Publications by authors named "Elisabetta Antonioli"

42 Publications

A real-world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma.

Hematol Oncol 2021 Feb 1;39(1):41-50. Epub 2020 Nov 1.

Azienda Ospedaliero-Universitaria di Bologna, Italia - Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale - Università degli Studi, Bologna, Italy.

Carfilzomib-lenalidomide-dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real-life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1-8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3-4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression-free survival (PFS) was 19.8 months and 1-year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p < 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p < 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p < 0.001 and HR = 0.18, p < 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real-world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
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http://dx.doi.org/10.1002/hon.2820DOI Listing
February 2021

Aggressive Disease Course of Multiple Myeloma with Concomitant ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report with an Unusual Presentation.

Case Rep Hematol 2020 16;2020:6309736. Epub 2020 Jan 16.

Haematology Unit, Careggi University Hospital, Florence, Italy.

ALK-negative anaplastic large cell lymphoma is a rare T-cell neoplasm with an aggressive course requiring prompt diagnostic work-up and treatment. Few cases of concomitant multiple myeloma and T-cell neoplasm are described in the literature, mainly regarding primary cutaneous anaplastic large cell lymphoma. We present the case of a 65-year-old man, simultaneously diagnosed with ALK-negative anaplastic large cell lymphoma with extranodal localization in the gastrocnemius muscle (stage 1AE) and IgG lambda multiple myeloma (ISS 2, Durie-Salmon stage 3A). Both diseases required therapeutic intervention due to the high proliferative index of lymphoma and the presence of bone lesions attributable to myeloma. The therapeutic program initially included chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; CHOEP), radiotherapy on the leg, bortezomib, and then consolidation with autologous hematopoietic stem cell transplantation. Despite being on bortezomib treatment and waiting for transplantation, the patient experienced an early myeloma progression that turned out to be refractory to second-line lenalidomide-based treatment. To our knowledge, this is the first case of concurrent diagnosis of extranodal ALK-negative anaplastic large cell lymphoma of the muscle and multiple myeloma. Simultaneous onset can be challenging for clinicians as both diseases may have an aggressive course requiring multiple treatments with increased risk of toxicity and complicated management.
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http://dx.doi.org/10.1155/2020/6309736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201522PMC
January 2020

Elotuzumab, lenalidomide, and dexamethasone as salvage therapy for patients with multiple myeloma: Italian, multicenter, retrospective clinical experience with 300 cases outside of controlled clinical trials.

Haematologica 2021 01 1;106(1):291-294. Epub 2021 Jan 1.

Hemato-Oncology Department, Augusta Victoria Hospital of Jerusalem.

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http://dx.doi.org/10.3324/haematol.2019.241513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776255PMC
January 2021

Autologous stem cell transplantation is safe in selected elderly multiple myeloma patients.

Eur J Haematol 2020 Feb 12;104(2):138-144. Epub 2019 Dec 12.

Cellular Therapy and Transfusion Medicine Unit, Careggi University Hospital, Florence, Italy.

Objectives: ASCT is currently the "gold standard" first-line treatment for multiple myeloma patients younger than 65 years old, and limited data on efficacy and safety in older patients are available.

Methods: We retrospectively analyzed a cohort of 83 newly diagnosed multiple myeloma patients aged 65 or older. All patients were evaluated for fitness at diagnosis and after bortezomib-based induction treatment.

Results And Conclusions: All patients collected an adequate PBSC graft, mainly after G-CSF plus cyclophosphamide; a median of 6.47 × 10 /kg CD34 + cells was collected. The conditioning regimen consisted of melphalan 100, 140 and 200 mg/m in 40, 15 and 28 patients, respectively. Median time to neutrophils' and platelets' recovery was 11 and 12 days, respectively. Adverse events of any grade were referred by 40% of patients. The overall response rate was 93%, CR/sCR were 39%. Median PFS was 35 months; median OS was not reached. In our study cohort, the achievement of at least VGPR after induction therapy and the obtainment of CR/sCR after ASCT are the only parameters that were associated with an improved PFS. ASCT is an effective and safe first-line treatment approach, a careful patients selection reduce the toxicity of the procedure.
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http://dx.doi.org/10.1111/ejh.13357DOI Listing
February 2020

Chemotherapy-related nail toxicity.

Int J Hematol 2019 Nov 10;110(5):519-520. Epub 2019 Aug 10.

Haematology Unit, Careggi Hospital-University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

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http://dx.doi.org/10.1007/s12185-019-02724-9DOI Listing
November 2019

Pregnancy complications predict thrombotic events in young women with essential thrombocythemia.

Am J Hematol 2014 Mar 19;89(3):306-9. Epub 2014 Feb 19.

Dept of Medicine -DIMED, Internal Medicine, University of Padua, Padua, Italy.

Although Philadelphia-negative myeloproliferative neoplasms (MPNs) occur typically in middle to advanced age, any age group may be affected, posing a challenge for their management during pregnancy when they occur in young females. There is a high incidence of thromboembolic events and pregnancy complications in patients with myeloproliferative neoplasms, and a possible relationship between these complications is a matter of concern. The aim of this article was to correlate thrombosis and pregnancy outcome in 158 females with ET experiencing 237 pregnancies. Seven patients had a thrombotic event before their first pregnancy, one of them ended (14.3%) in a miscarriage. Among the 151 patients with no history of thrombosis before they became pregnant, 40 (26.5%) had a miscarriage (P = NS). Eighteen patients (11.4%) developed major thrombotic complications (12 splanchnic vein, 1 cerebral vein, 2 coronary syndromes, and 3 strokes) after at least one pregnancy (4 uneventful and 14 complicated). The occurrence of thrombosis was significantly more frequent (P < 0.001) in patients with a history of pregnancy complications (28%) than in those experiencing a normal pregnancy and delivery (3.7%). Pregnancy complications in women with ET are associated with a higher risk of subsequent thromboses, so pregnant women with this neoplasm who miscarry need to be carefully monitored.
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http://dx.doi.org/10.1002/ajh.23635DOI Listing
March 2014

A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment.

Blood 2012 Aug 26;120(6):1197-201. Epub 2012 Jun 26.

Division of Hematology, Department of Internal Medicine, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy.

Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 10(9)/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 10(9)/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.
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http://dx.doi.org/10.1182/blood-2012-01-403279DOI Listing
August 2012

Leukocytosis as an important risk factor for arterial thrombosis in WHO-defined early/prefibrotic myelofibrosis: an international study of 264 patients.

Am J Hematol 2012 Jul 10;87(7):669-72. Epub 2012 May 10.

Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

We aimed to determine risk factors for thrombotic events in early/prefibrotic myelofibrosis diagnosed according to the World Health Organization criteria. Multivariate Cox regression analysis was calculated on a total number of 264 patients derived from an international database. After a median follow-up of 6.28 years, 42 (15.9%) patients experienced arterial (n = 31) or venous thrombosis (n = 11). A higher leukocyte count correlated with an increased risk for total thrombosis and in particular, with an increased risk for arterial thrombosis (P = 0.005, HR 1.15 and P = 0.047, HR 1.12, respectively). A platelet count above 870 × 10⁹/L was associated with a lower risk for total thrombosis and also for venous thrombosis (P = 0.022, HR 0.44 and P = 0.027, HR 0.19). Moreover, a lower hemoglobin level was associated with an increased risk for venous thrombosis (P = 0.007, HR 0.59). Our data indicate that leukocytosis is a prominent risk factor for thrombosis in early/prefibrotic MF.
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http://dx.doi.org/10.1002/ajh.23217DOI Listing
July 2012

Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN.

Am J Hematol 2012 May 4;87(5):552-4. Epub 2012 Apr 4.

Hematology Unit, AOU Careggi Largo Brambilla 3, Firenze, IT.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.
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http://dx.doi.org/10.1002/ajh.23160DOI Listing
May 2012

Blood tests may predict early primary myelofibrosis in patients presenting with essential thrombocythemia.

Am J Hematol 2012 Feb 11;87(2):203-4. Epub 2012 Jan 11.

Division of Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy.

According to World Health Organization (WHO)-defined criteria, patients presenting clinically as essential thrombocythemia (ET) may show early primary myelofibrosis (PMF) with accompanying thrombocythemia [1]. Previous clinicopathological studies revealed that laboratory parameters like gender-matched hemoglobin (Hb), white blood cell (WBC) count, and particularly lactate dehydrogenase (LDH) values are significantly different in PMF [2]. By strictly applying the WHO criteria, our investigation was aimed to study sensitivity and specificity of these features in an exploratory cohort of 536 patients and to validate the results on an independently recruited series of 321 strictly corresponding patients. The discriminatory power of these parameters (Hb, WBC, and LDH) was tested by plotting their receiver operating characteristic curves. The best performance was found for LDH (areas under the curve, AUC 5 0.7059). WBC and Hb had superimposable curves, with AUC of 0.6279 and 0.6257, respectively. A diagnostic algorithm was generated by applying these parameters in a stepwise fashion. Nearly half of the patients could be correctly allocated to WHO-defined ET or early PMF in both cohorts investigated. It is important to note that this result does not substitute bone marrow morphology with hematological parameters, however, in clinical practice may alert physicians to get more suspicious of early PMF in a patient presumably presenting with ET.
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http://dx.doi.org/10.1002/ajh.22241DOI Listing
February 2012

Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study.

J Clin Oncol 2011 Aug 11;29(23):3179-84. Epub 2011 Jul 11.

Ospedali Riuniti di Bergamo, Bergamo, Italy.

Purpose: The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction.

Methods: Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review.

Results: Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10(9)/L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population.

Conclusion: This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.
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http://dx.doi.org/10.1200/JCO.2010.34.5298DOI Listing
August 2011

Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.

Blood 2011 Aug 1;118(8):2069-76. Epub 2011 Jul 1.

Department of Medical and Surgical Care, Section of Hematology, University of Florence, Florence, Italy.

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant.
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http://dx.doi.org/10.1182/blood-2011-01-330563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365876PMC
August 2011

Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients.

Blood 2011 Jun 13;117(22):5857-9. Epub 2011 Apr 13.

Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo, Italy.

In an international collaborative study, a central histologic review identified 891 patients with essential thrombocythemia, strictly defined by World Health Organization criteria. After a median follow-up of 6.2 years, 109 (12%) patients experienced arterial (n = 79) or venous (n = 37) thrombosis. In multivariable analysis, predictors of arterial thrombosis included age more than 60 years (P = .03; hazard ratio [HR] = 1.7), thrombosis history (P = .003; HR = 2.1), cardiovascular risk factors including tobacco use, hypertension, or diabetes mellitus (P = .007; HR = 1.9), leukocytosis (> 11 × 10(9)/L; P = .04; HR = 1.7), and presence of JAK2V617F (P = .009; HR = 2.6). In contrast, only male gender predicted venous thrombosis. Platelet count more than 1000 × 10(9)/L was associated with a lower risk of arterial thrombosis (P = .007; HR = 0.4). These associations, except the one with leukocytosis, remained significant (or near significant) when analysis was restricted to JAK2V617F-positive cases. The current study clarifies the contribution of specific disease and host characteristics to the risk of arterial versus venous thrombosis in essential thrombocythemia.
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http://dx.doi.org/10.1182/blood-2011-02-339002DOI Listing
June 2011

Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3.

Haematologica 2011 Feb 20;96(2):315-8. Epub 2010 Dec 20.

Hematology Department, Ospedali Riuniti, Largo Barozzi 1, 24128 Bergamo, Italy.

We tested the hypothesis that levels of pentraxin high sensitivity C-reactive protein and pentraxin 3 might be correlated with cardiovascular complications in patients with essential thrombocythemia and polycythemia vera. High sensitivity C-reactive protein and pentraxin 3 were measured in 244 consecutive essential thrombocythemia and polycythemia vera patients in whom, after a median follow up of 5.3 years (range 0-24), 68 cardiovascular events were diagnosed. The highest C-reactive protein tertile was compared with the lowest (>3 vs. <1 mg/L) and correlated with age (P=0.001), phenotype (polycythemia vera vs. essential thrombocythemia, P=0.006), cardiovascular risk factors (P=0.012) and JAK2V617F allele burden greater than 50% (P=0.003). Major thrombosis rate was higher in the highest C-reactive protein tertile (P=0.01) and lower at the highest pentraxin 3 levels (P=0.045). These associations remained significant in multivariate analyses and indicate that blood levels of high sensitivity C-reactive protein and petraxin 3 independently and in opposite ways modulate the intrinsic risk of cardiovascular events in patients with myeloproliferative disorders.
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http://dx.doi.org/10.3324/haematol.2010.031070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031701PMC
February 2011

Hydroxyurea in essential thrombocythemia: rate and clinical relevance of responses by European LeukemiaNet criteria.

Blood 2010 Aug 17;116(7):1051-5. Epub 2010 May 17.

Hematology Department, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo, Italy.

A definition of response by cytoreductive therapy in essential thrombocythemia was recently provided by the European LeukemiaNet (ELN). Complete, partial, or no clinicohematologic responses were defined on the bases of platelet count, disease-related symptoms, spleen size, and white blood cell count. To provide estimates and clinical correlation of responses according to these criteria, we retrospectively examined 416 essential thrombocythemia patients treated with hydroxyurea for at least 12 months. Complete response, partial response, and no response were 25%, 58%, and 17%, respectively. Age more than 60 years and JAK2V617F mutation were significant predictors of response. After a median follow-up of 3.9 years, we registered 23 deaths, 16 hematologic transformations, and 27 thrombotic events (rate, 1.66% patients/year). Age, previous thrombosis, leukocytosis (white blood cell count > 10 x 10(9)/L), but not ELN responses, were independently associated with higher risk of thrombosis. The actuarial probability of thrombosis was significantly influenced by leukocytosis (P = .017) and not by platelet count, indicating that platelet number does not seem of prime relevance in the definition of ELN response.
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http://dx.doi.org/10.1182/blood-2010-03-272179DOI Listing
August 2010

Thrombosis in primary myelofibrosis: incidence and risk factors.

Blood 2010 Jan 20;115(4):778-82. Epub 2009 Nov 20.

Hematology Department, Ospedali Riuniti di Bergamo, Bergamo, Italy.

We assessed frequency and predictive factors for major cardiovascular (CV) events in 707 patients with primary myelofibrosis (PMF) followed in 4 European institutions. A total of 236 deaths (33%) were recorded for an overall mortality of 7.7% patient-years (pt-yr). Fatal and nonfatal thromboses were registered in 51 (7.2%) patients, with a rate of 1.75% pt-yr. If deaths from non-CV causes were considered as competing events, we estimated that the adjusted rate of major thrombotic events would have been 2.2% pt-yr. In a multivariable model, age older than 60 years (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.24-4.39, P = .01) and JAK2 mutational status (HR, 1.92; 95% CI, 1.10-3.34; P = .02) were significantly associated with thrombosis, whereas the strength of the association between leukocyte count higher than 15 x 10(9)/L and CV events was of borderline significance (HR, 1.72; 95% CI, 0.97-2.72; P = .06). The highest incidence of fatal and nonfatal thrombosis was observed when the mutation was present along with leukocytosis (3.9% pt-yr; HR, 3.13; 95% CI, 1.26-7.81). This study is the largest hitherto carried out in this setting and shows that the rate of major CV events in PMF is comparable with that reported in essential thrombocythemia, and it is increased in aged patients and those with JAK2 V617F mutation and leukocytosis.
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http://dx.doi.org/10.1182/blood-2009-08-238956DOI Listing
January 2010

JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera.

Exp Hematol 2009 Sep 24;37(9):1016-21. Epub 2009 Jun 24.

Hematology Department, Ospedali Riuniti di Bergamo, Bergamo, Italy.

Objective: A direct comparison of the incidence and risk factors of major thrombosis in essential thrombocythemia (ET) and polycythemia vera (PV) according to their respective JAK2V617F allele burden is the object of this study.

Materials And Methods: We compared the rate (%/patients/year) of major thrombosis in 867 ET patients (57% JAK2V617F) with that of 415 PV patients (all JAK2V617F) and examined risk factors.

Results: Patients with ET wild-type, ET V617F, and PV showed a rate of thrombosis of 1.4%, 2.1%, and 2.7%/patients/year, respectively. The latter was found to progressively increase according to time of diagnosis. Actuarial probability of arterial and venous thrombosis in the first 5 years of diagnosis was roughly similar in the three groups. While in the subsequent periods, the curves of mutated ET patients diverged from wild-type, and after 10 to 15 years the ET-mutated arm approached PV.

Conclusion: These findings support the concept of a continuum between ET JAK2 mutated and PV, not only in reference to the hematological phenotype, but also in terms of vascular events.
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http://dx.doi.org/10.1016/j.exphem.2009.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746993PMC
September 2009

Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele.

Blood 2009 Aug 23;114(8):1477-83. Epub 2009 Jun 23.

Unità Funzionale di Ematologia, Dipartimento di Area Critica, Università di Firenze, and Istituto Toscano Tumori, Firenze, Italy.

A total of 186 patients with primary myelofibrosis (PMF) were genotyped for JAK2V617F at diagnosis aimed at analyzing the correlation of mutational status and mutated allele burden with outcome variables, including time to anemia, leukocytosis, leukopenia, thrombocytopenia, massive splenomegaly, leukemia, and with overall survival. A total of 127 JAK2V617F-mutated patients (68% of whole series) were divided in quartiles of V617F allele burden. After a median follow-up of 17.2 months, 23 patients died, 15 because of leukemia. A JAK2V617F mutated status did not impact on the rate of leukemia transformation or overall survival. Patients in the lower quartile had shorter time to anemia and leukopenia and did not progress to large splenomegaly. Furthermore, survival was significantly reduced in the lower quartile compared with upper quartiles and JAK2 wild-type patients. In multivariate analysis, factors associated with reduced survival were age, a blast count more than 1%, and a JAK2V617F burden within first quartile. Causes of death in the lower quartile were represented mainly by systemic infections. We conclude that a low JAK2V617F allele burden at diagnosis is preferentially associated with a myelodepletive rather than myeloproliferative phenotype and represents an independent factor associated with shortened survival in patients with PMF.
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http://dx.doi.org/10.1182/blood-2009-04-216044DOI Listing
August 2009

Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms.

Cancer Epidemiol Biomarkers Prev 2009 Jul 16;18(7):2068-73. Epub 2009 Jun 16.

Unità Funzionale di Ematologia, Dipartimento di Area Critica, Università degli Studi di Firenze, Florence, Italy.

Association of myeloproliferative neoplasm (MPN) with lymphoproliferative neoplasm (LPN) has been occasionally reported. The aim of this study, which included 353 patients with polycythemia vera and 467 with essential thrombocythemia, was to assess whether the risk of developing LPN is increased in MPN patients. Expected numbers of LPN incident cases were calculated based on 5-year age group, gender, and calendar time-specific cancer incidence rates in the general population of the same area. Standardized incidence ratios were computed to estimate the relative risk of developing LPN. Analyses were carried out for the whole series and then separately for essential thrombocythemia and polycythemia vera, gender, and JAK2V617F genotype. With 4,421 person-years, we found 11 patients developing LPN, including four chronic lymphocytic leukemias, five non-Hodgkin's lymphomas, and two plasma cell disorders, after a median interval time of 68 months from MPN diagnosis. Cumulative risk to develop LPN at 5 and 10 years was 0.93% (95% confidence interval, 0.39-2.22) and 2.96% (95% confidence interval, 1.52-5.72), respectively. There was a 3.44-fold increased risk of LPN compared with the general population, ranging from 2.86 for plasma cell disorder to 12.42 for chronic lymphocytic leukemia; the risk was significantly increased in JAK2V617F mutated patients (5.46-fold) and in males (4.52-fold). The JAK2V617F mutation was found in lymphoid tumor cells in two of three cases evaluated, indicating that, in some patients, LPN originated in a JAK2V617F mutated common lymphoid-myeloid hematopoietic progenitor cell. We conclude that the risk of developing LPN is significantly increased in MPN patients compared with the general population.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0353DOI Listing
July 2009

Treatment options for essential thrombocythemia and polycythemia vera.

Expert Rev Hematol 2009 Feb;2(1):41-55

UF di Ematologia, Dipartimento di Area Critica Medico-Chirurgica, Università degli Studi, Viale Morgagni, Florence, Italy.

Polycythemia vera and essential thrombocythemia are the most common chronic myeloproliferative neoplasms; their molecular basis has been appreciated only recently and is briefly discussed in this article. Major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as by evolution to myelofibrosis or transformation to acute leukemia. Therapy is currently aimed at reducing the rate of thrombosis without increasing the risk of hematologic transformation that might be caused by exposure to cytotoxic drugs. A risk-oriented approach is employed for stratifying patients to the most appropriate therapeutic options. However, results of clinical trials with interferon, and the expected effects of novel drugs selectively targeting the abnormal pathways that are involved in the clonal myeloproliferation, are pushing therapeutic goals from disease control only to cure. These different issues, and current recommendations for treatment, will be discussed in the review.
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http://dx.doi.org/10.1586/17474086.2.1.41DOI Listing
February 2009

Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia.

Blood 2008 Oct 27;112(8):3135-7. Epub 2008 Jun 27.

Department of Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy.

To elucidate the role of thrombocytosis, alone or in combination with standard (age, previous cardiovascular events) and novel (leukocytosis, JAK2(V617F) mutational status) risk factors, in the cardiovascular events of essential thrombocythemia (ET), we analyzed a cohort of 1063 patients. We found that a platelet count at diagnosis greater than 1000 x 10(9)/L was associated with significantly lower rate of thrombosis in multivariable analysis and, if combined with leukocytes less than 11 x 10(9)/L, pointed to a "low-risk" category with a rate of thrombosis of 1.59% of patients/year. On the contrary, the highest risk category (thrombosis rate, 2.95% of patients/year) was constituted of patients with leukocytosis, lower platelet count, and a JAK2(V617F) mutated genotype in most cases (77% vs 26% in the low-risk group), independently from standard risk factors. These data challenge the theory that elevated platelet count increases thrombosis risk in ET and suggest prospective clinical trials to support this hypothesis.
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http://dx.doi.org/10.1182/blood-2008-04-153783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569168PMC
October 2008

Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia.

Blood 2008 Aug 2;112(3):844-7. Epub 2008 Jun 2.

Unita Funzionale di Ematologia, Dipartimento di Area Critica Medico-Chirurgica, Università degli Studi, Florence, Italy.

Among 994 patients with essential thrombocythemia (ET) who were genotyped for the MPLW515L/K mutation, 30 patients carrying the mutation were identified (3.0%), 8 of whom also displayed the JAK2V671F mutation. MPLW515L/K patients presented lower hemoglobin levels and higher platelet counts than did wild type (wt) MPL; these differences were highly significant compared with MPLwt/JAK2V617F-positive patients. Reduced hemoglobin and increased platelet levels were preferentially associated with the W515L and W515K alleles, respectively. MPL mutation was a significant risk factor for microvessel disturbances, suggesting platelet hyperreactivity associated with constitutively active MPL; arterial thromboses were increased only in comparison to MPLwt/JAK2wt patients. MPLW515L/K patients presented reduced total and erythroid bone marrow cellularity, whereas the numbers of megakaryocytes, megakaryocytic clusters, and small-sized megakaryocytes were all significantly increased. These data indicate that MPLW515L/K mutations do not define a distinct phenotype in ET, although some differences depended on the JAK2V617F mutational status of the counterpart.
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http://dx.doi.org/10.1182/blood-2008-01-135897DOI Listing
August 2008

Leukocytosis and risk stratification assessment in essential thrombocythemia.

J Clin Oncol 2008 Jun 28;26(16):2732-6. Epub 2008 Apr 28.

Hematology Department, Ospedali Riuniti di Bergamo, Bergamo, Italy.

Purpose: Established risk factors for thrombosis in essential thrombocythemia (ET) include age and previous vascular events. We aimed to refine this risk stratification by adding baseline leukocytosis.

Patients And Methods: We enrolled 657 patients with ET followed for a median of 4.5 years who developed 72 major thrombosis. Cox proportional hazard model was performed to analyze the thrombotic risk and to discriminate ET patients with or without thrombosis, multivariable C statistic index was used. We searched for leukocytes cutoff with the best sensitivity and specificity by a receiver operating characteristic curve.

Results: Results confirmed that age and prior events are independent risk factors for thrombosis and showed a gradient between baseline leukocytosis and thrombosis. On the contrary, no significant association was found either for JAK2(V617F) allele burden and for other laboratory parameters, including platelet number. In the model with conventional risk factors alone, C statistic ratio for total thrombosis was 0.63 and when leukocytosis was added, the change was small (C = 0.67). In contrast, in younger and asymptomatic patients (low-risk category), C statistic value indicated an high risk for thrombosis in patients with leukocytosis, similar to that calculated in conventionally defined high-risk group (C = 0.65). The best leukocyte cutoff values for predicting the events was found to be 9.4 (x 10(9)/L).

Conclusion: We suggest to include baseline leukocytosis in the risk stratification of ET patients enrolled in clinical trials.
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http://dx.doi.org/10.1200/JCO.2007.15.3569DOI Listing
June 2008

Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia.

Haematologica 2008 Jan;93(1):41-8

Department of Hematology, University of Florence, 50134, Florence, Italy.

Background: Fifty to sixty percent of patients with essential thrombocythemia harbor the JAK2(V617F) mutation. The impact of this mutation on clinical phenotype is still debated. The aim of this study was to evaluate possible correlations between JAK2(V617F) mutant allele burden and both clinical presentation and hematologic abnormalities in essential thrombocythemia patients.

Design And Methods: In this single-center retrospective study, JAK2(V617F) allele load was measured by sensitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the granulocytes of 260 patients diagnosed as having essential thrombocythemia according to WHO criteria.

Results: Median V617F allele burden in patients with the mutation (n=165, 63.4%) was 24%, ranging from 1% to 87%; an allele burden greater than 51% was found in 5% of the patients. Older patients presented progressively higher percentages of the V617F allele. Signs of stimulated erythropoiesis and myelopoiesis, as well as higher PRV-1 levels, were found in patients with the mutation, but no linear correlation with load of mutant allele could be ascertained; on the other hand, the frequency of patients with erythropoietin-independent erythroid colonies progressively increased depending on mutant allele load. Splenomegaly and microvessel symptoms were significantly more represented among patients with greater than 50% and 25% JAK2(V617F) allele burden, respectively. Increasing mutant allele load correlated with higher frequency of arterial thrombosis at diagnosis, as confirmed also in multivariate analysis; the relative risk was 3.0 (95% CI 1.3-6.8; p=0.01) in patients having a greater than 25% mutant allele burden.

Conclusions: The JAK2(V617F) mutant allele burden contributes to determining the clinical phenotype in patients with essential thrombocythemia.
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http://dx.doi.org/10.3324/haematol.11653DOI Listing
January 2008

Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria.

Blood 2008 Feb 30;111(4):1840-7. Epub 2007 Nov 30.

Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, non-placebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 +/- 2 days for 4 weeks; 900 mg 7 +/- 2 days later; followed by 900 mg every 14 +/- 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 +/- 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at http://clinicaltrials.gov as NCT00130000.
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http://dx.doi.org/10.1182/blood-2007-06-094136DOI Listing
February 2008