Publications by authors named "Sabina Russo"

42 Publications

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

Cancer Med 2021 Feb 16. Epub 2021 Feb 16.

Unit of Blood Disease and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili, Brescia, 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progressed to accelerated/blastic phase, all the patients (23.5%) losing MR regained the MR and none suffered from TKI withdrawn syndrome.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
February 2021

Next-generation sequencing improves BCR-ABL1 mutation detection in Philadelphia chromosome-positive acute lymphoblastic leukaemia.

Br J Haematol 2021 Jan 6. Epub 2021 Jan 6.

Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

BCR-ABL1 kinase domain mutation testing in tyrosine kinase inhibitor (TKI)-resistant Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) patients is routinely performed by Sanger sequencing (SS). Recently, next-generation sequencing (NGS)-based approaches have been developed that afford greater sensitivity and straightforward discrimination between compound and polyclonal mutations. We performed a study to compare the results of SS and NGS in a consecutive cohort of 171 Ph+ ALL patients. At diagnosis, 0/44 and 3/44 patients were positive for mutations by SS and NGS respectively. Out of 47 patients with haematologic resistance, 45 had mutations according to both methods, but in 25 patients NGS revealed additional mutations undetectable by SS. Out of 80 patients in complete haematologic response but with BCR-ABL1 ≥0·1%, 28 (35%) and 52 (65%) were positive by SS and NGS respectively. Moreover, in 12 patients positive by SS, NGS detected additional mutations. NGS resolved clonal complexity in 34 patients with multiple mutations at the same or different codons and identified 35 compound mutations. Our study demonstrates that, in Ph+ ALL on TKI therapy, NGS enables more accurate assessment of mutation status both in patients who fail therapy and in patients with minimal residual disease above 0·1%.
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http://dx.doi.org/10.1111/bjh.17301DOI Listing
January 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.

Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, 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

Successful Management of a Pregnant Patient With Chronic Myeloid Leukemia Receiving Standard Dose Imatinib.

In Vivo 2019 Sep-Oct;33(5):1593-1598

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

Background/aim: As approximately 10% of individuals developing chronic myeloid leukemia (CML) are females aged 20-44 years, a considerable number will consider a planned pregnancy if disease is well controlled by pharmacological treatment. The management of these young patients during pregnancy represents a therapeutic dilemma due to the potential teratogen effects of several tyrosine kinase inhibitors (TKIs) and is a matter of continuous debate. Indeed, despite the existence of several studies, there is currently no consensus on how to manage different pregnancy situations in subjects with CML.

Patients And Methods: We describe a female patient diagnosed with Ph-positive CML one month after her first delivery who achieved excellent hematological, cytogenetic and molecular responses while on imatinib mesylate (IM) treatment.

Results: The excellent responses allowed the patient to suspend TKI treatment in order to plan a second pregnancy. Despite IM discontinuation, stringent molecular monitoring of her BCR-ABL1/ABL1 levels allowed the safe delivery of the child and, while the patient eventually developed a molecular relapse after four years of treatment discontinuation, upon restarting IM she quickly regained a deep molecular response that is still ongoing.

Conclusion: Our case report demonstrates that, if the pregnancy is properly planned in CML patients, it can result in excellent management of the clinical therapeutic option for the benefit of both mother and child.
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http://dx.doi.org/10.21873/invivo.11641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755009PMC
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.

Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, 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

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.

Int J Mol Sci 2019 May 6;20(9). Epub 2019 May 6.

Division of Hematology and Bone Marrow Transplant, AOU Policlinico - V. Emanuele, 95123 Catania, Italy.

A reduction in transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR; 71.5% vs. 16.1%) compared to individuals with levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with values >10% at 3 months but <1% at 6 months fared significantly better than individuals with <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; < 0.001). Likewise, subjects with at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR compared to patients with <10% at 3 months but >1% at 6 months (75% vs. 18.2%; < 0.001). Finally, lower transcripts at diagnosis were associated with values <1% at 6 months ( < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.
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http://dx.doi.org/10.3390/ijms20092226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539817PMC
May 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.

Department of Clinical and Biological Sciences, University of Turin, Orbassano.

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

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

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

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

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

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

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

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

Disappearance of Acquired Hemophilia A after Complete Remission in a Multiple Myeloma Patient.

Turk J Haematol 2017 06 12;34(2):184-185. Epub 2017 Jan 12.

Messina University Faculty of Medicine, Department of Human Pathology and the Adult Developmental, Division of Hematology, Messina, Italy Phone: 0039 090 2212364

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http://dx.doi.org/10.4274/tjh.2016.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440874PMC
June 2017

Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies.

Cancer Invest 2017 Jan 20;35(1):1-22. Epub 2016 Dec 20.

a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy.

Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.
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http://dx.doi.org/10.1080/07357907.2016.1247166DOI Listing
January 2017

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Oncotarget 2016 Nov;7(48):80083-80090

Oncohematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, University of Milan, Milan, Italy.

Background: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.

Methods: 296 patients at 35 Italian hematological institutions were evaluated.

Results: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.

Conclusion: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.
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http://dx.doi.org/10.18632/oncotarget.11657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346773PMC
November 2016

Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity.

Turk J Haematol 2015 Jun;32(2):168-71

University of Messina Faculty of Medicine, Department of General Surgery and Oncology, Division of Hematology, Messina, Italy Phone: 0039 090 221 23 64 E-mail:

Imatinib mesylate is a small-molecule tyrosine kinase inhibitor (TKi) designed to target c-ABL and BCR-ABL, approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent. The aim of this work was to investigate the possible contribution of interleukin (IL)-33 and IL-31, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in a patient undergoing imatinib mesylate treatment. His IL-31 and IL-33 serum levels were significantly higher than in the control group (respectively 96.6 pg/mL vs. 7.623±7.681 pg/mL and 27.566 pg/mL vs. 6.170±7.060 pg/mL). In light of these findings, imatinib mesylate-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that TKi usage could cause keratinocyte injury, the release of IL-33, and the consequent interaction with its receptor on mast cells that induces the secretion of several factors capable of causing skin manifestations, including IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing the possible involvement of the IL-31/IL-33 axis in the pathogenesis of skin side effects related to imatinib mesylate treatment.
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http://dx.doi.org/10.4274/tjh.2014.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451486PMC
June 2015

Castleman-Kojima disease (TAFRO syndrome) in a Caucasian patient: A rare case report and review of the literature.

Blood Cells Mol Dis 2015 Oct 25;55(3):206-7. Epub 2015 Jun 25.

Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy, University of Messina, Via Consolare Valeria, 1, 98125 Messina, Italy.

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http://dx.doi.org/10.1016/j.bcmd.2015.06.013DOI Listing
October 2015

Vaccination of multiple myeloma: Current strategies and future prospects.

Crit Rev Oncol Hematol 2015 Nov 18;96(2):339-54. Epub 2015 Jun 18.

Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy-University of Messina, Messina, Italy.

Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses.
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http://dx.doi.org/10.1016/j.critrevonc.2015.06.003DOI Listing
November 2015

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

Leuk Res 2014 Oct 7;38(10):1173-6. Epub 2014 Jul 7.

Dipartimento di Biotecnologie Cellulari ed Ematologia, Università "La Sapienza", Via Benevento 6, Roma 00161, Italy.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.
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http://dx.doi.org/10.1016/j.leukres.2014.06.020DOI Listing
October 2014

Effect of therapeutic plasma exchange on plasma levels of oxidative biomarkers in a patient with thrombotic thrombocytopenic purpura.

Eur J Haematol 2015 Apr 2;94(4):368-73. Epub 2014 Jun 2.

School and Division of Allergy and Clinical Immunology, Department of Clinical and Expèerimental Medicine, University Hospital "G. Martino", Messina, Italy; Institute of Clinical Physiology, IFC CNR, Messina Unit, Messina, Italy.

Background: The role of oxidative stress in the initiation and progression of endothelial damage in thrombotic thrombocytopenic purpura (TTP) syndrome has been the subject of much speculation in the recent past.

Objectives: The aim of this study was to measure the concentration of plasma advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and carbonyl groups (CG) as markers of oxidative stress in plasma of a patient with TTP during the course of the disease until recovery and to evaluate the effect of plasmapheresis (PE) on these biomarkers.

Materials And Methods: The study consisted of plasma analysis of the patient, and 23 healthy subjects served as controls. In the patient with TTP, AOPP, AGE, and CG analysis was performed before and after each PE at the days +1 (Tα), +2, +4, +6, +10, +9, and +17 after the last plasmapheresis (Tω).

Results: Plasma concentrations of AOPPs were increased in the acute phase of TTP, and at Tα, the patient had AOPPs levels higher than 99°‰ of controls. AOPPs decreased in the recovery phase, and at Tω, their values were between 84° and 85°‰ of controls. No significant difference was found in AOPP levels before and after each PE. No significant differences for AGEs or CG concentrations were found at Tα with respect to the control group, while only a trend was observed for reduction of plasma AGEs after each plasmapheresis.

Conclusion: Our data seem to confirm the hypothesis that oxidative stress is a critical component of the pathogenesis of TTP.
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http://dx.doi.org/10.1111/ejh.12378DOI Listing
April 2015

MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma.

Br J Haematol 2014 Jun 12;165(6):801-13. Epub 2014 Mar 12.

Department of Biomedical Sciences and Morphological and Functional Images, University of Messina, Messina, Italy.

MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B-cell malignancy, multiple myeloma (MM). However, although MM is a disease of plasma cells, abnormalities have been detected in the peripheral blood of the patients. The goal of our study was to analyse the entire miRNome in peripheral lymphocytes of MM patients using reverse transcription quantitative polymerase chain reaction. Using in silica analysis, we also evaluated some of the most interesting and significant pathways. Analysis revealed that MM samples had a distinct miRNA profile compared to the controls. This resulted in the identification of 203 miRNAs, 85 of which were over-expressed and 118 under-expressed. Of these, 184 possessed validated or highly predicted mRNA targets. We identified 12 354 mRNA targets of the transcriptome: 36·4% of the related proteins are involved in death processes while the 21% are required for growth and cell proliferation. We have demonstrated that miRNAs are differentially expressed in the peripheral blood of MM patients compared to controls, affecting some pathways involved in the anti-apoptotic process, cell proliferation and maybe anti-angiogenesis.
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http://dx.doi.org/10.1111/bjh.12828DOI Listing
June 2014

New orally active proteasome inhibitors in multiple myeloma.

Leuk Res 2014 Jan 29;38(1):1-9. Epub 2013 Oct 29.

Division of Hematology University of Messina, Messina, Italy.

Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM.
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http://dx.doi.org/10.1016/j.leukres.2013.10.018DOI Listing
January 2014

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era.

Am J Hematol 2014 Feb;89(2):119-24

Chair of Haematology, Unit of Blood Diseases and Stem Cell Transplantation, University of Brescia, 25100, Brescia, Italy.

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.
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http://dx.doi.org/10.1002/ajh.23593DOI Listing
February 2014

Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study.

Drugs Aging 2013 Aug;30(8):629-37

Dipartimento di Biotecnologie Cellulari ed Ematologia, Università, La Sapienza, Via Benevento 6, 00161, Rome, Italy.

Background: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries.

Patients And Methods: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy.

Results: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively.

Conclusions: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.
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http://dx.doi.org/10.1007/s40266-013-0088-6DOI Listing
August 2013

Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma.

Eur J Haematol 2013 Jun 17;90(6):441-68. Epub 2013 Apr 17.

Division of Haematology, University of Messina, Messina, Italy.

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma (MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies (MoAbs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that MoAbs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, MoAbs have shown the ability to overcome resistance to these therapies. It remains to be defined how MoAb therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment.
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http://dx.doi.org/10.1111/ejh.12107DOI Listing
June 2013

Decreased plasma levels of IL-33 could contribute to the altered function of Th2 lymphocytes in patients with polycythemia vera and essential thrombocythemia.

Cancer Invest 2013 Mar 12;31(3):212-3. Epub 2013 Feb 12.

Department of Clinical and Experimental Medicine, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy.

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http://dx.doi.org/10.3109/07357907.2013.764566DOI Listing
March 2013

Evaluation of interleukin-23 plasma levels in patients with polycythemia vera and essential thrombocythemia.

Cell Immunol 2012 Jul-Aug;278(1-2):91-4. Epub 2012 Aug 1.

School and Division of Allergy and Clinical Immunology, Department of Human Pathology, University of Messina, Italy.

Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis share the same acquired genetic lesion, JAK2V617F. It is believed that cytokines participate in the activation of JAK2V617F. In this study, we analyzed the plasma levels of interleukin (IL)-23, IL-10 and IL-22 in patients with PV and ET. In the same subjects we also performed analysis of the JAK2(V617F) mutation, and evaluated a possible relationship between interleukin levels and thrombotic complications or with the symptom pruritus. Plasma levels of IL-23 were significantly increased in all patients with MPN in comparison to controls. Moreover, there was a significant difference between the levels of IL-23 in patients affected by PV and those measured in controls (8.57±3.69pg/mL vs. 6.55±4.125pg/mL; p<0.03). No difference was found between IL-23 levels in ET patients and controls. No statistically significant differences were found between the levels of IL-23, Il-22 or IL-10 in PV or ET subjects with or without thrombosis, in patients with or without pruritus, or according the JAK2V617F burden. In PV patients the JAK2 burden and Hb levels correlated with occurrence of pruritus. Our study seems to point out a possible involvement of IL-23 in the pathogenesis of PV.
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http://dx.doi.org/10.1016/j.cellimm.2012.07.003DOI Listing
January 2013

Changes in advanced oxidation protein products, advanced glycation end products, and s-nitrosylated proteins, in patients affected by polycythemia vera and essential thrombocythemia.

Clin Biochem 2012 Nov 28;45(16-17):1439-43. Epub 2012 Jul 28.

Division of Haematology, University of Messina, Messina, Italy.

Objectives: Oxidative stress has a clear pro tumoral effect in myeloproliferative neoplasms (MPDs). In this study, we analyzed oxidative stress in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Design and methods We analyzed serum levels of advanced oxidation protein products (AOPPs) degradation, advanced glycation end products (AGEs), and protein nitrosylation in ET and PV patients. We also evaluated neutrophil gelatinase-associated lipocalin (NGAL) levels, an acute phase protein isolated in human neutrophils, the activation status of platelets and leukocytes, and the JAK2 (V617F) mutation status.

Results: AOPPs and s-nitrosylated proteins were significantly higher in PV and ET subjects as compared to healthy volunteers, while AGEs were higher in ET subjects with respect to controls. Moreover, in PV patients we found a correlation between s-nitrosylated proteins and Hb value. In ET patients AGEs were significantly higher in patients with thrombosis compared with those without thrombotic events.

Conclusions: Our results suggest that oxidative stress could play a role in the physiopathology of MPDs and in the onset of myeloproliferative associated thrombotic risk.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.07.100DOI Listing
November 2012

Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions.

Inflamm Res 2012 Oct 7;61(10):1063-7. Epub 2012 Jun 7.

Department of Human Pathology, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy.

Objectives: Protein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS).

Methods: We evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects.

Results: Serum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions.

Conclusions: MM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications.
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http://dx.doi.org/10.1007/s00011-012-0498-7DOI Listing
October 2012

Relationship between advanced oxidation protein products, advanced glycation end products, and S-nitrosylated proteins with biological risk and MDR-1 polymorphisms in patients affected by B-chronic lymphocytic leukemia.

Cancer Invest 2012 Jan;30(1):20-6

School and Division of Allergy and Clinical Immunology, Department of Human Pathology, University of Messina, Messina, Italy.

The aim of our study was to analyze the serum levels of advanced oxidation protein products (AOPPs) and advanced glycation end products (AGEs), and protein nitrosylation in patients with B-chronic lymphocytic leukemia (B-CLL). AOPPs, AGEs, and S-nitrosylated were increased in B-CLL patients. The mutation of IgVH gene, CD 38, and Zap 70 expression were not associated with increased oxidative stress. The mutant 2677GT genotype was found to be associated with higher AGEs levels with respect to wild-type genotype, while as far the C3435T MDR1 polymorphism is concerned, subjects presenting wild-type genotype showed higher values of AOPPs with respect to heterozygous genotype. Our results suggest that B-CLL is associated with oxidative stress.
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http://dx.doi.org/10.3109/07357907.2011.629383DOI Listing
January 2012