Publications by authors named "Claudia Baratè"

51 Publications

Prospective cardiac magnetic resonance imaging survey in myelodysplastic syndrome patients: insights from an Italian network.

Ann Hematol 2021 May 19;100(5):1139-1147. Epub 2021 Mar 19.

MRI Unit, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, 56124, Pisa, Italy.

We prospectively evaluated changes in cardiac and hepatic iron overload (IO) and in morpho-functional cardiac parameters and myocardial fibrosis by magnetic resonance imaging (MRI) in patients with low-risk and intermediate-1-risk myelodysplastic syndromes (MDS). Fifty patients enrolled in the Myocardial Iron Overload in MyElodysplastic Diseases (MIOMED) study were followed for 12 months. IO was quantified by the T2* technique and biventricular function parameters by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Twenty-eight patients (71.89±8.46 years; 8 females) performed baseline and follow-up MRIs. Thirteen patients had baseline hepatic IO, with a higher frequency among transfusion-dependent patients. Out of the 15 patients with a baseline MRI liver iron concentration <3 mg/g/dw, two (non-chelated) developed hepatic IO. Thirteen (46.4%) patients had an abnormal T2* value in at least one myocardial segment. One patient without hepatic IO and non-transfused had baseline global T2* <20 ms. Among the 15 patients with no baseline myocardial IO (MIO), 2 worsened. There was a significant increase in both left and right ventricular end-diastolic volume indexes. Thirty-six percent of patients showed myocardial fibrosis correlating with aging. Two new occurrences were detected at the follow-up. In conclusion, by a more sensitive segmental approach, MIO is quite frequent in MDS patients and it can be present also in non-transfused patients and in absence of detectable hepatic iron. The incidence of cardiac and hepatic IO and of myocardial fibrosis and the increase in biventricular volumes after a 12-month interval suggest performing periodic MRI scans to better manage MDS patients.
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http://dx.doi.org/10.1007/s00277-021-04495-yDOI Listing
May 2021

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors.

Hematol Oncol 2021 Feb 22. Epub 2021 Feb 22.

Hematology, Department of Translational and Precision Medicine, Policlinico Umberto I, Sapienza University, Rome, Italy.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.
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http://dx.doi.org/10.1002/hon.2851DOI Listing
February 2021

Myeloid neoplasms and autoimmune diseases: markers of association.

Clin Exp Rheumatol 2021 Jan 6. Epub 2021 Jan 6.

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

Objectives: To investigate the prognostic significance of concomitant autoimmune diseases (ADs) in myeloproliferative neoplasms (MPNs).

Methods: 435 subjects with a diagnosis of MPNs were included in this observational single institution longitudinal study. Of them, 34 patients presented an overt AD at diagnosis of MPN. Clinical presenting features, progression-free and overall survival were compared between MPN subgroups in relation to co-existence of AD at diagnosis of MPN.

Results: Compared to cases without ADs, the subjects with ADs were significantly younger, had lower haemoglobin and haematocrit levels and more frequently presented with splenomegaly. The clinical and biological features associated to progression-free and overall survival were: age, presence of splenomegaly, histotype (MF vs. PV vs. ET), anaemia, high platelet count and presence of any AD at diagnosis of MPN. The age-adjusted hazard ratio (HR) of progression for the presence of AD at diagnosis of MPN was 2.76. Overall survival was not significantly associated to AD at diagnosis, but the HR of progression for the presence of AD at diagnosis of MPN was 2.18.

Conclusions: A possible common genetic predisposition, the inflammatory bone marrow microenvironment and the activation of theJAK/STAT pathway could be considered as responsible for the observed association between MPNs and ADs.
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January 2021

Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib.

Ann Hematol 2021 Jan 3. Epub 2021 Jan 3.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.
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http://dx.doi.org/10.1007/s00277-020-04392-wDOI Listing
January 2021

Response assessment to venetoclax in relapsed/refractory chronic lymphocytic leukemia by ultrasonography.

Leuk Res 2021 01 30;100:106488. Epub 2020 Nov 30.

Azienda Ospedaliero-Universitaria Pisana, Department of Clinical and Experimental Medicine, UO Hematology, University of Pisa, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106488DOI Listing
January 2021

Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2.

Front Oncol 2020 2;10:1428. Epub 2020 Sep 2.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several "antiviral" genes, such as and , were upregulated, while genes with "proviral" action, such as , and , were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.
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http://dx.doi.org/10.3389/fonc.2020.01428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493657PMC
September 2020

Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms.

J Clin Med 2020 Jul 8;9(7). Epub 2020 Jul 8.

Department of Clinical and Experimental Medicine, UO Haematology, Azienda Ospedaliero-Universitaria Pisana, 56127 Pisa, Italy.

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV ( = 0.9); however, both MF and PV groups had significantly higher SS than the ET group ( = 0.011 and = 0.035, respectively) and healthy controls ( < 0.0001 and = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) ( = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) ( < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) ( < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively ( = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls ( = 0.001), but not between the patient cohorts with ET and PV and healthy controls ( = 0.999 and = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.
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http://dx.doi.org/10.3390/jcm9072149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408647PMC
July 2020

Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors.

Ann Hematol 2020 Jul 30;99(7):1525-1530. Epub 2020 May 30.

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

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rd TKIs.
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http://dx.doi.org/10.1007/s00277-020-04102-6DOI Listing
July 2020

The CoV-2 outbreak: how hematologists could help to fight Covid-19.

Pharmacol Res 2020 07 6;157:104866. Epub 2020 May 6.

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

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.
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http://dx.doi.org/10.1016/j.phrs.2020.104866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202852PMC
July 2020

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

Eur J Haematol 2020 Sep 22;105(3):286-291. Epub 2020 May 22.

Department of Translational and Precision Medicine, University "La Sapienza" of Rome, Rome, Italy.

Background: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined.

Methods: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated.

Results: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed.

Conclusions: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.
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http://dx.doi.org/10.1111/ejh.13436DOI Listing
September 2020

Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study.

Blood 2020 02;135(8):534-541

Department of Hematology, Ospedale San Carlo, Potenza, Italy.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.
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http://dx.doi.org/10.1182/blood.2019002969DOI Listing
February 2020

Myeloproliferative and lymphoproliferative disorders: State of the art.

Hematol Oncol 2020 Apr 27;38(2):121-128. Epub 2019 Dec 27.

UOC Ematologia Aziendale, Azienda Usl Toscana Nord Ovest, Pisa, Italy.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders complicated mainly by vascular events and transformation to myelofibrosis (for PV and ET) or leukemia. Although secondary malignancies, in particular, lymphoproliferative disorders (LPNs), are rare, they occur at a higher frequency than found in the general population, and there has been recent scientific discussion regarding a hypothetical relationship between treatment with JAK inhibitors in MPN and the risk of development of LPN. This has prompted increased interest regarding the coexistence of MPN and LPN. This review focuses on the role of JAK2 and the JAK/STAT pathway in MPN and LPN, whether there is a role for the genetic background in the occurrence of both MPN and LPN and whether there is a role for cytoreductive drugs in the occurrence of both MPN and LPN. Furthermore, whether an increased risk of lymphoma development is limited to patients who receive the JAK inhibitor ruxolitinib, is a more general phenomenon that occurs following JAK1/2 inhibition or is associated with preferential JAK1 or JAK2 targeting is discussed.
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http://dx.doi.org/10.1002/hon.2701DOI Listing
April 2020

Tracing the decision-making process for myelofibrosis: diagnosis, stratification, and management of ruxolitinib therapy in real-word practice.

Ann Hematol 2020 Jan 12;99(1):65-72. Epub 2019 Dec 12.

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

The management of patients with myelofibrosis (MF) has dramatically changed since the introduction of ruxolitinib as a tailored treatment strategy. However, the perceptions about the use of this drug in clinical practice remain, at times, a matter of discussion. We conducted a survey about the diagnostic evaluation, prognostic assessment, and management of ruxolitinib in real-life clinical practice in 18 Italian hematology centers. At diagnosis, most hematologists do not use genetically or molecularly inspired score systems to assess prognosis, mainly due to scarce availability of next-generation sequencing (NGS) methodology, with NGS conversely reserved only for a subset of lower-risk MF patients with the aim of possibly improving the treatment strategy. Some common points in the management of ruxolitinib were 1) clinical triggers for ruxolitinib therapy, regardless of risk category; 2) evaluation of infectious risk before the starting of the drug; and 3) schedule of monitoring during the first 12 weeks with the need, in some instances, of supportive treatment. Further development of international recommendations and insights will allow the achievement of common criteria for the management of ruxolitinib in MF, before and after treatment, and for the definition of response and failure.
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http://dx.doi.org/10.1007/s00277-019-03847-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944647PMC
January 2020

Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib.

Front Oncol 2019 7;9:1186. Epub 2019 Nov 7.

Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania, Italy.

The JAK-STAT signaling pathway plays a central role in signal transduction in hematopoietic cells, as well as in cells of the immune system. The occurrence in most patients affected by myeloproliferative neoplasms (MPNs) of driver mutations resulting in the constitutive activation of JAK2-dependent signaling identified the deregulated JAK-STAT signal transduction pathway as the major pathogenic mechanism of MPNs. It also prompted the development of targeted drugs for MPNs. Ruxolitinib is a potent and selective oral inhibitor of both JAK2 and JAK1 protein kinases. Its use in patients with myelofibrosis is associated with a substantial reduction in spleen volume, attenuation of symptoms and decreased mortality. With growing clinical experience, concerns about infectious complications, and increased risk of B-cell lymphoma, presumably caused by the effects of JAK1/2 inhibition on immune response and immunosurveillance, have been raised. Evidence shows that ruxolitinib exerts potent anti-inflammatory and immunosuppressive effects. Cellular targets of ruxolitinib include various components of both the innate and adaptive immune system, such as natural killer cells, dendritic cells, T helper, and regulatory T cells. On the other hand, immunomodulatory properties have proven beneficial in some instances, as highlighted by the successful use of ruxolitinib in corticosteroid-resistant graft vs. host disease. The objective of this article is to provide an overview of published evidence addressing the key question of the mechanisms underlying ruxolitinib-induced immunosuppression.
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http://dx.doi.org/10.3389/fonc.2019.01186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854013PMC
November 2019

Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors.

Int J Cardiol 2020 02 24;301:163-166. Epub 2019 Oct 24.

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

Background: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2/3 TKIs) in the real-life practice.

Methods: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib.

Results: The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control.

Conclusion: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.
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http://dx.doi.org/10.1016/j.ijcard.2019.10.036DOI Listing
February 2020

Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches.

Front Oncol 2019 6;9:833. Epub 2019 Sep 6.

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

More than 15 years ago, imatinib entered into the clinical practice as a "magic bullet"; from that point on, the prognosis of patients affected by chronic myeloid leukemia (CML) became comparable to that of aged-matched healthy subjects. The aims of treatment with tyrosine kinase inhibitors (TKIs) are for complete hematological response after 3 months of treatment, complete cytogenetic response after 6 months, and a reduction of the molecular disease of at least 3 logs after 12 months. Patients who do not reach their goal can switch to another TKI. Thus, the molecular monitoring of response is the main consideration of management of CML patients. Moreover, cases in deep and persistent molecular response can tempt the physician to interrupt treatment, and this "dream" is possible due to the quantitative PCR. After great international effort, today the BCR-ABL1 expression obtained in each laboratory is standardized and expressed as "international scale." This aim has been reached after the establishment of the EUTOS program (in Europe) and the LabNet network (in Italy), the platforms where biologists meet clinicians. In the field of quantitative PCR, the digital PCR is now a new and promising, sensitive and accurate tool. Some authors reported that digital PCR is able to better classify patients in precise "molecular classes," which could lead to a better identification of those cases that will benefit from the interruption of therapy. In addition, digital PCR can be used to identify a point mutation in the ABL1 domain, mutations that are often responsible for the TKI resistance. In the field of resistance, a prominent role is played by the NGS that enables identification of any mutation in ABL1 domain, even at sub-clonal levels. This manuscript reviews how the molecular tools can lead the management of CML patients, focusing on the more recent technical advances.
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http://dx.doi.org/10.3389/fonc.2019.00833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742705PMC
September 2019

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia.

Front Oncol 2019 24;9:532. Epub 2019 Jun 24.

Hematology Division, University of Pisa, Pisa, Italy.

Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a "real-life" setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were "resistant;" after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a "low" up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a "high" gene over-expression ( = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a "low" up-regulation were event-free vs. 33% of those who presented a "high" gene expression ( = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.
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http://dx.doi.org/10.3389/fonc.2019.00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601352PMC
June 2019

Incidence and evaluation of predisposition to cardiovascular toxicity in chronic myeloid leukemia patients treated with bosutinib in the real-life practice.

Ann Hematol 2019 Aug 1;98(8):1885-1890. Epub 2019 May 1.

Division of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, Sapienza University, Rome, Italy.

There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.
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http://dx.doi.org/10.1007/s00277-019-03705-yDOI Listing
August 2019

Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention.

Int J Cardiol 2019 08 17;288:124-127. Epub 2019 Apr 17.

Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Background: Risk of death is particularly high in patients with a previous history of arterial occlusive events (AOEs) and the probability for a recurrent event is around 20%. Little is known about recurrent AOE and the role of secondary prevention in patients with Chronic Myeloid Leukemia (CML) with previous AOE, treated with second- and third-generation tyrosine kinase inhibitors (2/3 TKIs), nilotinib, dasatinib, bosutinib and ponatinib.

Methods: We identified a real-life cohort of 57 consecutive adult CML patients treated with 2/3 TKI. All patients had a previous history of AOE. Ongoing use of secondary prevention of AOE (including antiplatelet agents, anticoagulant therapy, and statins) before starting a 2/3 TKI was recorded, as well as CV risk factors.

Results: The 60-month cumulative incidence rate of recurrent AOEs was 47.8 ± 10.9%. Despite a history of AOE, 10 patients (16%) were not receiving secondary preventative measures. Patients treated with nilotinib and ponatinib showed a higher incidence of recurrent AOEs (76.7 ± 14.3% and 64 ± 20.1%, respectively) than those treated with dasatinib and bosutinib (44 ± 24.2% and 30.5 ± 15.5%, respectively) (p = 0.01). Only treatment with a 2/3 TKI given as second or subsequent line therapy showed a significant association with an increased incidence of recurrent AOE (p = 0.039). Overall, 17 recurrent AOEs were observed; 3 CV-related deaths were reported.

Conclusion: CML patients with a previous history of AOE treated with 2/3 TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE; individualized treatment is needed to optimize secondary prevention.
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http://dx.doi.org/10.1016/j.ijcard.2019.04.051DOI Listing
August 2019

Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart.

Hematol Oncol 2019 Aug 17;37(3):296-302. Epub 2019 Apr 17.

Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.
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http://dx.doi.org/10.1002/hon.2606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766852PMC
August 2019

Chronic Myeloid Leukemia Patient's Voice About the Experience of Treatment-Free Remission Failure: Results From the Italian Sub-Study of ENESTPath Exploring the Emotional Experience of Patients During Different Phases of a Clinical Trial.

Front Psychol 2019 20;10:329. Epub 2019 Feb 20.

Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy.

The main objective of this study is to gain further insights on how chronic myeloid leukemia (CML) patients involved in an interventional clinical trial with the purpose of reaching treatment free remission (TFR) phase, perceived and experienced TFR failure. TFR failure was defined for the individual patient as either not being eligible for drug discontinuation or as having relapse in the TFR phase with reintroduction of nilotinib treatment. Using a qualitative approach, out of 25 patients with CML who experienced TFR failure 14 were interviewed. Patients' views and experiences were explored using in-depth interviews, analyzed using the Interpretative Phenomenological Analysis (IPA). The analysis of the interviews revealed that the experience of the diagnosis seems to have been lived as a traumatic break that has created a dichotomy, like an ambivalence in the ways in which CML patients perceived and experienced the whole disease journey, with contradictory feelings of both positive and negative emotions (e.g., a diagnosis of cancer, that is something distressing and of being afraid of, but also with a treatment and a life expectancies of which being grateful). This ambivalence of feelings was found to give meaning to the way in which patients cognitively and emotionally experienced the different steps of their disease history. Thus, four main issues, corresponding to different steps of the patients' journey, were identified: (1) the moment of the diagnosis, (2) the experience of the illness journey: disease and treatment, (3) the moment of "TFR failure," and (4) the impact of disease, treatment and relapse on the patient's life. This qualitative analysis helps in understanding patients' perspective, both in terms of getting access to the inner subjective experience of having CML and its strict relationship with the involvement in a trial or its cessation. Clinicians should consider that the way in which CML patients feel engaged in a clinical trial, create expectancies about TFR or experience the TFR failure is linked to the process of coping with the diagnosis, which is characterized by ambivalence.
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http://dx.doi.org/10.3389/fpsyg.2019.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391340PMC
February 2019

Flow Cytometry Assessment of CD26 Leukemic Stem Cells in Peripheral Blood: A Simple and Rapid New Diagnostic Tool for Chronic Myeloid Leukemia.

Cytometry B Clin Cytom 2019 07 3;96(4):294-299. Epub 2019 Feb 3.

Hematology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Background: Recent investigations in chronic myeloid leukemia (CML) have focused on the identification and characterization of leukemic stem cells (LSCs). These cells reside within the CD34 /CD38 /Lin fraction and score positive for CD26 (dipeptidylpeptidase IV) a marker, expressed in both bone marrow (BM) and peripheral blood (PB) samples, that discriminates CML cells from normal hematopoietic stem cells (HSCs) or from LSCs of other myeloid neoplasms. CD26 evaluation could be a useful tool to improve the identification of CML LCSs by using flow-cytometry assay.

Methods: CD26 LSCs have been isolated from EDTA PB and BM samples of patients with leucocytosis suspected for CML. Analysis of LSCs CML has been performed by using custom-made lyophilized pre-titrated antibody mixture test and control tube and a CD45 /CD34 /CD38 /CD26 panel as a strict flow cytometric gating strategy.

Results: The expression of CD26 on CD34 /CD38 population was detectable in 211/211 PB and 84/84 BM samples of subsequently confirmed BCR-ABL CP-CML patients. None of the 32 samples suspicious for CML but scoring negative for circulating CD26 LSCs were diagnosed as CML after conventional cytogenetic and molecular testing. To validate our results, we checked for PB CD26 LSCs in patients affected by other hematological disorders and they all scored negative for CD26 expression.

Conclusions: We propose flow cytometry evaluation of CD26 expression on PB CD34 /CD38 population as a new rapid, reproducible, and powerful diagnostic tool for the diagnosis of CML. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767040PMC
July 2019

The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia.

Front Oncol 2018 6;8:555. Epub 2018 Dec 6.

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

The Polycomb gene expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a -independent way. Even if, it is unknown where in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the expression, but they summed up what previously observed about the expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.
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http://dx.doi.org/10.3389/fonc.2018.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291509PMC
December 2018

Residual Peripheral Blood CD26 Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission.

Front Oncol 2018 30;8:194. Epub 2018 May 30.

Hematology Unit, Ospedale Oncologico A. Businco, Cagliari, Italy.

Chronic myeloid leukemia (CML) patients in sustained "deep molecular response" may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34/CD38 LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26 LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45/CD34/CD38 stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26 LSCs (median 19.20/μL, range 0.27-698.6). PB CD26 LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012-0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006-0.76). Notably, no correlation between BCR-ABL/ABL ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that "circulating" CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26 LSCs during TKI treatment and the role of a "stem cell response" threshold to achieve and maintain TFR are ongoing.
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http://dx.doi.org/10.3389/fonc.2018.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988870PMC
May 2018

Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment.

Stem Cells Transl Med 2018 03 8;7(3):305-314. Epub 2018 Feb 8.

Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018;7:305-314.
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http://dx.doi.org/10.1002/sctm.17-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827745PMC
March 2018

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