Alessandro Vannucchi - Academia.edu (original) (raw)

Papers by Alessandro Vannucchi

Research paper thumbnail of The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group

Cancer, Jan 12, 2016

Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thromboc... more Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexu...

Research paper thumbnail of Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms

Leukemia Research, 2016

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thro... more In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes >10×10(9)/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up.

Research paper thumbnail of splenomegaly and leukemic transformation in primary myelofibrosis V617F mutational status predicts progression to large JAK2

Research paper thumbnail of The prognostic impact of bone marrow fibrosis in primary myelofibrosis

American journal of hematology, Jan 24, 2016

The prognostic impact of bone marrow fibrosis in primary myelofibrosis To the Editor: We would li... more The prognostic impact of bone marrow fibrosis in primary myelofibrosis To the Editor: We would like to congratulate Guglielmelli et al. on their important study describing the prognostic impact of bone marrow fibrosis in 490 patients with primary myelofibrosis (PMF), evaluated at diagnosis with relevant clinical and molecular assessment and extensive follow-up information. [1] The authors conclude that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease including constitutional symptoms, cytopenias, larger splenomegaly, a higher IPSS risk category and more frequent prognostically adverse mutations (i.e., ASXL and EZH2) and a greater total number of same. Median survival was significantly reduced in patients with Grades 2 and 3 fibrosis as compared with Grade 1 and on multivariate analysis, the fibrosis grade independently predicted for survival. This study is important, as the authors point out it has the advantage of a "real-life" setting: fibrosis grading was performed as part of routine diagnostic approach by local pathologists, who were experienced in fibrosis assessment in the context of being established at reference centers with large accrual of patients with myeloproliferative neoplasms. Although we acknowledge and applaud the significance of their observations we had some thoughts on the authors deliberate "inclusion of only patients with a diagnosis of PMF fulfilling the 2008 WHO criteria and fibrosis grade 1 to avoid the inclusion of early/prefibrotic (prePMF) forms of PMF" even though fifty (9.3%) such patients were initially presented as part of a total of 540 patients originally included in this study [2]. In their paper, they cite the European consensus classification of bone marrow fibrosis, and its grading: Grades 0-3 and note these criteria have been reinforced in the revised 2016 WHO criteria for diagnosis of PMF [3]. As the 2016 WHO classification of PMF with fibrosis grades 0 or 1 now defines prePMF (Table I), inclusion of patients with Grade 1 fibrosis in a study of the prognostic significance of fibrosis in PMF is problematic, now that the diagnosis of PMF requires the presence of Grade 2 or 3 fibrosis [3]. The original report of this study in which patents with fibrosis grades 0-3 were included (n 5 540), provided much needed information on both prefibrotic and overt PMF. The authors reported that compared with patients with fibrosis grades 0 and 1, those with fibrosis grades 2 and 3, presented more clinical features of advanced disease. Importantly there was no correlation between fibrosis grades (0-3) and phenotypic driver mutations and triple negative patients were equally distributed (10, 10.6, 14.3, and 8.8% from Grades 0-3, respectively). In addition, according to fibrosis grades 0-3, the frequency of ASXL1 (12, 15, 23.5, and 36%) and EZH2 (2, 3.9, 8.2, and 13.2%) mutations, showed similar frequencies in PMF with grade 0-1 versus 2-3 fibrosis. Similarly, the overall survival of patients with Grade 0 (which they had used as their reference group) and Grade 1 fibrosis was significantly longer than with fibrosis grades 2-3 (i.e., not reached and 14.7 vs. 6.7 and 7.2 years, respectively). As such, retaining the patients with fibrosis grade 0 and combining these with fibrosis grade 1 would have allowed for the demonstration of the clear differences (clinical, molecular, and prognostic) between prePMF (fibrosis grades 0-1) and frank PMF (Grades 2-3), as currently WHO-defined, and would have increased the current relevance of this excellent and important study [2,3]. This valuable work would have been further enriched with the inclusion of details regarding the risk of progression of lower to higher grades of fibrosis, although perhaps this will require longer follow up.

Research paper thumbnail of Validation and molecular integration of the RR6 model to predict survival after 6 months of therapy with ruxolitinib

Haematologica, May 30, 2024

Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid disse... more Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors.

Research paper thumbnail of Resolving complex structural variants via nanopore sequencing

Frontiers in Genetics

The recent development of high-throughput sequencing platforms provided impressive insights into ... more The recent development of high-throughput sequencing platforms provided impressive insights into the field of human genetics and contributed to considering structural variants (SVs) as the hallmark of genome instability, leading to the establishment of several pathologic conditions, including neoplasia and neurodegenerative and cognitive disorders. While SV detection is addressed by next-generation sequencing (NGS) technologies, the introduction of more recent long-read sequencing technologies have already been proven to be invaluable in overcoming the inaccuracy and limitations of NGS technologies when applied to resolve wide and structurally complex SVs due to the short length (100–500 bp) of the sequencing read utilized. Among the long-read sequencing technologies, Oxford Nanopore Technologies developed a sequencing platform based on a protein nanopore that allows the sequencing of “native” long DNA molecules of virtually unlimited length (typical range 1–100 Kb). In this review,...

Research paper thumbnail of Clinical Benefit Associated with Biomarker Changes Indicative of Disease Modification in Patients with Myelofibrosis Treated with the BET Inhibitor Pelabresib As Monotherapy or in Combination with Ruxolitinib

Research paper thumbnail of Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives

International Journal of Hematology

Research paper thumbnail of Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

Cells

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hem... more Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may...

Research paper thumbnail of Differential prognostic impact of cytopenic phenotype in prefibrotic vs overt primary myelofibrosis

Research paper thumbnail of Mutation Landscape and Prognostic Correlates of ASXL1 Variants in Primary and Secondary Myelofibrosis

Blood

Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera o... more Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocytemia, is characterized by a complex and partially undeciphered molecular architecture. Besides mutations in driver genes (JAK2, CALR, MPL), somatic mutations in selected myeloid-associated genes have been shown to impact prognosis of MF patients (pts). Among these, ASXL1 mutations (ASXL1MTs) are associated with poor outcomes in myeloid malignancies including PMF, where they are included in the category of "high molecular risk" (HMR) mutations along with EZH2MTs, IDH1/2MTs, and SRSF2MTs (Vannucchi AM, Leukemia 2013). However, a recent study (Luque Paz D, Blood Adv 2021) questioned the value of ASXL1MTs in MF. The current study aimed at further characterizing the prognostic role of ASXL1MTs in MF. Methods: After IRB approval, pts with WHO-defined MF were included in the study. Mutational analysis by targeted NGS was performed as previously described (Gugliel...

Research paper thumbnail of The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis

Antioxidants, 2022

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the ... more Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidan...

Research paper thumbnail of T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker

Cancers, 2021

Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lympho... more Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic implications. LIM domain only 2 (LMO2) is overexpressed in most T-LBL, but not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations (iT-LBP). Methods and Results: We retrospectively evaluated 11 cases of T-LBL occurring in the context of M/LNs-Eo. Clinical, histological, immunohistochemical and molecular features were collected and LMO2 immunohistochemical staining was performed. The critical re-evaluation of these cases confirmed the diagnosis of T-LBL with morphological, immunohistochemical and molecular features consistent with T-LBL occurring in M/LNs-Eo. Interestingly, LMO2 immunohistochemical analysis was negative i...

Research paper thumbnail of A Globally Applicable "Triple AAA" Risk Model for Essential Thrombocythemia Based on Age, Absolute Neutrophil Count, and Absolute Lymphocyte Count

Blood, 2021

Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MP... more Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MPN) has been well established for primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET ) (JCO. 2018;36:310; BJH. 2020;189:291) Previous studies have also implicated leukocytosis as a risk factor for leukemic transformation (Mayo Clin Proc. 2017;92:1118) and thrombosis in MPN (Blood Adv. 2019;3:1729). However, it is currently not clear as to which component(s) of white blood cells is responsible for these observations. In the current study, we sought to examine the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival and in ET. Methods Study patients (n=349) were retrospectively recruited from the Mayo Clinic MPN database of 1,249 WHO-defined ET patients, evaluated over five decades (1967-2021), based on availability of inform...

Research paper thumbnail of A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis

Blood, 2021

There is an unmet need for novel therapies with distinct modes of action to offer clinical benefi... more There is an unmet need for novel therapies with distinct modes of action to offer clinical benefit for patients with myelofibrosis (MF) who become resistant or intolerant to JAK inhibitors. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal potential of malignant myeloid cells for hematopoietic differentiation, e.g., LSD1 licenses maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, mutant cell burden and overall survival (Jutzi et al. 2018). IMG-7289-CTP-102 is a global, open-label Phase 1/2 study evaluating bomedemstat dosed once daily in MF patients (NCT03136185). Data from this ongoing study are presented. Key eligibility criteria include IPSS int.-1 or -2 or high-risk patients refractory or resistant to, inadequately controlled by or intolerant of availab...

Research paper thumbnail of A Randomized, Phase 3 Trial of Fedratinib Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Previously Treated with Ruxolitinib (FREEDOM2)

Blood, 2021

Background: Until recently, ruxolitinib (RUX) was the only drug approved for treatment of interme... more Background: Until recently, ruxolitinib (RUX) was the only drug approved for treatment of intermediate- or high-risk myelofibrosis (MF). Many patients discontinue RUX due to lack of response, loss of efficacy, or intolerance. Fedratinib (INREBIC) is an oral, selective kinase inhibitor with activity against mutant and wild-type JAK2 and FLT3. Fedratinib is approved in the United States, Canada, European Union, United Kingdom, and elsewhere as front-line therapy for treatment of patients with JAK-inhibitor-naïve MF and those previously treated with RUX. In the single-arm, phase 2 JAKARTA2 trial of fedratinib 400 mg/day (starting dose) in patients with MF relapsed, refractory, or intolerant to prior RUX, 31% of pts achieved a spleen volume response and 27% achieved a symptom response with fedratinib (Harrison, Am J Hematol 2020). Gastrointestinal (GI) events were among the most common adverse events (AEs) reported during fedratinib treatment in JAKARTA2. A clinical hold was placed on f...

Research paper thumbnail of Neutrophil-to-Lymphocyte Ratio (NLR) Is a Risk Factor for Venous Thrombosis in Polycythemia Vera

Blood, 2021

Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to t... more Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to the JAK2-mutant clone which leads to hypercellularity and functional interplay between abnormal erythrocytes, platelets, leukocytes and dysfunctional endothelium. The resulting cell activation that also involves stromal cells in their microenvironment, has been shown associated with chronic, systemic, subclinical pro-inflammatory state, and has been implicated in the pathogenesis of thrombosis in MPN. Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker found to be associated with the severity and prognosis of cardiovascular diseases but there is little evidence for its prognostic significance in MPN. We investigated whether NLR could predict the onset of arterial and venous thrombosis in polycythemia vera (PV). Methods. Subjects of this study were 1508 patients included in the ECLAP trail with NLR evaluation available. In addition to standard statistical methods, we used p...

Research paper thumbnail of Updated results of the placebo‐controlled, phase III JAKARTA trial of fedratinib in patients with intermediate‐2 or high‐risk myelofibrosis

British Journal of Haematology, 2021

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves sym... more SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.

Research paper thumbnail of Fedratinib Induces Spleen Responses and Reduces Symptom Burden as First-line or Salvage Therapy in Patients with Myeloproliferative Neoplasm-Associated Intermediate- or High-Risk Myelofibrosis (MF) and Low Platelet Counts

Clinical Lymphoma Myeloma and Leukemia, 2019

disorders and allogeneic transplantation provides the only chance for a cure. This study examined... more disorders and allogeneic transplantation provides the only chance for a cure. This study examined outcomes of allogeneic transplantation in elderly patients with MPN or MDS/MPN. Objective: To determine the factors that are associated with improved survival rates in elderly patients undergoing allogeneic transplantation for myeloproliferative neoplasms. Design: This was a retrospective analysis and patients were identified using our institutional transplant database and confirmed with our electronic medical record database. Setting: This study was performed at a large academic center. Patients: Thirty-seven (37) patients that had a diagnosis of an MPN or MDS/MPN overlap syndrome that were 60 or older that received an allogeneic transplant between April 2008 and October 2017 at Winship Cancer Institute of Emory University were included in the study. Patients that had progressed to acute myeloid leukemia were excluded. Main Outcomes Measures: The primary outcome was overall survival. Results: In the univariate analysis, induction therapy with chemotherapy prior to transplantation and high disease risk index score was significantly associated with worse outcomes (p¼0.16, p<0.001). Median overall survival for patients that received chemotherapy is 10.5 months and has not been reached in patients that received Jak2 inhibitors or best supportive care (BSC) prior to transplant. In multivariate analysis, only a high disease risk index score remained significant (p¼0.002). There was no statistically significant difference in age, initial blast count, co-morbidity index or donor source between patients that received chemotherapy, Jak2 inhibitor or BSC. Patients that received chemotherapy were more likely to have a diagnosis of CMML and patients that received Jak2 inhibitors were more likely to have primary or secondary myelofibrosis (p¼0.013). Conclusions: To our knowledge, this is the first study examining outcomes of allogeneic transplantations in elderly patients with MPN or MPN/MDS. Patients with high disease risk index scores had all failed induction treatment with chemotherapy. Our data suggests that chemotherapy prior to allogeneic transplantation may not be beneficial in elderly patients, however, a larger cohort of patients is needed to validate our results.

Research paper thumbnail of Emerging treatments for classical myeloproliferative neoplasms

Blood, Jan 9, 2017

There has been a major revolution in the management of patients with myeloproliferative neoplasms... more There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients' major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibr...

Research paper thumbnail of The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group

Cancer, Jan 12, 2016

Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thromboc... more Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexu...

Research paper thumbnail of Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms

Leukemia Research, 2016

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thro... more In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10×10(9)/L), higher hematocrit (HCT &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up.

Research paper thumbnail of splenomegaly and leukemic transformation in primary myelofibrosis V617F mutational status predicts progression to large JAK2

Research paper thumbnail of The prognostic impact of bone marrow fibrosis in primary myelofibrosis

American journal of hematology, Jan 24, 2016

The prognostic impact of bone marrow fibrosis in primary myelofibrosis To the Editor: We would li... more The prognostic impact of bone marrow fibrosis in primary myelofibrosis To the Editor: We would like to congratulate Guglielmelli et al. on their important study describing the prognostic impact of bone marrow fibrosis in 490 patients with primary myelofibrosis (PMF), evaluated at diagnosis with relevant clinical and molecular assessment and extensive follow-up information. [1] The authors conclude that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease including constitutional symptoms, cytopenias, larger splenomegaly, a higher IPSS risk category and more frequent prognostically adverse mutations (i.e., ASXL and EZH2) and a greater total number of same. Median survival was significantly reduced in patients with Grades 2 and 3 fibrosis as compared with Grade 1 and on multivariate analysis, the fibrosis grade independently predicted for survival. This study is important, as the authors point out it has the advantage of a "real-life" setting: fibrosis grading was performed as part of routine diagnostic approach by local pathologists, who were experienced in fibrosis assessment in the context of being established at reference centers with large accrual of patients with myeloproliferative neoplasms. Although we acknowledge and applaud the significance of their observations we had some thoughts on the authors deliberate "inclusion of only patients with a diagnosis of PMF fulfilling the 2008 WHO criteria and fibrosis grade 1 to avoid the inclusion of early/prefibrotic (prePMF) forms of PMF" even though fifty (9.3%) such patients were initially presented as part of a total of 540 patients originally included in this study [2]. In their paper, they cite the European consensus classification of bone marrow fibrosis, and its grading: Grades 0-3 and note these criteria have been reinforced in the revised 2016 WHO criteria for diagnosis of PMF [3]. As the 2016 WHO classification of PMF with fibrosis grades 0 or 1 now defines prePMF (Table I), inclusion of patients with Grade 1 fibrosis in a study of the prognostic significance of fibrosis in PMF is problematic, now that the diagnosis of PMF requires the presence of Grade 2 or 3 fibrosis [3]. The original report of this study in which patents with fibrosis grades 0-3 were included (n 5 540), provided much needed information on both prefibrotic and overt PMF. The authors reported that compared with patients with fibrosis grades 0 and 1, those with fibrosis grades 2 and 3, presented more clinical features of advanced disease. Importantly there was no correlation between fibrosis grades (0-3) and phenotypic driver mutations and triple negative patients were equally distributed (10, 10.6, 14.3, and 8.8% from Grades 0-3, respectively). In addition, according to fibrosis grades 0-3, the frequency of ASXL1 (12, 15, 23.5, and 36%) and EZH2 (2, 3.9, 8.2, and 13.2%) mutations, showed similar frequencies in PMF with grade 0-1 versus 2-3 fibrosis. Similarly, the overall survival of patients with Grade 0 (which they had used as their reference group) and Grade 1 fibrosis was significantly longer than with fibrosis grades 2-3 (i.e., not reached and 14.7 vs. 6.7 and 7.2 years, respectively). As such, retaining the patients with fibrosis grade 0 and combining these with fibrosis grade 1 would have allowed for the demonstration of the clear differences (clinical, molecular, and prognostic) between prePMF (fibrosis grades 0-1) and frank PMF (Grades 2-3), as currently WHO-defined, and would have increased the current relevance of this excellent and important study [2,3]. This valuable work would have been further enriched with the inclusion of details regarding the risk of progression of lower to higher grades of fibrosis, although perhaps this will require longer follow up.

Research paper thumbnail of Validation and molecular integration of the RR6 model to predict survival after 6 months of therapy with ruxolitinib

Haematologica, May 30, 2024

Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid disse... more Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors.

Research paper thumbnail of Resolving complex structural variants via nanopore sequencing

Frontiers in Genetics

The recent development of high-throughput sequencing platforms provided impressive insights into ... more The recent development of high-throughput sequencing platforms provided impressive insights into the field of human genetics and contributed to considering structural variants (SVs) as the hallmark of genome instability, leading to the establishment of several pathologic conditions, including neoplasia and neurodegenerative and cognitive disorders. While SV detection is addressed by next-generation sequencing (NGS) technologies, the introduction of more recent long-read sequencing technologies have already been proven to be invaluable in overcoming the inaccuracy and limitations of NGS technologies when applied to resolve wide and structurally complex SVs due to the short length (100–500 bp) of the sequencing read utilized. Among the long-read sequencing technologies, Oxford Nanopore Technologies developed a sequencing platform based on a protein nanopore that allows the sequencing of “native” long DNA molecules of virtually unlimited length (typical range 1–100 Kb). In this review,...

Research paper thumbnail of Clinical Benefit Associated with Biomarker Changes Indicative of Disease Modification in Patients with Myelofibrosis Treated with the BET Inhibitor Pelabresib As Monotherapy or in Combination with Ruxolitinib

Research paper thumbnail of Role of JAK inhibitors in myeloproliferative neoplasms: current point of view and perspectives

International Journal of Hematology

Research paper thumbnail of Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

Cells

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hem... more Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may...

Research paper thumbnail of Differential prognostic impact of cytopenic phenotype in prefibrotic vs overt primary myelofibrosis

Research paper thumbnail of Mutation Landscape and Prognostic Correlates of ASXL1 Variants in Primary and Secondary Myelofibrosis

Blood

Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera o... more Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocytemia, is characterized by a complex and partially undeciphered molecular architecture. Besides mutations in driver genes (JAK2, CALR, MPL), somatic mutations in selected myeloid-associated genes have been shown to impact prognosis of MF patients (pts). Among these, ASXL1 mutations (ASXL1MTs) are associated with poor outcomes in myeloid malignancies including PMF, where they are included in the category of "high molecular risk" (HMR) mutations along with EZH2MTs, IDH1/2MTs, and SRSF2MTs (Vannucchi AM, Leukemia 2013). However, a recent study (Luque Paz D, Blood Adv 2021) questioned the value of ASXL1MTs in MF. The current study aimed at further characterizing the prognostic role of ASXL1MTs in MF. Methods: After IRB approval, pts with WHO-defined MF were included in the study. Mutational analysis by targeted NGS was performed as previously described (Gugliel...

Research paper thumbnail of The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis

Antioxidants, 2022

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the ... more Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidan...

Research paper thumbnail of T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker

Cancers, 2021

Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lympho... more Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic implications. LIM domain only 2 (LMO2) is overexpressed in most T-LBL, but not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations (iT-LBP). Methods and Results: We retrospectively evaluated 11 cases of T-LBL occurring in the context of M/LNs-Eo. Clinical, histological, immunohistochemical and molecular features were collected and LMO2 immunohistochemical staining was performed. The critical re-evaluation of these cases confirmed the diagnosis of T-LBL with morphological, immunohistochemical and molecular features consistent with T-LBL occurring in M/LNs-Eo. Interestingly, LMO2 immunohistochemical analysis was negative i...

Research paper thumbnail of A Globally Applicable "Triple AAA" Risk Model for Essential Thrombocythemia Based on Age, Absolute Neutrophil Count, and Absolute Lymphocyte Count

Blood, 2021

Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MP... more Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MPN) has been well established for primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET ) (JCO. 2018;36:310; BJH. 2020;189:291) Previous studies have also implicated leukocytosis as a risk factor for leukemic transformation (Mayo Clin Proc. 2017;92:1118) and thrombosis in MPN (Blood Adv. 2019;3:1729). However, it is currently not clear as to which component(s) of white blood cells is responsible for these observations. In the current study, we sought to examine the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival and in ET. Methods Study patients (n=349) were retrospectively recruited from the Mayo Clinic MPN database of 1,249 WHO-defined ET patients, evaluated over five decades (1967-2021), based on availability of inform...

Research paper thumbnail of A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Advanced Myelofibrosis

Blood, 2021

There is an unmet need for novel therapies with distinct modes of action to offer clinical benefi... more There is an unmet need for novel therapies with distinct modes of action to offer clinical benefit for patients with myelofibrosis (MF) who become resistant or intolerant to JAK inhibitors. Lysine-specific demethylase-1 (LSD1) is a histone demethylase critical for self-renewal potential of malignant myeloid cells for hematopoietic differentiation, e.g., LSD1 licenses maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Bomedemstat is an orally active LSD1 inhibitor that in mouse models of MPNs reduced peripheral cell counts, splenomegaly, inflammatory cytokines, marrow fibrosis, mutant cell burden and overall survival (Jutzi et al. 2018). IMG-7289-CTP-102 is a global, open-label Phase 1/2 study evaluating bomedemstat dosed once daily in MF patients (NCT03136185). Data from this ongoing study are presented. Key eligibility criteria include IPSS int.-1 or -2 or high-risk patients refractory or resistant to, inadequately controlled by or intolerant of availab...

Research paper thumbnail of A Randomized, Phase 3 Trial of Fedratinib Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Previously Treated with Ruxolitinib (FREEDOM2)

Blood, 2021

Background: Until recently, ruxolitinib (RUX) was the only drug approved for treatment of interme... more Background: Until recently, ruxolitinib (RUX) was the only drug approved for treatment of intermediate- or high-risk myelofibrosis (MF). Many patients discontinue RUX due to lack of response, loss of efficacy, or intolerance. Fedratinib (INREBIC) is an oral, selective kinase inhibitor with activity against mutant and wild-type JAK2 and FLT3. Fedratinib is approved in the United States, Canada, European Union, United Kingdom, and elsewhere as front-line therapy for treatment of patients with JAK-inhibitor-naïve MF and those previously treated with RUX. In the single-arm, phase 2 JAKARTA2 trial of fedratinib 400 mg/day (starting dose) in patients with MF relapsed, refractory, or intolerant to prior RUX, 31% of pts achieved a spleen volume response and 27% achieved a symptom response with fedratinib (Harrison, Am J Hematol 2020). Gastrointestinal (GI) events were among the most common adverse events (AEs) reported during fedratinib treatment in JAKARTA2. A clinical hold was placed on f...

Research paper thumbnail of Neutrophil-to-Lymphocyte Ratio (NLR) Is a Risk Factor for Venous Thrombosis in Polycythemia Vera

Blood, 2021

Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to t... more Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to the JAK2-mutant clone which leads to hypercellularity and functional interplay between abnormal erythrocytes, platelets, leukocytes and dysfunctional endothelium. The resulting cell activation that also involves stromal cells in their microenvironment, has been shown associated with chronic, systemic, subclinical pro-inflammatory state, and has been implicated in the pathogenesis of thrombosis in MPN. Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker found to be associated with the severity and prognosis of cardiovascular diseases but there is little evidence for its prognostic significance in MPN. We investigated whether NLR could predict the onset of arterial and venous thrombosis in polycythemia vera (PV). Methods. Subjects of this study were 1508 patients included in the ECLAP trail with NLR evaluation available. In addition to standard statistical methods, we used p...

Research paper thumbnail of Updated results of the placebo‐controlled, phase III JAKARTA trial of fedratinib in patients with intermediate‐2 or high‐risk myelofibrosis

British Journal of Haematology, 2021

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves sym... more SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.

Research paper thumbnail of Fedratinib Induces Spleen Responses and Reduces Symptom Burden as First-line or Salvage Therapy in Patients with Myeloproliferative Neoplasm-Associated Intermediate- or High-Risk Myelofibrosis (MF) and Low Platelet Counts

Clinical Lymphoma Myeloma and Leukemia, 2019

disorders and allogeneic transplantation provides the only chance for a cure. This study examined... more disorders and allogeneic transplantation provides the only chance for a cure. This study examined outcomes of allogeneic transplantation in elderly patients with MPN or MDS/MPN. Objective: To determine the factors that are associated with improved survival rates in elderly patients undergoing allogeneic transplantation for myeloproliferative neoplasms. Design: This was a retrospective analysis and patients were identified using our institutional transplant database and confirmed with our electronic medical record database. Setting: This study was performed at a large academic center. Patients: Thirty-seven (37) patients that had a diagnosis of an MPN or MDS/MPN overlap syndrome that were 60 or older that received an allogeneic transplant between April 2008 and October 2017 at Winship Cancer Institute of Emory University were included in the study. Patients that had progressed to acute myeloid leukemia were excluded. Main Outcomes Measures: The primary outcome was overall survival. Results: In the univariate analysis, induction therapy with chemotherapy prior to transplantation and high disease risk index score was significantly associated with worse outcomes (p¼0.16, p<0.001). Median overall survival for patients that received chemotherapy is 10.5 months and has not been reached in patients that received Jak2 inhibitors or best supportive care (BSC) prior to transplant. In multivariate analysis, only a high disease risk index score remained significant (p¼0.002). There was no statistically significant difference in age, initial blast count, co-morbidity index or donor source between patients that received chemotherapy, Jak2 inhibitor or BSC. Patients that received chemotherapy were more likely to have a diagnosis of CMML and patients that received Jak2 inhibitors were more likely to have primary or secondary myelofibrosis (p¼0.013). Conclusions: To our knowledge, this is the first study examining outcomes of allogeneic transplantations in elderly patients with MPN or MPN/MDS. Patients with high disease risk index scores had all failed induction treatment with chemotherapy. Our data suggests that chemotherapy prior to allogeneic transplantation may not be beneficial in elderly patients, however, a larger cohort of patients is needed to validate our results.

Research paper thumbnail of Emerging treatments for classical myeloproliferative neoplasms

Blood, Jan 9, 2017

There has been a major revolution in the management of patients with myeloproliferative neoplasms... more There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients' major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibr...