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Pagano L.,Catholic University of the Sacred Heart | Verga L.,University of Milan Bicocca | Martino B.,Azienda Ospedaliera Bianchi Melacrino Morelli | Mitra M.E.,Policlinico di Palermo | And 11 more authors.
The Journal of antimicrobial chemotherapy | Year: 2014

OBJECTIVES: To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis.METHODS: From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925.RESULTS: In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ∼30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities.CONCLUSIONS: This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.


Palandri F.,University of Bologna | Latagliata R.,University of Rome La Sapienza | Polverelli N.,University of Bologna | Crugnola M.,University of Parma | And 12 more authors.
Leukemia | Year: 2015

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (≤40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P=0.04), longer survival (100% versus 96%, P=0.05) and better combined-EFS (86% versus 71%, P=0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients. © 2015 Macmillan Publishers Limited.


PubMed | University of Rome La Sapienza, Azienda Ospedaliera Bianchi Melacrino Morelli, University of Parma and University of Bologna
Type: Journal Article | Journal: Leukemia | Year: 2015

We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients ( 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations (minor mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these triple-negative patients.


PubMed | Ospedale F. Miulli, Azienda Ospedaliera della Provincia di Lecco, Azienda Ospedaliera Carlo Poma, Azienda Ospedaliera Bianchi Melacrino Morelli and 18 more.
Type: Journal Article | Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | Year: 2014

Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial.This analysis was performed in the database of a multicentre, open label and randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: on-line pre-dilution HF (36 patients) or on-line pre-dilution haemodiafiltration (40 patients).CTs did not affect P (P = 0.526), calcium (Ca) (P = 0.849) and parathyroid hormone levels (P = 0.622). P levels were associated with the use of phosphate binders including aluminium-based phosphate binders (P < 0.001) and sevelamer (P < 0.001), pre-dialysis bicarbonate levels (P < 0.001) and pre-dialysis blood K levels (P < 0.001). On multivariate analysis (generalized linear model), serum P was again largely unassociated with CTs (P = 0.631). Notably, participating centres were by far the strongest independent correlate of serum P, explaining 45.3% of the variance of serum P over the trial and this association was confirmed at multivariate analysis. Bicarbonate (P < 0.001) and, to a weaker extent, serum K (P = 0.032) were independently related to serum P.In comparison with low-flux HD, CTs did not significantly affect serum P levels. Participating centres were the main source of P variability during the trial followed by treatment with phosphate binders, serum bicarbonate and, to a weak extent, serum potassium levels (ClinicalTrials.gov Identifier: NCT011583309).


PubMed | SODc Ematologia, University of Rome La Sapienza, UO Ematologia e Centro Trapianti, AO S Maria di Terni and 14 more.
Type: Journal Article | Journal: Leukemia | Year: 2016

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients 75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade 3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade 3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.


Adornato E.,Casa di Cura S. Feliciano | Adornato E.M.F.,Azienda Ospedaliera Bianchi Melacrino Morelli
Policlinico - Sezione Medica | Year: 2013

Efficacy and improvement in CRT device implantation - In the last decade Cardiac Resynchronization Therapy (CRT) using biventricular pacing system has been introduced, as a complementary therapy, for the tratment of moderate to severe Heart Failure in patients with left bundle branch block, cardiac dyssinchrony, LVEF inferior to 35%, that are in functional class HI o IV, symptomatic despite stable optimal medical therapy. Several prospective randomized clinical studies have demostrated the effectiveness of CRT to improve the exercise capacity, the quality of life, the LV systolic function and to reduce mortality form progressive heart failure. Accurate selection of patients with chronic heart failure that are candidates to CRT, adequate patient preparation, correct implant procedure, including venous access for pacing leads placement, location of the coronary sinus and proper placement of the LV lead on the lateral or posterolateral wall of the LV are crucial to ensure the success of CRT and to reduce the number of non-responders.


PubMed | ZNA Stuivenberg, University of Kansas Medical Center, University of Houston, University of Nottingham and 11 more.
Type: Journal Article | Journal: British journal of haematology | Year: 2016

The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10mg BID (n=54) or hydroxycarbamide (prerandomization dose/schedule; n=56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, 50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 434% vs. 296% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 182; 95% confidence interval, 082-404; P=0139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13-16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio2) receiving ruxolitinib than hydroxycarbamide (474% vs. 250%; P=00346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.


PubMed | Novartis, University of British Columbia, University of Leipzig, Princess Margaret Cancer Center and 10 more.
Type: Journal Article | Journal: Haematologica | Year: 2016

JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis - a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinibs mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a 50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov.


Pagano L.,Catholic University of the Sacred Heart | Caira M.,Catholic University of the Sacred Heart | Offidani M.,Marche Polytechnic University | Martino B.,Azienda Ospedaliera Bianchi Melacrino Morelli | And 8 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2010

Objectives and methods: In order to assess physicians' compliance with international guidelines for the targeted treatment of invasive aspergillosis, 136 patients with acute myeloid leukaemia and proven/probable invasive aspergillosis were analysed. Results: Compliance with Infectious Diseases Society of America (IDSA) and European Conference on Infections in Leukaemia (ECIL) guidelines was found to be relatively low (28% for ECIL and 55% for IDSA), although no significant differences were found between the two groups (adherence versus non-adherence). In both subgroup analyses (IDSA and ECIL), compliance with the guidelines did not impact the 120 day survival rate. Instead, adherence to guidelines led to a higher response rate to first-line antifungal treatment (76% in the IDSA group and 84% in the ECIL group). Conclusions: Guidelines establish categories of patients with homogeneous characteristics, and suggest optimal diagnostic and therapeutic options for them. Acquisition of good results through adherence to guidelines is confirmed by our series. Unfortunately, there are frequently reasons to deviate from these general recommendations, particularly in patients with acute myeloid leukaemia. Despite evidence-based recommendations, adherence to the guidelines does not constitute the best therapeutic choice in each and every patient. Subjects' clinical conditions and co-morbidities vary widely, and sometimes render the 'recommended' drug a non-applicable strategy. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


PubMed | Azienda Ospedaliera Papardo, University of Bari, Italian Group for Adult Hematologic Diseases GIMEMA, University of Udine and 11 more.
Type: Clinical Trial, Phase II | Journal: Leukemia research | Year: 2014

In 45, 60 years old patients with CLL and an adverse biologic profile, a front-line treatment with Fludarabine and Campath (Alemtuzumab()) was given. The overall response rate was 75.5%, the complete response rate (CR) 24.4% with the lowest CR rates, 16.7% and 8.3%, in 11q and 17p deleted cases. The 3-year progression-free survival (PFS) and overall survival were 42.5% and 79.9%, respectively. PFS was significantly influenced by CLL duration, beta2-microglobulin, and improved by post-remissional stem cell transplantation. Front-line fludarabine and alemtuzumab showed a manageable safety profile and evidence of a benefit in a small series of CLL patients with adverse biologic features.

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