: Primary Immune thrombocytopenia (ITP) in the elderly is a major clinical challenge which is increasingly frequent due to global ageing population.

Materials And Methods: To describe baseline ITP features, management, and outcome, a centralized electronic database was established, including data of 451 patients aged ≥60 years that were treated from 2000 onwards and were observed for ≥1 year (total observation of 2704 patient-years).

Results: At ITP diagnosis, median age was 71.1 years (age ≥ 75: 42.8%); 237 (53.9%) patients presented with haemorrhages (grade ≥ 3: 7.5%). First-line therapy included prednisone (82.9%), dexamethasone (14.6%), thrombopoietin-receptor agonists (TRAs, 1.3%), and oral immunosuppressive agents (1.1%). Prednisone starting dose ≥1 mg/kg/d (p = .01) and dexamethasone 40 mg/d (p < .001) were mainly reserved to patients aged 60-74, who were more treated with rituximab (RTX, p = .02) and splenectomy (p = .03) second-line. Overall response rates to first and second-line therapies were 83.8% and 84.5%, respectively, regardless of age and treatment type/dose. A total of 178 haemorrhages in 101 patients (grade ≥ 3: n. 52, 29.2%; intracranial in 6 patients), 49 thromboses in 43 patients (grade ≥ 3: n. 26, 53.1%) and 115 infections in 94 patients (grade ≥ 3: n. 23, 20%) were observed during follow-up. Incidence rates of complications per 100 patient-years were: 4.5 (haemorrhages, grade ≥ 3: 1.7), 1.7 (thromboses, grade ≥ 3: 0.9), and 3.9 (infections, grade ≥ 3: 0.7). TRAs use were associated with reduced risk of bleeding and infections, while cardiovascular risk factors (particularly, diabetes) significantly predicted thromboses and infections.

Conclusions: Age-adapted treatment strategies are required in elderly and very elderly patients.
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http://dx.doi.org/10.1016/j.thromres.2019.11.026DOI Listing
January 2020

Eltrombopag for immune thrombocytopenia secondary to chronic lymphoproliferative disorders: a phase 2 multicenter study.

Blood 2019 11;134(20):1708-1711

Division of Hematology, San Bortolo Hospital, Vicenza, Italy.

Immune thrombocytopenia (ITP) secondary to chronic lymphoproliferative disorders (LPDs) is poorly responsive to conventional treatments. We conducted a multicenter phase 2 prospective 24-week study in 18 patients with ITP secondary to LPDs to assess the safety and efficacy of eltrombopag. Responsive patients entered an extension study for up to 5 years. For inclusion, patients should not require cytotoxic treatment and should have a platelet count <30 × 109/L or have symptoms of bleeding. Eltrombopag was initiated at 50 mg/day, with a maximum of 150 mg/day. The primary end point was platelet response after 4 weeks. Median age was 70 years (range, 43-83 years), and 14 patients had chronic lymphocytic leukemia, 2 had classic Hodgkin lymphoma, and 2 had Waldenström macroglobulinemia. All patients had received previous ITP treatments. Response rate at week 4 was 78% (95% confidence interval [CI], 58%-97%), with 50% of patients having a complete response (CR) (95% CI, 43%-57%); respective results at week 24 were 59% (95% CI, 36%-82%) with 30% reaching a CR (95% CI, 8%-52%). Median exposure to eltrombopag was 16 months; median dose at week 4 was 50 mg/day (range, 25-100 mg/day), and at week 24, it was 50 mg/day (range, 25-150 mg/day). No grade >2 adverse events were reported. Eltrombopag is active and well tolerated in ITP secondary to LPDs. This trial was registered at www.clinicaltrials.gov as #NCT01610180.
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http://dx.doi.org/10.1182/blood.2019001617DOI Listing
November 2019

ACUTE HF score, a multiparametric prognostic tool for acute heart failure: A real-life study.

Int J Cardiol 2019 12 8;296:103-108. Epub 2019 Jul 8.

Department of Cardiovascular Diseases, University of Siena, Italy.

Background: Acute heart failure (AHF) is the first cause of hospitalization for over-65 individuals, associated with high mortality and readmission rate. The aim of this study was to assess the prognostic value of a multiparametric score combining clinical, biochemical and echocardiographic indexes in AHF for clinical practice.

Methods: 830 patients hospitalized for AHF were enrolled. Exclusion criteria were: active neoplasms; previous heart transplantation or left ventricular assist device implantation. Different variables were analyzed: etiology of AHF, clinical and biochemical data, lung congestion on chest-X ray, echocardiographic parameters and administered therapy. The endpoints were: all-cause mortality at 30 days, 6 months and 5 years and the duration of hospitalization.

Results: 771 patients met eligibility criteria. Using the univariate and multivariate analysis the indexes with the best correlation with outcome were discretized and used to create the ACUTE HF score, computed as: 1.4*[serum creatinine>2 mg/dl] + 0.8*[ejection fraction<30] + 0.7*[age > 76] + 0.7*[prior hospitalization for AHF] + 0.9*[prior stroke/transient ischemic attack] + 0.5*[more than moderate mitral regurgitation] + 0.8*[use of non-invasive ventilation] and used to divide patients into 3 groups according to the risk of 6-months mortality. With the receiver operating curves and Kaplan-Meier analysis, this score proved to have a high predictive power for mortality at 30 days, 6 months and 5 years from hospitalization, and for event-free survival rates, providing a risk stratification capability superior to that of single variables.

Conclusions: The ACUTE HF score could be a complete and useful tool for assessing prognosis of AHF patients. It could represent a step in the long standardization pathway of prognostic protocols for AHF.
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http://dx.doi.org/10.1016/j.ijcard.2019.07.015DOI Listing
December 2019

Second cancer in Philadelphia negative myeloproliferative neoplasms (MPN-K). A nested case-control study.

Leukemia 2019 08 29;33(8):1996-2005. Epub 2019 May 29.

Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy.

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.
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http://dx.doi.org/10.1038/s41375-019-0487-8DOI Listing
August 2019

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B assay as an evaluation tool of different aspirin dosing regimens in the clinical setting.

Blood Cancer J 2018 06 1;8(6):49. Epub 2018 Jun 1.

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

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB as a reliable end point for dose-finding studies of novel aspirin regimens.
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http://dx.doi.org/10.1038/s41408-018-0078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992153PMC
June 2018

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi.

Biol Blood Marrow Transplant 2018 09 29;24(9):1814-1822. Epub 2018 May 29.

Oncologia Medica 1, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.018DOI Listing
September 2018

Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms.

Blood Cancer J 2018 02 28;8(3):25. Epub 2018 Feb 28.

Hematology Division, Papa Giovanni XXIII hospital, Bergamo, Italy.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.
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http://dx.doi.org/10.1038/s41408-018-0048-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849668PMC
February 2018

Beyond immune thrombocytopenia: the evolving role of thrombopoietin receptor agonists.

Ann Hematol 2017 Sep 8;96(9):1421-1434. Epub 2017 Mar 8.

Department of Hematology, S. Bortolo Hospital, Vicenza, Italy.

Since its discovery, the thrombopoietin (TPO) pathway has been an important pharmaceutical target for the treatment of thrombocytopenia. The first generation of TPO mimetics included peptide agents sharing homology with endogenous TPO, but these introduced a risk of antibody formation to endogenous TPO and were not successful. However, second-generation TPO mimetics or TPO receptor agonists (RAs) are currently being used to treat thrombocytopenia associated with a number of conditions, such as immune thrombocytopenia (ITP), severe aplastic anaemia (SAA), and hepatitis C virus-associated chronic liver disease. Accumulating efficacy and safety data suggest that the role of TPO-RAs in the treatment of thrombocytopenia may evolve in the near future with broader use of these agents in ITP and SAA, as well as approval in other indications, potentially including myelodysplastic syndromes, chemotherapy-associated thrombocytopenia, and post-transplant thrombocytopenia. This review provides an overview of clinical data on the efficacy and safety of TPO-RAs, emphasising recent findings that may expand their clinical utility.
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http://dx.doi.org/10.1007/s00277-017-2953-6DOI Listing
September 2017

Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma.

World J Gastroenterol 2016 Oct;22(38):8447-8458

Michele Merli, Division of Hematology, University Hospital Ospedale di Circolo & Fondazione Macchi, University of Insubria, 36100 Varese, Italy.

The association of hepatitis C virus (HCV) and B-cell non-Hodgkin lymphomas (NHL) has been highlighted by several epidemiological and biological insights; however the most convincing evidence is represented by interventional studies demonstrating the capability of antiviral treatment (AT) with interferon (IFN) with or without ribavirin to induce the regression of indolent lymphomas, especially of marginal-zone origin. In the largest published retrospective study (100 patients) the overall response rate (ORR) after first-line IFN-based AT was 77% (44% complete responses) and responses were sustainable (median duration of response 33 mo). These results were confirmed by a recent meta-analysis on 254 patients, demonstrating an ORR of 73%. Moreover this analysis confirmed the highly significant correlation between the achievement of viral eradication sustained virological response (SVR) and hematological responses. Two large prospective studies demonstrated that AT is associated with improved survival and argue in favor of current guidelines' recommendation of AT as preferential first-line option in asymptomatic patients with HCV-associated indolent NHL. The recently approved direct-acting antiviral agents (DAAs) revolutionized the treatment of HCV infection, leading to SVR approaching 100% in all genotypes. Very preliminary data of IFN-free DAAs therapy in indolent HCV-positive NHL seem to confirm their activity in inducing lymphoma regression.
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http://dx.doi.org/10.3748/wjg.v22.i38.8447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064026PMC
October 2016

Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients.

Oncotarget 2016 May;7(19):27676-88

Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona, Italy.

Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b+CD33dimHLA-DR-granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear.The percentage and immunophenotype of CD66b+CD33dimHLA-DR-cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b+CD33dimHLA-DR-cells and patient clinicopathological features and outcome, were evaluated.CD66b+CD33dimHLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02-70.92) vs 0.42 (0.04-2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28-26.34), 2.15 (0.02-20.08), and 2.96 (0.25-70.92), respectively, p < 0.0001. CD66b+CD33dimHLA-DR-cells in patient PBMCs were mostly composed of mature CD11b+CD16+ low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b+ cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b+CD33dimHLA-DR- G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression.PBMCs from HL and B-cell NHL patients contain a population of CD66b+CD33dimHLA-DR- G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053680PMC
http://dx.doi.org/10.18632/oncotarget.8507DOI Listing
May 2016

Evans syndrome secondary to chronic lymphocytic leukaemia: presentation, treatment, and outcome.

Ann Hematol 2016 May 22;95(6):863-70. Epub 2016 Mar 22.

Department of Cell Therapy and Haematology, San Bortolo Hospital, Via Rodolfi 37, 36100, Vicenza, Italy.

Evans syndrome (ES) is defined by the combination (either simultaneous or sequential) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA). When related to secondary conditions, ES may arise in patients with chronic lymphocytic leukaemia (CLL), which is frequently associated to autoimmune cytopenias (AIC). We analysed 25 patients with ES secondary to CLL, which were identified from a large series of consecutive patients with CLL, diagnosed and followed up in two institutions. They represented 2.9 % of the whole series. Thirteen patients presented with concurrent ITP and AIHA (simultaneous ES), while others developed the two AIC sequentially. Occurrence of ES was associated with unfavourable biological prognostic factors like ZAP-70 expression, unmutated immunoglobulin heavy chain variable region gene status, 17-p13 deletion and TP53 gene mutations. Of note, the majority of patients with ES (66 %) had stereotyped B cell receptor configuration. Most patients had short-lasting remissions and required second-line treatments to control the autoimmune manifestations of ES. Patients with ES were associated with inferior survival compared to patients not developing AIC, especially when ES developed early in the course of CLL, although the reduced survival was not confirmed by multivariate analysis. In conclusion, ES secondary to CLL is a difficult-to-treat complication, characterised by adverse biological features and clinical outcome.
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http://dx.doi.org/10.1007/s00277-016-2642-xDOI Listing
May 2016

Safety and efficacy of rituximab plus bendamustine in relapsed or refractory diffuse large B-cell lymphoma patients: an Italian retrospective multicenter study.

Leuk Lymphoma 2016 08 15;57(8):1823-30. Epub 2015 Dec 15.

a Hematology Unit, Department of Onco-Hematology , Guglielmo da Saliceto Hospital , Piacenza , Italy ;

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.
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http://dx.doi.org/10.3109/10428194.2015.1106536DOI Listing
August 2016

Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival.

Oncotarget 2015 Jul;6(21):18653-63

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an independent retrospective cohort of 112 patients with CLL. EBV DNA load was detectable in 59%, and high (≥2000 copies/µg DNA) in 19% of patients, but it was negative in plasma samples. EBV DNA load was significantly higher in CLL patients than in healthy subjects (P < .0001). No relation was found between high EBV load and clinical stage or biological variables, except for 11q deletion (P = .004), CD38 expression (P = .003), and NOTCH1 mutations (P = .05). High EBV load led to a 3.14-fold increase in the hazard ratio of death and to a shorter overall survival (OS; P = .001). Poor OS was attributable, at least in part, to shorter time-to-first-treatment (P = .0008), with no higher risk of Richter's transformation or second cancer. Multivariate analysis selected high levels of EBV load as independent predictor of OS after controlling for confounding clinical and biological variables. EBV DNA load at presentation is an independent predictor of OS in patients with CLL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621917PMC
http://dx.doi.org/10.18632/oncotarget.4418DOI Listing
July 2015

Autoimmune haemolytic anaemia in mantle cell lymphoma : an insidious complication associated with leukemic disease.

Hematol Oncol 2017 Mar 15;35(1):135-137. Epub 2015 Jun 15.

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

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http://dx.doi.org/10.1002/hon.2241DOI Listing
March 2017

The impact of sensitive KIT D816V detection on recognition of indolent Systemic Mastocytosis.

Leuk Res 2015 Mar 6;39(3):273-8. Epub 2014 Dec 6.

Department of Haematology/Oncology, L. and A. Seragnoli, University of Bologna, Bologna, Italy.

Patients with Systemic Mastocytosis (SM) need a highly sensitive diagnostic test for D816V detection of the KIT receptor gene. Along with histology/cytology and flow cytometry evaluation, bone marrow (BM) from 110 consecutive adult patients referred with a suspicion of SM to Multidisciplinary Outpatient Clinic for Mastocytosis in Verona were tested both by Amplification Refractory Mutation System Reverse Transcriptase quantitative real time Polymerase Chain Reaction (ARMS-RT-qPCR) and RT-PCR+Restriction Fragment Length Polymorphism (RFLP) followed by Denaturing-High Performance Liquid Chromatography (D-HPLC) and Sanger sequencing. ARMS-RT-qPCR identified D816V mutation in 77 patients, corresponding to 100% of cases showing CD25(+) mast cells (MCs) whereas RT-PCR+RFLP/D-HPLC+sequencing revealed D816V mutations in 47 patients. According to the 2008 WHO criteria 75 SM, 1 Cutaneous Mastocytosis (CM), 1 monoclonal MC activation syndrome (MMAS), and 1 SM Associated with Haematologic Non-Mast Cell Disorder (SM-AHNMD) were diagnosed. Seventeen out 75 SM patients (23%) would have not satisfied sufficient WHO criteria on the basis of the sole RT-PCR+RFLP: these patients had significantly lower serum tryptase levels and amount of CD25(+) MCs. Therefore, ARMS-RT-qPCR might result particularly useful, in patients that do not fulfil major BM histological criterion, for the recognition of indolent SM with a very low MC burden.
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http://dx.doi.org/10.1016/j.leukres.2014.11.029DOI Listing
March 2015