Publications by authors named "Giulia Fontanelli"

17 Publications

  • Page 1 of 1

Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy.

Hematol Oncol 2019 Oct 20;37(4):447-455. Epub 2019 Aug 20.

UO Ematologia e Trapianto Midollo Osseo, IRCCS Istituto Scientifico Universitario San Raffaele, Milan, Italy.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.
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http://dx.doi.org/10.1002/hon.2663DOI Listing
October 2019

Sudden ventricular fibrillation and death during ibrutinib therapy-A case report.

Eur J Haematol 2019 Oct 22;103(4):442-443. Epub 2019 Jul 22.

Oncology Unit, Ospedale S.Giuseppe, Empoli, Italy.

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase approved for the treatment of chronic lymphocytic leukaemia, mantle cell lymphoma and refractory Waldenstrom's disease. It increases progression-free survival, overall survival, response rate. The most frequent adverse reactions, are increased risk in of bleeding and atrial fibrillation, but several reports of more dangerous rhythm disturbances have been recently reported in literature. A case of a patient with refractory Waldenstrom's disease, who developed ventricular fibrillation while taking ibrutinib, is reported, along with a concise literature review.
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http://dx.doi.org/10.1111/ejh.13290DOI Listing
October 2019

The and polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia.

Oncotarget 2017 Oct 30;8(50):88021-88033. Epub 2017 Sep 30.

Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of (rs683369 [c.480C>G]) and (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, and polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, n contrast to data obtained in patients treated with imatinib, and polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
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http://dx.doi.org/10.18632/oncotarget.21406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675690PMC
October 2017

Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia.

Cancer Chemother Pharmacol 2017 04 13;79(4):767-773. Epub 2017 Mar 13.

Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.

Purpose: The present study was aimed at investigating whether imatinib pharmacogenetics is related to its pharmacodynamics in patients affected by chronic myeloid leukemia.

Methods: Through a procedure based on a sequence of classical statistics methods, we investigated the possible relationships between treatment efficacy/tolerability and combinations of time-independent variables as gender and genetic covariates in the form of single nucleotide polymorphisms (SNPs) or combinations thereof. Moreover, since the drug tolerability has a strong incidence on the discontinuation of the therapy, we investigated whether the time of manifestation of the most frequent toxic effects can be related to time-independent patients' characteristics or not.

Results: We found that a combination of two polymorphisms, namely hOCT1 c.480C>G (rs683369) and ABCB1 c.3435C>T (rs1045642), seems to play the role of predictor for imatinib in both efficacy and toxicity. Furthermore, the time of manifestation of edema toxicity is found to be associated to a combination of gender and ABCB1 c.3435C>T, whereas the time of manifestation of cramp toxicity appears related to gender.

Conclusions: The novelty of this study is dual: the achievement of results that potentially have a significant clinical interest and the demonstration that the adoption of composed covariates may represent a unique tool to study different aspects of the treatment with imatinib.
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http://dx.doi.org/10.1007/s00280-017-3271-3DOI Listing
April 2017

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients.

Oncotarget 2016 Nov;7(44):72311-72321

Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.
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http://dx.doi.org/10.18632/oncotarget.11100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342164PMC
November 2016

Polycomb genes are associated with response to imatinib in chronic myeloid leukemia.

Epigenomics 2015 Aug 7;7(5):757-65. Epub 2015 Sep 7.

Experimental Therapeutics, BCCA Research Centre, 675 W 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.

Aim: Imatinib is a tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia (CML). Despite its efficacy, about a third of patients discontinue the treatment due to therapy failure or intolerance. The rational identification of patients less likely to respond to imatinib would be of paramount clinical relevance. We have shown that transmembrane transporter hOCT1 genotyping predicts imatinib activity. In parallel, Polycomb group genes (PcGs) are epigenetic repressors implicated in CML progression and in therapy resistance.

Patients & Methods: We measured the expression of eight PcGs in paired pre- and post-imatinib bone marrow samples from 30 CML patients.

Results: BMI1, PHC3, CBX6 and CBX7 expression was significantly increased during imatinib treatment. Post-treatment levels of CBX6 and CBX7 predicted 3-month response rate. Measurement of post-treatment BMI1 levels improved the predictive power of hOCT1 genotyping.

Conclusion: These results suggest that the expression levels of PcGs might be useful for a more accurate risk stratification of CML patients.
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http://dx.doi.org/10.2217/epi.15.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551942PMC
August 2015

Increased values of the circulating PDGFβ sustains the "withdrawal syndrome" after tyrosine kinase inhibitor discontinuation in patients affected by chronic myeloid leukemia.

Blood Cells Mol Dis 2015 Oct 23;55(3):211-2. Epub 2015 Jun 23.

Department of Clinical and Experimental Medicine, Section of Hematology - University of Pisa, Pisa, Italy.

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http://dx.doi.org/10.1016/j.bcmd.2015.06.010DOI Listing
October 2015

Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions.

PLoS One 2014 14;9(7):e101991. Epub 2014 Jul 14.

Department of Pharmacy and BioTechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

Sulforaphane is a dietary isothiocyanate found in cruciferous vegetables showing antileukemic activity. With the purpose of extending the potential clinical impact of sulforaphane in the oncological field, we investigated the antileukemic effect of sulforaphane on blasts from patients affected by different types of leukemia and, taking into account the intrinsically hypoxic nature of bone marrow, on a leukemia cell line (REH) maintained in hypoxic conditions. In particular, we tested sulforaphane on patients with chronic lymphocytic leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, and blastic NK cell leukemia. Sulforaphane caused a dose-dependent induction of apoptosis in blasts from patients diagnosed with acute lymphoblastic or myeloid leukemia. Moreover, it was able to cause apoptosis and to inhibit proliferation in hypoxic conditions on REH cells. As to its cytotoxic mechanism, we found that sulforaphane creates an oxidative cellular environment that induces DNA damage and Bax and p53 gene activation, which in turn helps trigger apoptosis. On the whole, our results raise hopes that sulforaphane might set the stage for a novel therapeutic principle complementing our growing armature against malignancies and advocate the exploration of sulforaphane in a broader population of leukemic patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101991PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096754PMC
November 2015

Impressive activity of lenalidomide monotherapy in refractory angioimmunoblastic T-cell lymphoma: report of a case with long-term follow-up.

Hematol Oncol 2013 Dec 14;31(4):213-7. Epub 2012 Nov 14.

Unit of Hematology, "S. Maria alle Scotte" University Hospital, Siena, Italy.

Angioimmunoblastic T-cell lymphoma (AITL) is characterized by an aggressive clinical course and unfavourable prognosis. Refractory AITL patients have very few treatment options. Lenalidomide has previously been reported to have clinical efficacy in this setting; however, long-term reports are limited. A 59-year-old man was referred to the hospital with fatigue, skin rash, weight loss and generalized lymphadenopathy and was diagnosed with AITL; clinical stage was IV B with bone marrow involvement. The patient had an unsatisfactory response despite three lines of conventional chemotherapy and radiotherapy. The patient received lenalidomide monotherapy (25 mg once daily) on days 1 to 21 of every 28-day cycle for six cycles, followed by maintenance therapy with six cycles of lenalidomide 15 mg once daily on days 1 to 21 of every 28-day cycle. A computed tomography scan was assessed before lenalidomide treatment, after the third cycle, at disease restaging 2 months after completion of the induction phase, every 3 months during the maintenance phase and every 6 months during the follow-up period. At the last evaluation, after a follow-up of 30 months, the patient maintained a clinical and radiological complete response. The treatment was well tolerated with manageable toxicity. Lenalidomide treatment demonstrated for the first time in the literature impressive and long-term clinical efficacy in a heavily pretreated chemorefractory AITL patient.
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http://dx.doi.org/10.1002/hon.2038DOI Listing
December 2013

Heliox non-invasive ventilation for preventing extubation failure in preterm infants.

J Matern Fetal Neonatal Med 2013 Apr 12;26(6):603-7. Epub 2012 Dec 12.

Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Italy.

Objectives: Our aim was to assess whether non-invasive ventilation with heliox may decrease the incidence of extubation failure in preterm infants with RDS.

Methods: Infants <29 weeks of gestation were treated immediately after extubation with heliox combined with nasal continuous airway pressure (Hx-NCPAP) or bilevel NCPAP (Hx-BiPAP) for 24 h, while infants in the control groups were treated with conventional NCPAP or BiPAP. The primary endpoint was the comparison of the extubation failure rate in the two groups, where failure was defined as the need for MV during the 24 h following extubation.

Results: Eighteen infants were assigned to the heliox group and 18 to the control group. The extubation failure rate was similar (p = 0.249) in the heliox (n = 6; 33%) and in the control group (n = 9; 50%), but required mean airway pressure (MAP: 4.0+1.0 vs. 4.8+1.2 cm H2O; p = 0.037) and PaCO2 (39+8 mmHg vs. 52+7 mmHg; p < 0.001) at 24 h of treatment were lower in the heliox group.

Conclusions: Non-invasive ventilation with heliox was not effective in decreasing extubation failure in preterm infants with RDS, but did improve their respiratory function. Our findings might support the planning of large randomized controlled studies to evaluate the effectiveness of heliox non-invasive ventilation for decreasing extubation failure in premature infants.
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http://dx.doi.org/10.3109/14767058.2012.745501DOI Listing
April 2013

Relationship between platelet count and volume and spontaneous and pharmacological closure of ductus arteriosus in preterm infants.

Am J Perinatol 2013 May 23;30(5):359-64. Epub 2012 Aug 23.

Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy.

It has been reported that low platelet count may increase the risk of patent ductus arteriosus (PDA) in preterm infants. Moreover, high mean platelet volume (MPV) has been found to be associated with the development of prematurity complications due to enhanced platelet reactivity. Our aim was to assess the relationship between platelet count and MPV and the occurrence of PDA and its resistance to ibuprofen closure in a cohort of extremely preterm infants. Platelet count <100 (×10(3)/mm(3); odds ratio 4.50; 95% confidence limits 1.39 to 14.61) at birth is an independent risk factor for PDA but does not affect its response to ibuprofen. MPV values did not influence PDA fate. Low platelet count increases the risk of developing a hemodynamically significant PDA but does not affect the ibuprofen closure rate. MPV is unrelated to the DA outcome.
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http://dx.doi.org/10.1055/s-0032-1324702DOI Listing
May 2013

Mean platelet volume and risk of bronchopulmonary dysplasia and intraventricular hemorrhage in extremely preterm infants.

Am J Perinatol 2011 Aug 14;28(7):551-6. Epub 2011 Mar 14.

Section of Neonatology, Department of Surgical and Medical Critical Care, Careggi University Hospital of Florence, Viale Morgagni 85, Florence, Italy.

The possible correlation between the mean platelet volume (MPV) and the occurrence of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in a cohort of preterm infants was assessed. We studied infants with gestational age <30 weeks. Enrolled infants were divided into BPD and no-BPD groups and IVH and no-IVH groups. MPV was evaluated at birth and at 24 to 48 hours of life. MPV measured at birth was similar in BPD and no-BPD groups, but at 24 to 48 hours of life was higher in the BPD than in the no-BPD group (11.1 ± 0.9 versus 10.8 ± 0.9 fL, P = 0.033) and multivariate analysis demonstrated that MPV >11 fL increases (relative risk 1.40, 95% confidence interval 1.08 to 1.80) the risk of developing BPD. MPV was similar in infants with or without IVH. We concluded that high MPV in the first days of life is a risk factor for the development of BPD in extremely preterm infants. This might be because high MPV could favor inflammatory and oxidative lung damage. On the contrary, our data indicate that MPV is not associated with the development of IVH in our population.
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http://dx.doi.org/10.1055/s-0031-1274503DOI Listing
August 2011

Effects of epidural and systemic maternal analgesia in term infants: the NoPiL study.

Front Biosci (Elite Ed) 2010 Jun 1;2:1514-9. Epub 2010 Jun 1.

Department of Surgical and Medical Critical Care, Section of Neonatology, University Hospital of Florence, Florence, Italy.

The aim of the No Pain in Labour (NoPiL) study was to evaluate the stress and clinical outcome of infants vaginally born without maternal analgesia and after maternal epidural or systemic analgesia. We studied 120 healthy term infants, 41 in the no analgesia group, 38 in the epidural analgesia group, and 41 in the systemic analgesia group. Cortisol, beta-endorphin, oxidative stress markers (ie: total hydroperoxide (TH) and advanced oxidation protein products (AOPP)), interleukin-1beta (IL-1beta), and interleukin-8 (IL-8) cytokines were measured in arterial cord blood samples. Infants in the 3 groups had similar Apgar score, cord blood pH and occurrence of hypoglycaemia, hyperbilirubinemia, and respiratory depression. Cortisol and endorphin plasma levels did not differ in the groups, nor did TH and AOPP values. IL-1beta and IL-8 cytokine were higher in infants born after maternal epidural analgesia than in other groups. Short-term outcome and stress were similar in infants vaginally born without maternal analgesia and after epidural and systemic analgesia. The possible implications of the highest interleukin levels in the epidural analgesia group deserve further study.
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http://dx.doi.org/10.2741/e210DOI Listing
June 2010

The INSURE method in preterm infants of less than 30 weeks' gestation.

J Matern Fetal Neonatal Med 2010 Sep;23(9):1024-9

Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Viale Morgagni, 85, 50134 Florence, Italy.

Objectives: Our aim was to identify the clinical characteristics which could distinguish infants who can be managed with INSURE (intubatio-surfactant-extubation) method for preventing mechanical ventilation (MV) and which could predict INSURE success or failure.

Methods: Inborn infants with gestational age <30 weeks were Infants were categorised into three groups: (1) infants who needed MV in the delivery room; (2) infants spontaneously breathing who were treated only with NCPAP; (3) infants who were treated with INSURE method.

Results: We studied 125 infants: 30 (24%) required MV, 75 (60%) received INSURE treatment, and 20 (16%) were treated with NCPAP. Sixty-eight (91%) infants were successfully treated with the INSURE method. Infants in the success group had less severe RDS and less occurrence of sepsis and pneumothorax, lower mortality, and shorter duration of stay in the NICU than infants in the failure group. A birth weight <750 g, pO(2)/FiO(2) <218, and a/ApO(2) <0.44 at the first blood gas analysis were independent risk factor for INSURE failure.

Conclusions: The INSURE method can be applied to the majority of extremely preterm infants and is followed by a high percentage of success.
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http://dx.doi.org/10.3109/14767050903572174DOI Listing
September 2010

Blood transfusions increase cerebral, splanchnic, and renal oxygenation in anemic preterm infants.

Transfusion 2010 Jun 22;50(6):1220-6. Epub 2010 Jan 22.

Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy.

Background: Multiprobe near infrared spectroscopy (NIRS) has been used to study regional cerebral (rSO(2)C), splanchnic (rSO(2)S), and renal (rSO(2)R) tissue oxygenation in newborns. We used this method to study the effects of red blood cell (RBC) transfusions in anemic preterm infants to assess if thresholds for transfusions were appropriate for recognizing a clinical condition permitting tissue oxygenation improvement.

Study Design And Methods: Multiprobe NIRS (INVOS 5100, Somanetics) was applied during transfusion to 15 preterm infants with symptomatic anemia of prematurity (hematocrit level of <25%). rSO(2)C, rSO(2)S, and rSO(2)R were recorded at selected times, and then fractional oxygen cerebral extraction ratio [FOEC: (SaO(2)-rSO(2)C)/SaO(2)], fractional oxygen splanchnic extraction ratio [FOES: (SaO(2)-rSO(2)S)/SaO(2)], fractional oxygen renal extraction ratio [FOER: (SaO(2)-rSO(2)R)/SaO(2)], cerebrosplanchnic oxygenation ratio [CSOR: (rSO(2)S/rSO(2)C)], and cerebrorenal oxygenation ratio [CROR: (rSO(2)R/rSO(2)C)] were calculated. In addition, we used Doppler ultrasonography for evaluating cerebral blood flow (CBF), splanchnic blood flow (SBF), and renal blood flow (RBF) velocity.

Results: rSO(2)C, rSO(2)S, and rSO(2)R significantly increased during transfusions, while FOEC, FOES, and FOER decreased. CSOR and CROR increased during transfusions. CBF velocity decreased during the study period, while SBF and RBF velocities did not vary.

Conclusion: RBC transfusions performed at used thresholds permitted an increase in cerebral, splanchnic, and renal oxygenation. The associated decreases in oxygen tissue extraction might suggest that transfusions were well timed for preventing tissue hypoxia or too early and theoretically prooxidant. Further studies could help to clarify this issue.
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http://dx.doi.org/10.1111/j.1537-2995.2009.02575.xDOI Listing
June 2010