Publications by authors named "Anna Sicuranza"

25 Publications

  • Page 1 of 1

First reported case of secondary mixed phenotype acute leukemia after multiple myeloma.

Am J Blood Res 2021 20;11(1):123-131. Epub 2021 Feb 20.

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

In recent years the outcome of patients with multiple myeloma (MM) has significantly improved, due to new drugs. However, some agents, i.e. the alkylating drug melphalan, can be associated with an increased incidence of secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia are reported in the literature, and rarely acute lymphoblastic leukemia. Here we describe a unique case of a 56-years old female patient affected by MM since 2015 in complete remission after autologous stem cell transplant and in lenalidomide maintenance, who developed 2 years later mixed phenotype acute leukemia (MPAL). The patient, refractory to both lymphoblastic and myeloid acute leukemia regimens, achieved complete remission with bi-specific anti-CD19/anti-CD3 monoclonal antibody blinatumomab and with hypomethylating agent azacytidine plus the BCL-2 inhibitor venetoclax. She then underwent hematopoietic stem cell transplantation from HLA-identical sibling donor and she is still in complete remission after 9 months. To the best of our knowledge, there are no cases in the literature describing MPAL after autologous transplant for MM. Our patient was treated with blinatumomab and venetoclax and achieved complete remission 9 months from allogeneic transplant. The mechanism underlying the development of MPAL is not completely understood and therapies are still lacking. In this context the combination of blinatumomab, azacytidine and venetoclax successfully used in this patient may provide food for thought for further studies in this rare setting of patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010609PMC
February 2021

Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients.

Front Oncol 2020 21;10:570187. Epub 2020 Dec 21.

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

Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.
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http://dx.doi.org/10.3389/fonc.2020.570187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783633PMC
December 2020

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, Businco Hospital, ARNAS Brotzu, Cagliari, 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

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of -ITD in Mutated AML, Irrespectively of -ITD Allelic Burden.

Cancers (Basel) 2020 Dec 24;13(1). Epub 2020 Dec 24.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, 16132 Genova, Italy.

The mutations of and -ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an mutation reduces the negative prognostic impact of -ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the and/or -ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both mut ( < 0.05) and ELN 2017 risk score ( < 0.05) were significant predictors of survival. -mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant -ITD ( = 0.372), irrespective of -ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with mut and question the role of HSCT in 1st CR in mut patients with concomitant -ITD.
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http://dx.doi.org/10.3390/cancers13010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796342PMC
December 2020

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia.

Clin Case Rep 2020 Oct 7;8(10):2000-2002. Epub 2020 Jul 7.

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

A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.
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http://dx.doi.org/10.1002/ccr3.3041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562845PMC
October 2020

Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice.

J Pers Med 2020 Sep 10;10(3). Epub 2020 Sep 10.

Division of Hematology, University of Siena, 53100 Siena, Italy.

Novel drugs have revolutionized multiple myeloma therapy in the last 20 years, with median survival that has doubled to up to 8-10 years. The introduction of therapeutic strategies, such as consolidation and maintenance after autologous stem cell transplants, has also ameliorated clinical results. The goal of modern therapies is becoming not only complete remission, but also the deepest possible remission. In this context, the evaluation of minimal residual disease by techniques such as next-generation sequencing (NGS) and next-generation flow (NGF) is becoming part of all new clinical trials that test drug efficacy. This review focuses on minimal residual disease approaches in clinical trials, with particular attention to real-world practices.
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http://dx.doi.org/10.3390/jpm10030120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565263PMC
September 2020

Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.

Am J Blood Res 2020 25;10(4):97-108. Epub 2020 Aug 25.

Unit of Pathology, Department of Medical Biotechnologies, University of Siena Siena, Italy.

Introduction: Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR).

Objective: The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL.

Methods: We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81.

Results: CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS.

Conclusion: M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486489PMC
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 Medical Sciences and Public Health, University of Cagliari, Hematology Businco Hospital, Cagliari, 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

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.

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

Hodgkin lymphoma in the elderly: new perspectives and a 10-year monocenter real-life experience.

Hematol Oncol 2019 Oct 11;37(4):493-495. Epub 2019 Sep 11.

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

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http://dx.doi.org/10.1002/hon.2675DOI Listing
October 2019

Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy.

Hematol Oncol 2019 Oct 20;37(4):447-455. Epub 2019 Aug 20.

UO Ematologia, ASST Spedali Civili di Brescia, Brescia, Italy.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.
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http://dx.doi.org/10.1002/hon.2663DOI Listing
October 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

Prognostic significance of lymphocyte/monocyte count and neutrophil/lymphocyte count in peripheral T cell lymphoma.

Leuk Res 2019 02 22;77:5-7. Epub 2018 Dec 22.

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

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http://dx.doi.org/10.1016/j.leukres.2018.12.008DOI Listing
February 2019

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

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

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

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

Study of gene polymorphisms as predictors of treatment efficacy and toxicity in patients with indolent non-hodgkin lymphomas and mantle cell lymphoma receiving bendamustine and rituximab.

Br J Haematol 2019 01 11;184(2):223-231. Epub 2018 Sep 11.

Unit of Haematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m and bendamustine 90 mg/m every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.
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http://dx.doi.org/10.1111/bjh.15582DOI Listing
January 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, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, 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

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients.

Oncotarget 2016 Nov;7(44):72311-72321

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

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.
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http://dx.doi.org/10.18632/oncotarget.11100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342164PMC
November 2016

Peptide vaccines for hematological malignancies: a missed promise?

Int J Hematol 2014 Feb 8;99(2):107-16. Epub 2014 Jan 8.

Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Viale Bracci 16, 53100, Siena, Italy,

Despite the crucial aid that newly developed target therapies are providing to chemotherapy and stem cell transplant, the cure for many hematological malignancies is still an unmet need. Although available therapies are able to induce an effective debulking of the tumor, most of the time, an insidious minimal residual disease survives current treatments and it is responsible for an immediate or delayed relapse. Peptide-derived antitumor vaccines have been developed with the idea that an artificially "educated" immune system may exert an active specific antitumor response able to control and ultimately eradicate underlying post-treatment residual disease. This review will summarize current knowledge of peptide vaccines for hematological malignancies, trying to analyze promises and pitfalls of a safe and intelligent tool that after many years from its first appearance has not yet established its potential role as alternative immune mediated therapeutic approach for hematopoietic tumors.
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http://dx.doi.org/10.1007/s12185-013-1497-3DOI Listing
February 2014

Insight into the behavior of hairy cell leukemia by immunogenetic analysis.

Leuk Lymphoma 2011 Jun 19;52 Suppl 2:103-7. Epub 2011 Apr 19.

Sezione di Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università di Siena & AOUS, Siena, Italy.

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli: HCLs (i) have variable levels of IG somatic mutations, (ii) continue somatic mutations at low levels, (iii) have active processes of IG class switching after transformation, and (iv) have a relatively high frequency of selective events in the light chain of the BCR. It has recently emerged that an unmutated status of the HCL-derived IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG gene analysis may have biological and prognostic relevance in HCL and merits further characterization.
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http://dx.doi.org/10.3109/10428194.2011.569620DOI Listing
June 2011

Molecular insight into the biology and clinical course of hairy cell leukemia utilizing immunoglobulin gene analysis.

Leuk Lymphoma 2011 Jan 6;52(1):15-23. Epub 2010 Dec 6.

Ematologia e Trapianti, Università di Siena, Siena, Italy.

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several pieces of data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli. HCLs have variable levels of IG somatic mutations, and continue somatic mutations at low levels as well as IG class switching after transformation. More recent data also show the occurrence of selective events in the light chain of the BCR, suggesting a dominant role for IG status in the pathogenesis of HCL. Moreover, it has recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG analysis may have biological and prognostic relevance in HCL and merits further characterization.
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http://dx.doi.org/10.3109/10428194.2010.530362DOI Listing
January 2011

Lack of allelic exclusion by secondary rearrangements of tumour B-cell receptor light chains in hairy cell leukaemia.

Hematol Oncol 2011 Mar;29(1):31-7

Sezione and Unità di Ematologia, Università di Siena & AOUS, Italy.

Analyses of the tumour immunoglobulin (Ig) gene (IG) heavy (H) and light chains show heterogeneity of mutational status, but reveal common features of ongoing IGH isotype-switching with multiple IGH isotype expression and preference of IG lambda (IGL) light chain with selective use of IGLJ3. Phenotypic and immunogenetic analyses were performed in a series of 105 HCL patients to estimate prevalence of multiple IG light chain expression by the tumour cells. By phenotype, 3/105 HCL (2.9%) expressed double tumour-related Ig kappa (K) and L light chain proteins. By immunogenetic analysis, functional mutated double IGK(I) /IGK(II) , IGK(I) /IGL(I) and IGL(I) /IGL(II) transcripts were cloned and sequenced in 3/71 (4.2%) HCL. These latter three HCL expressed multiple IGH isotypes with mutated IGHVDJ rearrangements at the time of AID transcript expression. Most interestingly, the three cases had reinduced RAG1 transcript. In the double IGL expresser, single-cell analysis documented co-expression of the tumour-related IGLs in 5/6 cells (83%). In the IGK/IGL co-expresser, evidence of surface IgK/IgL isotype proteins confirmed functionality of the tumour-derived transcripts. The evidence of double light chain expression in single HCs and the new observation of RAG re-induction suggest ongoing selective influences on the BCR that may promote or maintain the HCL clone in the periphery.
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http://dx.doi.org/10.1002/hon.952DOI Listing
March 2011