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Olga Mulas

Bio: Olga Mulas is an academic researcher from University of Cagliari. The author has contributed to research in topics: Myeloid leukemia & Medicine. The author has an hindex of 8, co-authored 24 publications receiving 221 citations.

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Journal ArticleDOI
TL;DR: This cross-sectional study provides 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.
Abstract: Chronic Myeloid Leukemia (CML) patients in sustained “deep molecular response” (DMR) 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. 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/ABLIS 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.

69 citations

Journal ArticleDOI
TL;DR: KIR genotypes could prove useful in identifying patients that are likely to maintain MR(4.5) after discontinuing TKI treatment, and younger age, Bx haplotype, and the combination KIR3DS1/KIR3DL1 present/HLA-Bw4 present were significantly associated with relapse.

47 citations

Journal ArticleDOI
TL;DR: 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, and patients' AOEs were identified.
Abstract: 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.

46 citations

Journal ArticleDOI
TL;DR: It is suggested that a decrease in properly stimulated and activated NK cells might contribute to the occurrence of CML and homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.

28 citations

Journal ArticleDOI
TL;DR: A large real-life cohort of Italian patients with CML treated with a 2TKIs as firstor subsequent-line of treatment was analyzed to evaluate the incidence of CV AEs and the association with the SCORE assessment and other baseline risk factors and the role of primary prophylaxis in preventing CV atherothrombotic events.
Abstract: To the Editor: Long-term treatment with the second-generation tyrosine kinase inhibitors (2TKIs) nilotinib and dasatinib may result in cardiovascular (CV) complications. Accumulating evidence suggests that the combination of a median age at the time of chronic myeloid leukemia (CML) diagnosis of greater than 60 years, when CV adverse events (AEs) are common, and the CV toxicity of 2TKIs represents per se a potential predisposing factor, which requires preventive strategies and CV surveillance in patients with CML. Previous studies have suggested the usefulness of the systematic coronary risk evaluation (SCORE) assessment at disease baseline, a 10-year risk estimation of fatal CV disease based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels, to identify patients who are at heightened risk of CV AEs during nilotinib treatment. A preventive strategy with primary prophylaxis based on aspirin remains under discussion. We therefore analyzed a large real-life cohort of Italian patients with CML treated with a 2TKIs as firstor subsequent-line of treatment. The primary objective was to evaluate the incidence of CV AEs and the association with the SCORE assessment and other baseline risk factors. The secondary objectives were to evaluate the role of primary prophylaxis in preventing CV atherothrombotic events. We identified consecutive adult patients with CML who initiated nilotinib or dasatinib as firstor subsequent-line treatment, between January 2012 and December 2015 in 20 Italian centers. Patients were stratified into low-moderate (SCORE 5%) or high-very high (SCORE >5%) CV risk. Additional risk factors were the presence of diabetes, body mass index>24.5 kg/m, mild or severe renal insufficiency, and dyslipidemia. Patients were also evaluated for comorbidities and a positive anamnesis of CV diseases, including angina, myocardial infarction, stroke, heart failure, arterial hypertension, cardiomyopathy, heart arrhythmia, valvular heart disease, aortic aneurysms, ischemic cerebrovascular events, peripheral artery disease, thromboembolic disease, and venous thrombosis. The presence of antithrombotic prophylaxis before initiating CML treatment was also recorded. The probability of the cumulative incidence of CV and atherothrombotic AEs was estimated after initiating treatment with 2TKIs. The cumulative incidence of deep molecular response (MR) was evaluated from the initiation of 2TKIs treatment. Multivariate analyses were performed using the Cox proportional hazards regression model. A total of 506 patients with CML were retrospectively recruited. The patients’ characteristics are shown in Supporting Information Table S1. The mean age at diagnosis was 52 years (range 18–87) and 57% were men. Sokal score was intermediate-high in 55% of patients. The mean follow-up time since CML diagnosis was 5.4 years (range 0.2–23). Overall, 286 patients were treated with nilotinib and 220 with dasatinib. 2TKIs were administered as first-, second-, and third-line treatment in 61%, 32%, and 7% of cases, respectively. The reasons for switching treatments in 196 patients were inefficacy in 63.8%, intolerance in 29.6%, and protocol requirements in 6.6%. The majority of patients (93%) were classified as at low-intermediate risk (SCORE 5%) and 7% as at high-very high risk (SCORE>5%). A positive history for CV diseases was noted in 181 (35.8%) patients. The 60-month CV AE cumulative incidence registered in the total cohort of patients was 21.762.8%. Patients treated with nilotinib and dasatinib showed CV AE incidence of 24.763.9% and 16.463.7%, respectively (P5 .25; NS) (Supporting Information Figure S1). Patients treated with 2TKIs administered as firstor second-line of treatment and as subsequent-line treatment showed a CV AE incidence of 12.963.5% and 22.964.4%, respectively (P5 .004). Patients with high-very high SCORE showed significantly high incidence of CV AEs (46.6616.6% vs. 2062.8%; P< .001). The mean time between the initiation of 2TKI treatment and the occurrence of CV AEs was 35.5 (range 1–69) months. Overall, 68 CV AEs were registered, with 2 event-related deaths; 40% of CV AEs were graded as 3/4 of common toxicity criteria. Supporting Information Table S2 reports the CV AEs and their management in the reallife. We did not find any association between TKI dose and CV AE incidence. The frequency of peripheral arterial disease (PAOD or atheromasic carotid disease) was significantly high in patients undergoing nilotinib treatment. Two patients died due to myocardial infarction during treatment. Overall, in 44% of cases 2TKI treatment did not require dose modification; 16% of patients reduced the dose and

23 citations


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Journal ArticleDOI
29 Jan 2019-JAMA
TL;DR: Differences in associated lipid levels between the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins, and the associations between triglyceride and LDL-C levels with the risk ofCHD became null after adjusting for differences in ApOB.
Abstract: Importance Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in theLPLgene and LDL-C–lowering variants in theLDLRgene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures Differences in plasma triglyceride, LDL-C, and ApoB levels associated with theLPLandLDLRgenetic scores. Main Outcomes and Measures Odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, theLPLscore was associated with 69.9-mg/dL (95% CI, 68.1-71.6;P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4;P = .04) higher LDL-C levels; while theLDLRscore was associated with 14.2-mg/dL (95% CI, 13.6-14.8;P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9;P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, theLPLandLDLRscores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802],P = 3.9 × 10−38and OR, 0.773 [95% CI, 0.747-0.801],P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065],P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055],P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798],P = 7.51 × 10−20). Conclusions and Relevance Triglyceride-loweringLPLvariants and LDL-C–loweringLDLRvariants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

410 citations

Journal ArticleDOI
TL;DR: It is pointed out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers.
Abstract: The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

326 citations

Journal ArticleDOI
TL;DR: In this paper, the authors presented a risk stratification proformas for oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.
Abstract: This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

264 citations