Publications by authors named "Daniele Cattaneo"

84 Publications

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Unit of Hematology and Clinical Immunology, University of Padua, Padua, Italy.

Background: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities.

Methods: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival.

Results: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P = .004).

Conclusions: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.
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http://dx.doi.org/10.1002/cncr.33541DOI Listing
April 2021

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study.

Front Oncol 2021 12;11:637116. Epub 2021 Mar 12.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Lack of demonstrable mutations affecting , or driver genes within the spectrum of -negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5-10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the gene (55.0%), followed by (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.
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http://dx.doi.org/10.3389/fonc.2021.637116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006378PMC
March 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

Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19.

Blood Cancer J 2021 02 4;11(2):21. Epub 2021 Feb 4.

Hospital Moncloa, Madrid, Spain.

In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (-23.3%, p < 0.0001) than in PV (-16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.
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http://dx.doi.org/10.1038/s41408-021-00417-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871138PMC
February 2021

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge.

J Clin Med 2021 Feb 1;10(3). Epub 2021 Feb 1.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Policlinico Umberto 1, 00161 Rome, Italy.

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.
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http://dx.doi.org/10.3390/jcm10030515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867069PMC
February 2021

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib.

Leukemia 2021 02 7;35(2):485-493. Epub 2021 Jan 7.

Hospital Moncloa, Madrid, Spain.

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.
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http://dx.doi.org/10.1038/s41375-020-01107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789078PMC
February 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

Second primary malignancy in myelofibrosis patients treated with ruxolitinib.

Br J Haematol 2021 Apr 21;193(2):356-368. Epub 2020 Nov 21.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 10 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 10 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.
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http://dx.doi.org/10.1111/bjh.17192DOI Listing
April 2021

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

Cytogenetic study in primary myelofibrosis at diagnosis: Clinical and histological association and impact on survival according to WHO 2017 classification in an Italian multicenter series.

Hematol Oncol 2021 Feb 4;39(1):123-128. Epub 2020 Oct 4.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.
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http://dx.doi.org/10.1002/hon.2808DOI Listing
February 2021

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy.

Int J Mol Sci 2020 Aug 13;21(16). Epub 2020 Aug 13.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called "masked PV", as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients' prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.
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http://dx.doi.org/10.3390/ijms21165805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461104PMC
August 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

Management of Myelofibrosis: from Diagnosis to New Target Therapies.

Curr Treat Options Oncol 2020 04 30;21(6):46. Epub 2020 Apr 30.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

Opinion Statement: Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation.
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http://dx.doi.org/10.1007/s11864-020-00734-yDOI Listing
April 2020

Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real-world data.

Hematol Oncol 2020 Aug 20;38(3):372-380. Epub 2020 Apr 20.

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

The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P < .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count <150 × 10 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High-risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1-0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow-up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib-treated patients and is associated with DIPSS and MYSEC-PM risk in PMF and SMF, respectively.
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http://dx.doi.org/10.1002/hon.2737DOI Listing
August 2020

A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.

Blood 2020 07;136(2):171-182

Hematology Project Foundation, Vicenza, Italy.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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http://dx.doi.org/10.1182/blood.2019004596DOI Listing
July 2020

Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study.

Blood 2020 01;135(5):381-386

Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
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http://dx.doi.org/10.1182/blood.2019002614DOI Listing
January 2020

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis.

Cancer 2020 03 20;126(6):1243-1252. Epub 2019 Dec 20.

Unit of Hematology and Clinical Immunology, University of Padua, Padua, Italy.

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome.

Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis.

Results: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2-risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 ×10 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome.

Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.
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http://dx.doi.org/10.1002/cncr.32664DOI Listing
March 2020

Second cancers in MPN: Survival analysis from an international study.

Am J Hematol 2020 03 22;95(3):295-301. Epub 2019 Dec 22.

Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy.

One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.
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http://dx.doi.org/10.1002/ajh.25700DOI Listing
March 2020

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

Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms.

Blood 2020 01;135(2):133-144

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Approximately one-fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of the calreticulin gene (CALR), the gene encoding for calreticulin. A 52-bp deletion (type I mutation) and a 5-bp insertion (type II mutation) are the most frequent genetic lesions. The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and store-operated calcium (Ca2+) entry (SOCE) machinery in megakaryocytes (Mks) from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms (MPNs). In Mks from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of signal transducer and activator of transcription 5, AKT, and extracellular signal-regulated kinase 1/2, determining inositol triphosphate-dependent Ca2+ release from the endoplasmic reticulum (ER). This resulted in the dissociation of the ER protein 57 (ERp57)-mediated complex between calreticulin and stromal interaction molecule 1 (STIM1), a protein of the SOCE machinery that leads to Ca2+ mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca2+ flows in Mks contributes to the pathophysiology of CALR-mutated MPNs. In perspective, SOCE may represent a new therapeutic target to counteract Mk proliferation and its clinical consequences in MPNs.
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http://dx.doi.org/10.1182/blood.2019001103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952826PMC
January 2020

Hypereosinophilic syndromes in the precision medicine era: clinical, molecular aspects and therapeutic approaches (targeted therapies).

Expert Rev Hematol 2019 12 15;12(12):1077-1088. Epub 2019 Oct 15.

Division of Pathology, Department of Pathophysiology and Transplantation, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, Milan, Italy.

: Hypereosinophilic syndromes are a heterogeneous group of disorders that may be associated with life-threatening organ injury as a result of tissues infiltration by eosinophils. The main goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality.: Conventional therapies, including corticosteroids, hydroxyurea (hydroxycarbamide) and interferon-alpha, have shown variable efficacy and a non-negligible toxicity emphasizing the need of new therapeutic strategies based on drugs with different mechanisms of action.: Tyrosine kinase inhibitors have a central role among targeted therapies of hypereosinophilic syndromes. Imatinib, initially empirically used based on its activity in chronic myeloid leukemia, achieved preliminary excellent results further confirmed in large series of patients. Third-generation tyrosine kinase inhibitors such as ponatinib, while active in vitro and in vivo in animals, still deserve confirmation in properly designed clinical trials. In addition, clinical investigation on monoclonal antibodies against interleukin-5, interleukin-5Rα, IgE, and CD52 represents a promising area of research.
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http://dx.doi.org/10.1080/17474086.2019.1677461DOI Listing
December 2019

UGT1A1 genotype does not affect tyrosine kinase inhibitors efficacy and safety in chronic myeloid leukemia.

Am J Hematol 2019 11 9;94(11):E283-E285. Epub 2019 Aug 9.

Department of Clinical Sciences and Community Health, University of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.25596DOI Listing
November 2019