Publications by authors named "Fausto Castagnetti"

119 Publications

Dosing Strategies for Improving the Risk-Benefit Profile of Ponatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase.

Front Oncol 2021 16;11:642005. Epub 2021 Mar 16.

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

The treatment of chronic myeloid leukemia (CML) has been advanced by the development of small-molecule tyrosine kinase inhibitors (TKIs), which target the fusion protein BCR-ABL1 expressed by the Philadelphia chromosome. Ponatinib is a 3rd generation TKI that binds BCR-ABL1 with high affinity and inhibits most BCR-ABL1 mutants, including the T315I mutation. The approved starting dose of ponatinib is 45 mg once daily (full dose), however, the need for a full dose, especially in patients with dose adjustments due to tolerability problems, remains undemonstrated. Lower starting doses of ponatinib (30 mg or 15 mg once daily) for patients "with lesser degrees of resistance or multiple intolerances, especially those with an increased cardiovascular risk profile" has been recommended by the 2020 European LeukemiaNet. However, the available literature and guidance on the use of ponatinib at low dosage are limited. The objective of this paper is to describe how we select ponatinib dosage for CML patients in chronic phase in our clinical practice based on the available evidence and our clinical experience. We propose dosing regimens for the optimal starting dose for six generic cases of CML patients in chronic phase eligible for the switch to ponatinib and provide an algorithm to guide ponatinib dosing during treatment.
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http://dx.doi.org/10.3389/fonc.2021.642005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009177PMC
March 2021

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

Cancer Med 2021 Mar 16;10(5):1726-1737. Epub 2021 Feb 16.

University of Bologna, Bologna, Italy.

Background: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong.

Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR ) and to improve Health Related Quality of Life (HRQoL).

Results: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR /MR completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR was 81% and 23.5% of the patients who lost the molecular response regained the MR after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001).

Conclusions: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR /MR in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR regained the MR and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.
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http://dx.doi.org/10.1002/cam4.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940223PMC
March 2021

Hematology Patient Protection During the COVID-19 Pandemic in Italy: A Nationwide Nursing Survey.

Mediterr J Hematol Infect Dis 2021 1;13(1):e2021011. Epub 2021 Jan 1.

Hemato-Oncology Unit, Istituto Oncologico della Svizzera Italiana (IOSI), via A. Gallino 12, 6500 Bellinzona, Switzerland.

Background: Italy has been one of the first European countries hit by the COVID-19 pandemic, with many patients dying from severe respiratory issues, especially frail subjects. Hematology patients are generally thought to be at high risk of developing severe COVID-19-associated complications. The aim of this work was to describe the infection control measures adopted in Italian hematology settings to protect patients and health-care professionals.

Materials And Methods: On behalf of the Nursing Campus in Hematology Group, a nationwide nursing survey was conducted. Questionnaire items included general information, infection control measures, patient and health-care professional protection, information management, and participants' opinion on critical issues. Data have been analyzed by center location (Northern, Central, or Southern Italy) and by patient age (adult vs pediatric).

Results: Forty-four Italian hematology centers participated, representing 52.4% of those invited. Patients underwent nasopharyngeal swabs (93.2%) generally the day before admission (43.2%), though less frequently in Southern centers (p = 0.0377). Visitor restrictions were implemented in all centers: 65.9% barred all visitors, while 25.0% allowed visitors only for patients with specific conditions, especially in Central Italy. Deficiency of personal protective equipment, including masks (45.5%) and gloves (22.7%), was reported, although the nurses' opinion was that the emergency was nevertheless well managed to protect patients and professionals. Almost all health-care institutions (97.7%) provided recommendations on emergency management. No significant differences were found between adult and pediatric centers in terms of infection prevention and control.

Discussion: Low variability in patient protection strategies was observed, meaning that national recommendations were effective. However, some critical issues emerged regarding the management of infected health-care professionals and their contacts.
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http://dx.doi.org/10.4084/MJHID.2021.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813272PMC
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

Ceftolozane-Tazobactam Treatment of Hypervirulent Multidrug Resistant Infections in Neutropenic Patients.

Microorganisms 2020 Dec 21;8(12). Epub 2020 Dec 21.

Institute of Hematology "Seràgnoli", IRCCS-Azienda Ospedaliero Policlinico Sant'Orsola-Universitaria di Bologna, 40138 Bologna, Italy.

The effectiveness of ceftolozane/tazobactam for the treatment of infections in neutropenic patients caused by hypervirulent multidrug-resistant (MDR) has not been previously reported. We identified seven cases of MDR infection in neutropenic patients over a four-month period within the same hematology ward. Four cases were associated with rapid progression despite piperacillin-tazobactam or meropenem therapy, and three patients developed sepsis or extensive skin/soft tissue necrosis. In three of the four cases, patients were empirically switched from meropenem to ceftolozane/avibactam before carbapenem susceptibility test results were available, and all four patients underwent extensive surgical debridement or amputation of affected tissues and survived. Further investigation revealed a common bathroom source of MDR clonal subtypes ST175 and ST235 that harbored genes for type III secretion system expression and elaboration of ExoU or ExoS exotoxin. We conclude that ceftolozane/tazobactam plus early source control was critical for control of rapidly progressing skin and soft infection in these neutropenic patients caused by highly virulent ST175 and ST235 clones of MDR .
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http://dx.doi.org/10.3390/microorganisms8122055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767535PMC
December 2020

A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation.

J Clin Med 2020 Nov 17;9(11). Epub 2020 Nov 17.

Hematology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy.

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported-281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months-65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.
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http://dx.doi.org/10.3390/jcm9113692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698481PMC
November 2020

Validation and reference values of the EORTC QLQ-CML24 questionnaire to assess health-related quality of life in patients with chronic myeloid leukemia.

Leuk Lymphoma 2021 03 6;62(3):669-678. Epub 2020 Nov 6.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. & A. Seràgnoli", "Sant'Orsola-Malpighi" University Hospital, University of Bologna, Bologna, Italy.

Health-related quality of life (HRQOL) assessment is important to facilitate decisions in the current treatment landscape of chronic myeloid leukemia (CML). Therefore, the availability of a validated HRQOL questionnaire, specifically developed for CML patients treated with tyrosine kinase inhibitors (TKIs), may enhance quality of research in this area. We performed an international study including 782 CML patients to assess the validity of the EORTC QLQ-CML 24 questionnaire, and to generate HRQOL reference values to facilitate interpretation of results in future studies. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.66 to 0.83. In the confirmatory factor analysis, all standardized factor loadings exceeded the threshold of 0.40 (range 0.49-0.97), confirming the hypothesized scale structure. Reference values stratified by age and sex were also generated. Our findings support the use of the EORTC QLQ-CML 24, in conjunction with the EORTC QLQ-C30, as a valuable measure to assess HRQOL in CML patients.
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http://dx.doi.org/10.1080/10428194.2020.1838509DOI Listing
March 2021

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Leukemia 2020 08 29;34(8):2138-2149. Epub 2020 Jun 29.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie - IBE, Ludwig-Maximilians Universität, Munich, Germany.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
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http://dx.doi.org/10.1038/s41375-020-0931-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387299PMC
August 2020

Current Strategies and Future Directions to Achieve Deep Molecular Response and Treatment-Free Remission in Chronic Myeloid Leukemia.

Front Oncol 2020 2;10:883. Epub 2020 Jun 2.

Hematology Section, Department of Emergency and Organ Transplantation, University of Bari-Aldo Moro, Bari, Italy.

The treatment of chronic myeloid leukemia (CML) has been radically changed by the approval of tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity. CML is now managed as a chronic disease requiring long-term treatment and close molecular monitoring. It has been shown that in a substantial number of patients who have achieved a stable deep molecular response (DMR), TKI treatment can be safely discontinued without loss of response. Therefore, treatment-free remission (TFR), through the achievement of a DMR, is increasingly regarded as a feasible treatment goal in many CML patients. However, only nilotinib has approval in this setting and a number of controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication, and optimal strategies to achieve successful TFR. This narrative review aims to provide a comprehensive overview on how to optimize the path to DMR and TFR in patients with CML, and discusses recent data and future directions.
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http://dx.doi.org/10.3389/fonc.2020.00883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280484PMC
June 2020

Time to health-related quality of life improvement analysis was developed to enhance evaluation of modern anticancer therapies.

J Clin Epidemiol 2020 11 18;127:9-18. Epub 2020 Jun 18.

Italian Group for Adult Hematologic Diseases (GIMEMA) Data Center and Health Outcomes Research Unit, Rome, Italy; Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Objectives: Major advances have recently been made in the treatments of cancer, which now also have the potential to improve patients' health-related quality of life (HRQOL). We propose the time to HRQOL improvement (TTI) and the time to sustained HRQOL improvement (TTSI) as potentially important cancer outcomes to be used in longitudinal HRQOL analyses.

Study Design And Setting: As proof of principle, we defined TTI and TTSI, using the Fine-Gray model to include competing risks in estimates, in a case study in real life of a cohort of newly diagnosed patients with cancer receiving a targeted therapy. HRQOL was evaluated before and during therapy with six assessments over a 24-month period, using the well-validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30.

Results: For each assessed HRQOL domain, we assessed TTI and TTSI and estimated the cumulative incidence of patients' clinically meaningful improvements, also accounting for the occurrence of competing events.

Conclusion: TTI and TTSI are potentially important outcomes in the era of modern anticancer therapies. The analysis of TTI and TTSI by competing risks approach will further add to the statistical methods that can be used to inform on the impact of cancer therapies on patients' HRQOL.
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http://dx.doi.org/10.1016/j.jclinepi.2020.06.016DOI Listing
November 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

Ponatinib treatment in chronic myeloid leukemia cell lines targets aurora kinase A/FOXM1 axis.

Hematol Oncol 2020 Apr 28;38(2):201-203. Epub 2020 Jan 28.

Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale-DIMES-Istituto di Ematologia "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/hon.2703DOI Listing
April 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

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP.

Blood Adv 2019 12;3(24):4280-4290

Università Federico II, Naples, Italy.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.
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http://dx.doi.org/10.1182/bloodadvances.2019000865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929396PMC
December 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

Health-related quality of life of newly diagnosed chronic myeloid leukemia patients treated with first-line dasatinib versus imatinib therapy.

Leukemia 2020 02 2;34(2):488-498. Epub 2019 Sep 2.

Institute of Hematology "L. & A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Sant'Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

There is paucity of evidence-based data on health-related quality of life (HRQOL) outcomes of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We performed a multicenter propensity-matched case-control study to compare HRQOL of newly diagnosed CML patients treated with front-line dasatinib (cases) or imatinib (controls). Patient-reported HRQOL was assessed with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires. The impact on daily life scale of the EORTC QLQ-CML24 was selected a priori in the protocol as the primary HRQOL scale for the comparative analysis. Overall, 323 CML patients were enrolled of whom 223 in therapy with imatinib and 100 in therapy with dasatinib. Patients treated with dasatinib reported better disease-specific HRQOL outcomes in impact on daily life (Δ = 8.72, 95% confidence interval [CI]: 3.17-14.27, p = 0.002), satisfaction with social life (Δ = 13.45, 95% CI: 5.82-21.08, p = 0.001), and symptom burden (Δ = 7.69, 95% CI: 3.42-11.96, p = 0.001). Analysis by age groups showed that, in patients aged 60 years and over, differences favoring dasatinib were negligible across several cancer generic and disease-specific HRQOL domains. Our findings provide novel comparative HRQOL data that extends knowledge on safety and efficacy of these two TKIs and may help to facilitate first-line treatment decisions.
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http://dx.doi.org/10.1038/s41375-019-0563-0DOI Listing
February 2020

Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline.

Ann Hematol 2019 Oct 7;98(10):2329-2338. Epub 2019 Aug 7.

Institute of Hematology, Università Cattolica SacroCuore, Rome, Italy.

Very elderly (> 75 years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians' judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5 years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0 months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3-4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤ 80 years and > 80 years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80 years and > 80 years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.
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http://dx.doi.org/10.1007/s00277-019-03767-yDOI Listing
October 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

Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice.

Haematologica 2019 08 28;104(8):1589-1596. Epub 2019 Feb 28.

Chair and Hematology Section, Ferrarotto Hospital, Catania.

It is judged safe to discontinue treatment with tyrosine kinase inhibitors (TKI) for chronic myeloid leukemia (CML) in experimental trials on treatment-free remission (TFR). We collected a total of 293 Italian patients with chronic phase CML who discontinued TKI in deep molecular response. Seventy-two percent of patients were on treatment with imatinib, and 28% with second generation TKI at the time of discontinuation. Median duration of treatment with the last TKI was 77 months [Interquartile Range (IQR) 54;111], median duration of deep molecular response was 46 months (IQR 31;74). Duration of treatment with TKI and duration of deep molecular response were shorter with second generation TKI than with imatinib (<0.001). Eighty-eight percent of patients discontinued as per clinical practice, and reasons for stopping treatment were: toxicity (20%), pregnancy (6%), and shared decision between treating physician and patient (62%). After a median follow up of 34 months (range, 12-161) overall estimated TFR was 62% (95%CI: 56;68). At 12 months, TFR was 68% (95%CI: 62;74) for imatinib, 73% (95%CI: 64;83) for second generation TKI. Overall median time to restart treatment was six months (IQR 4;11). No progressions occurred. Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and second generation TKI is feasible and safe in clinical practice.
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http://dx.doi.org/10.3324/haematol.2018.205054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669161PMC
August 2019

The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview.

Leukemia 2019 05 23;33(5):1173-1183. Epub 2019 Jan 23.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität München, Munich, Germany.

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associated with gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.
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http://dx.doi.org/10.1038/s41375-018-0341-4DOI Listing
May 2019

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

Differential proteomic profile of leukemic CD34+ progenitor cells from chronic myeloid leukemia patients.

Oncotarget 2018 Apr 24;9(31):21758-21769. Epub 2018 Apr 24.

Hematology Unit, Sant'Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML. Our results showed that CP-CML CD34+ progenitors were characterized by significant lower phosphorylation of proteins involved in the regulation of growth and cell survival, such as tyrosine kinases of the Src family and members of STAT family, and by a significant higher phosphorylation of p53 (Ser15), compared to normal CD34+ cells from healthy donors. Consistent with these results, cell cycle analysis demonstrated that CP-CML CD34+ cells were characterized by higher percentage of cells in G0-phase compared to normal CD34+ cells. Analysis of expression profile on proteins involved in the apoptotic machinery revealed that, in addition, CD34+ cells from CP-CML were characterized by a significant lower expression of catalase and higher expression of HSP27 and FADD. In sum, we report that CD34+ cells from CP-CML are characterized by a proteomic and phospho-proteomic profile that promotes quiescence through the inhibition of proliferation and the promotion of survival. This differential signaling activation network may be addressed by novel targeted therapies aimed at eradicating CML stem cells.
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http://dx.doi.org/10.18632/oncotarget.24938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955129PMC
April 2018

Ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients in real-life practice.

Ann Hematol 2018 Sep 19;97(9):1577-1580. Epub 2018 Apr 19.

Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, "Sapienza" University, Via Benevento 6, 00161, Rome, Italy.

Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.
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http://dx.doi.org/10.1007/s00277-018-3337-2DOI Listing
September 2018

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib.

Cancer 2018 05 2;124(10):2228-2237. Epub 2018 Mar 2.

L. and A. Seràgnoli Institute of Hematology, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

Background: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib.

Methods: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis.

Results: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005).

Conclusions: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31323DOI Listing
May 2018