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Primary myelofibrosis: 2019 update on diagnosis, risk‐stratification and management

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Abstract

Disease overview Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL mutations; additional disease features include bone marrow stromal reaction including reticulin fibrosis, abnormal cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival. Diagnosis Diagnosis of PMF is based on bone marrow morphology. Presence of JAK2, CALR or MPL mutation, expected in ~90% of the patients, is supportive but not essential for diagnosis. The revised 2016 World Health Organization (WHO) classification system distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two. Risk stratification Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically‐inspired prognostic scoring system) and MIPSS70+ version 2.0 (mutation‐ and karyotype‐enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSS70+ version 2.0 utilizes both genetic and clinical risk factors. GIPSS features four and MIPSS70+ version 2.0 five risk categories. MIPSS70+ version 2.0 requires an online score calculator (http://www.mipss70score.it) while GIPPS offers a lower complexity prognostic tool. Risk‐adapted therapy Observation alone is advised for MIPSS70+ version 2.0 “low” and “very low” risk disease (estimated 10‐year survival 56%‐92%); allogeneic stem cell transplant is the preferred treatment of choice for “very high” and “high” risk disease (estimated 10‐year survival 0‐13%); treatment‐requiring patients with intermediate‐risk disease (estimated 10‐year survival 30%) are best served by participating in clinical trials. All other treatment approaches, including the use of JAK2 inhibitors, are mostly palliative and should not be used in the absence of clear treatment indications. Conventional treatment for anemia includes androgens, prednisone, thalidomide and danazol, for symptomatic splenomegaly hydroxyurea and ruxolitinib and for constitutional symptoms ruxolitinib. Splenectomy is considered for drug‐refractory splenomegaly and involved field radiotherapy for non‐hepatosplenic EMH and extremity bone pain. This article is protected by copyright. All rights reserved.

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... BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia, or other lymphoid neoplasm, metastatic malignancy or toxic (chronic) myelopathies Postessential thrombocythemia myelofibrosis. [12] Postpolycythemiavera myelofibrosis (post-PV MF) ...
... In pre-PMF might not display overt leukoerythroblastosis. [1,12] (Figure 1 Platelet counts increased in up to 50% of the cases at time of diagnosis and can be related with giant platelet and complications due to thrombosis (pre-PMF phase). In any case, progressive thrombocytopenia is a continuous event and turns out to be progressively as the progresses of disease. ...
... New prognostic models in primary myelofibrosis.[11,12] ...
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Primary myelofibrosis is another name, refreshing past names such as myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, and chronic idiopathic myelofibrosis.[1] PMF was first reported in 1879 by Hueck as a 'peculiar leukemia'. It was not until Dameshek's fundamental work in 1951 that PMF was perceived as a myeloproliferative neoplasm
... JAK inhibitors are a valuable therapeutic strategy for patients with MF who have splenomegaly and/or disease-related symptoms [4,5,18]. However, allogeneic stem cell transplantation remains the only curative treatment for MF, but it is typically limited by age-related comorbidities and high treatment-related mortality [19,20]. Therefore, a better understanding of the molecular pathogenesis and potential new therapies to modify the natural course of the disease is important. ...
... The most commonly affected genes are those important in epigenetic regulation, messenger RNA splicing, transcriptional mechanisms, and signal transduction. Although reported somatic mutations lack specificity because they can be found in a broad range of myeloid neoplasms, there is evidence to suggest that the identification of certain non-driver mutations in MPN patients is associated with a greater risk of disease progression or shortened survival [19,[46][47][48]. ...
... In particular, mutations in the spliceosome components U2AF1 and SRSF2 are known to lead to mis-splicing and nonsense-mediated decay of EZH2 [58,59] and are associated with MPNs with poor prognoses [19]. ...
Article
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The identification of driver mutations in Janus kinase (JAK) 2, calreticulin (CALR), and myeloproliferative leukemia (MPL) has contributed to a better understanding of disease pathogenesis by highlighting the importance of JAK signal transducer and activator of transcription (STAT) signaling in classical myeloproliferative neoplasms (MPNs). This has led to the therapeutic use of novel targeted treatments, such as JAK2 inhibitors. More recently, with the development of next-generation sequencing, additional somatic mutations, which are not restricted to MPNs, have been elucidated. Treatment decisions for MPN patients are influenced by the MPN subtype, symptom burden, and risk classification. Although prevention of vascular events is the main objective of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients, disease-modifying drugs are needed to eradicate clonal hematopoiesis and prevent progression to more aggressive myeloid neoplasms. JAK inhibitors are a valuable therapeutic strategy for patients with myelofibrosis (MF) who have splenomegaly and/or disease-related symptoms, but intolerance, refractory, resistance, and disease progression still present challenges. Currently, allogeneic stem cell transplantation remains the only curative treatment for MF, but it is typically limited by age-related comorbidities and high treatment-related mortality. Therefore, a better understanding of the molecular pathogenesis and potential new therapies with the aim of modifying the natural history of the disease is important. In this article, I review the current understanding of the molecular basis of MPNs and clinical studies on potential disease-modifying agents.
... Primary myelofibrosis (PMF) belongs to a group of Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms (MPN) of the multipotent hematopoietic stem cells, also including polycythaemia vera (PV) and essential thrombocythemia (ET) [1]. These malignancies are characterised by clonal proliferation of the myeloid lineages accompanied by progressive stromal cell activation, extracellular matrix production and impeded hemopoesis [2]. Myelofibrosis is an adverse prognostic factor in MPNs, which is mainly driven by impaired megakaryocyte functions resulting in the elevated expression of inflammatory cytokines, transforming growth factor-β (TGF-β), platelet derived growth factor (PDGF), as well as the aberrant JAK-STAT signaling as a result of JAK2V617F, MPL515 L/K or CALR mutations [3]. ...
... Despite the novel prognostic models considering driver and passenger mutations, karyotype and sex-adjusted hemoglobin levels, bone marrow fibrosis reflecting the abnormal activation of the fibrotic stromal microenvironment is still a major predictor of the outcome in primary myelofibrosis [2,5]. Here we tested growth related markers which were primarily expressed by stromal cells including L-NGFR/CD271, p-ERK1-2 and CXCL-12, and found that the density of positive cells for each marker was progressively increased in line with the Gomori's silver staining-based tumor grades. ...
... Myelofibrosis is driven by augmented and pathological extracellular matrix production resulted from the increasing number and activation of bone marrow stromal cells as a result of aberrant cytokine signaling and clonal megakaryocyte functions [3]. The extent of matrix overproduction, still assessed using Gomori's silver impregnation, determines grades in primary myelofibrosis and predicts disease progression and outcome [2]. However, selective silver deposition on reticular and collagen fibers can be highly dependent on preanalytical (fixation, decalcification) and staining (components, timing, ambient temperature and light conditions) variables [5]. ...
Article
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In myelofibrosis, pathologically enhanced extracellular matrix production due to aberrant cytokine signalling and clonal megakaryocyte functions result( s ) in impaired hemopoiesis. Disease progression is still determined by detecting reticulin and collagen fibrosis with Gomori’s silver impregnation. Here, we tested whether the expression growth related biomarkers L-NGFR/CD271, phospho-ERK1-2 and CXCL12 can be linked to the functional activation of bone marrow stromal cells during primary myelofibrosis progression. Immunoscores for all tested biomarkers showed varying strength of positive statistical correlation with the silver impregnation based myelofibrosis grades. The intimate relationship between spindle shaped stromal cells positive for all three markers and aberrant megakaryocytes was likely to reflect their functional cooperation. L-NGFR reaction was restricted to bone marrow stromal cells and revealed the whole length of their processes. Also, L-NGFR positive cells showed the most intersections, the best statistical correlations with myelofibrosis grades and the strongest interrater agreements. CXCL12 reaction highlighted stromal cell bodies and a weak extracellular staining in line with its constitutive release. Phospho-ERK1-2 reaction showed a similar pattern to CXCL12 in stromal cells with an additional nuclear staining in agreement with its role as a transcription factor. Both p -ERK1-2 and CXCL12 were also expressed at a moderate level in sinus endothelial cells. Connexin 43 gap junction communication channels, known to be required for CXCL12 release to maintain stem cell niche, were also expressed progressively in the myelofibrotic stromal network as a support of compartmental functions. Our results suggest that, diverse growth related pathways are activated in the functionally coupled bone marrow stromal cells during myelofibrosis progression. L-NGFR expression can be a useful biological marker of stromal cell activation which deserves diagnostic consideration for complementing Gomori’s silver impregnation.
... Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by hyperproliferation of myeloid cells, bone marrow fibrosis, and burdensome constitutional symptoms [1][2][3]. MF can develop de novo (primary MF) or may occur in patients with antecedent polycythemia vera (PV) or essential thrombocythemia (ET; secondary MF) [1]. Patients with MF have reduced overall survival (OS) compared with the general population [4,5]. ...
... Currently, NCCN® guidelines recommend stratification of patients into higher or lower risk, using scores from Mutation-Enhanced IPSS (MIPSS-70) or MIPSS-70 + version 2.0 (preferred), Dynamic IPSS (DIPSS)-Plus (if molecular testing is not available), DIPSS (if karyotyping is not available), or MF Secondary to PV and ET-Prognostic Model (MYSEC-PM) [23]. These newer prognostic systems take into account additional factors, such as molecular testing results, transfusion dependence, and karyotype [2], which may contribute to improved disease management compared with the IPSS. ...
Article
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The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P < 0.001 for both); post-approval, mortality risk was significantly lower in ruxolitinib-exposed versus ruxolitinib-unexposed patients (adjusted HR, 0.61; P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.
... Moreover, MPN and CMML frequently present with overlapping clinical, cytogenetic, and molecular features. The main clinical and laboratory characteristics of patients with CMML vs MPN are compared in Fig. 1 [12][13][14][15][16]. JAK2 V617F is present in 96% of patients with PV, and over 50% of patients with PMF, but only in 9% of those with CMML; consequently, it does not discriminate between these entities if used by itself [12]. ...
... However, the diagnosis may be difficult when CMML patients harbor JAK2 V617F mutation and in 10-15% of PMF patients that are JAK2, CALR, and MPL unmutated, called "triple negative" [18]. Pathological and molecular studies are not always diagnostically conclusive since presence of reticulin fibrosis is reported in 54% of CMML and TET2, SRSFR2, and ASXL1 are mutated in 17%, 17%, and 13% of PMF patients, respectively [14,19]. Flow cytometry is often a useful diagnostic tool in such situations [17 ••]. ...
Article
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Purpose of Review Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell neoplasms comprising of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) that share driver mutations (JAK2/CALR/MPL) resulting in constitutive activation of JAK/STAT and other signaling pathways. Patients with MPN have shortened survival and an inherent risk for leukemic evolution. Prognostically relevant clinical and genetic parameters have been incorporated into mutation-enhanced scoring systems (MIPSS70-plus version 2.0, MIPSS-ET/PV). In the current review, we describe clinical and pathological features along with prognostic significance of MPN with monocytosis. Recent Findings Monocytosis, defined by an absolute monocyte count (AMC) ≥ 1 × 10 ⁹/L, is a typical manifestation of chronic myelomonocytic leukemia (CMML) but is also associated with 21% and 17% of PV and PMF patients, respectively. Recent studies on the subject have reported that MPN patients with monocytosis are older and present with concomitant leukocytosis. In regard to PV, patients with monocytosis harbor unfavorable cytogenetic abnormalities including +8, 7/7q, i(17q), 5/5q−,12p−, inv(3), or 11q23 rearrangement and SRSF2 mutations, whereas PMF patients with monocytosis had significant thrombocytopenia, higher circulating blasts, higher symptom burden, and ASXL1 mutations. Moreover, presence of monocytosis predicted inferior survival in both PV and PMF. Summary Monocytosis in MPN is associated with a distinct clinical and genetic profile and may serve as a marker of aggressive disease biology.
... Moreover, additional complications may encompass thromboembolic events and there is an inherent risk of blastic transformation. MF can arise de novo (primary) or as a result of a transformation of Essential Thrombocythemia or Polycythemia Vera [1,2]. Several prognostic scores for primary MF have been developed over the years based on clinical, cytogenetics and molecular factors, permitting an enhanced stratification of these patients [3][4][5][6][7]. ...
... Several prognostic scores for primary MF have been developed over the years based on clinical, cytogenetics and molecular factors, permitting an enhanced stratification of these patients [3][4][5][6][7]. Estimated 5-year overall survival (OS) for intermediate to high-risk patients remains poor, and despite the significant improvements in available medical therapies, allogenic hematopoietic cell transplantation (allo-HCT) remains the only curative approach [2,8,9]. Conventionally, allo-HCT should be considered for both intermediate risk-2 or high-risk patients dependent on age, clinical phenotype and comorbidities, availability of medical therapies or clinical trials and donor availability [10][11][12][13][14]. Currently, estimated 5-year probability of survival after allo-HCT is 40-60% however not inconsiderable rates of both transplantrelated mortality and relapse remain of concern. ...
Article
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Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51–63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach.
... TO THE EDITOR: Unlike primary myelofibrosis (PMF), acute myelofibrosis (AMF) is a distinct clinicopathological entity characterized by the sudden onset of pancytopenia, extensive bone marrow (BM) fibrosis, megakaryocytic hyperplasia with or without dysplasia, leukoerythroblastic blood picture, and absence of hepatosplenomegaly (HSM) and no tear drop cells [1][2][3][4][5][6][7][8]. AMF is an uncommon presentation of acute myeloid leukemia (AML; particularly AML-M7), acute panmyelosis with myelofibrosis, and occasionally myeloproliferative neoplasm [especially chronic myeloid leukemia (CML)] [9,10]. ...
... Most probably, cytokines released from lymphoblasts (megakaryocytes in case-2 patient) resulted in AMF in our patients [1,8]. This is supported by the fact that BM fibrosis significantly reduced after ALL treatment. ...
... This condition is characterized by the accumulation of extracellular matrix in the bone marrow leading to disruption of hematopoiesis, eventually resulting in anemia, thrombocytosis with defective function, leukopenia, and death. Up to 20% of patients develop leukemia [87]. In myelofibrosis, not only is the hematopoietic stem cell defective [87], but mesenchymal stromal cells are also abnormal [88,89]. ...
... Up to 20% of patients develop leukemia [87]. In myelofibrosis, not only is the hematopoietic stem cell defective [87], but mesenchymal stromal cells are also abnormal [88,89]. Fibronectin itself modifies the severity of this disease. ...
Article
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Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell niche produce the various isoforms of this protein. Fibronectin not only provides the cells a scaffold to bind to, but it also modulates their behavior by binding to receptors on the adjacent hematopoietic stem cells and stromal cells. These receptors, which include integrins such as α4β1, α9β1, α4β7, α5β1, αvβ3, Toll-like receptor-4 (TLR-4), and CD44, are found on the hematopoietic stem cell. Because the knockout of fibronectin is lethal during embryonal development and because fibronectin is produced by almost all cell types in mammals, the study of its role in hematopoiesis is difficult. Nevertheless, strong and direct evidence exists for its stimulation of myelopoiesis and thrombopoiesis using in vivo models. Other reviewed effects can be deduced from the study of fibronectin receptors, which showed their activation modifies the behavior of hematopoietic stem cells. Erythropoiesis was only stimulated under hemolytic stress, and mostly late stages of lymphocytic differentiation were modulated. Because fibronectin is ubiquitously expressed, these interactions in health and disease need to be taken into account whenever any molecule is evaluated in hematopoiesis.
... Primary myelofibrosis (PMF) is a kind of breakpoint cluster region protein (BCR)-Abelson tyrosine-protein kinase (ABL)-negative myeloproliferative neoplasm (MPN) resulted from the clonal proliferation of abnormal hematopoietic stem cells. It is mainly characterized by bone marrow fibrodysplasia, severe anemia, splenomegaly, constitutional symptoms (fatigue, night sweats, fever, cachexia), extramedullary hematopoiesis, progression to leukemia, and short survival [1]. In the US Surveillance, Epidemiology, and End Results (SEER) database, the incidence of PMF is 0.31/ 100,000, and the median age of onset is about 70 years old [2], whose survival is much lower than that of polycythemia vera and essential thrombocythemia, and it is the most aggressive among the Philadelphia chromosome-negative (Ph-) MPNs [3]. ...
... PMF is a progressive malignant hematological disease with the worst prognosis in Ph-MPN, and its natural course is the transformation to acute myelocytic leukemia [1,3]. A variety of clinical and biological characteristics such as advanced age, constitutional symptoms, blood cells and peripheral blood blasts, and chromosome karyotype, as momentous factors affecting the prognosis of PMF patients, have been included in the current prognostic score system [4][5][6]. ...
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Additional sex combs like 1 (ASXL1) mutations are one of the most common molecular biological abnormalities in patients with primary myelofibrosis (PMF), and the effect of these mutations on prognosis remains controversial. Hence, we conducted a meta-analysis to assess the prognostic value and clinical characteristics of ASXL1 mutations in PMF patients. Eligible studies were systematically searched from PubMed, Embase, and the Cochrane Library. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and leukemia-free survival (LFS), the number of patients transformed to acute leukemia, and clinical characteristics to carry out a meta-analysis by fixed effect model or random effect model according to the heterogeneity between studies. A total of 4501 PMF patients from 16 cohorts of 14 studies were included in this meta-analysis. The results revealed that ASXL1 mutations might predict a shorter OS (HR = 2.30, 95% CI: 1.79–2.94, P < 0.00001) and a higher probability of transformation to acute leukemia (LFS: HR = 1.77, 95% CI: 1.30–2.42, P = 0.0003; the rate of acute leukemia transformation: OR = 2.06, 95% CI: 1.50–2.83, P < 0.00001). Furthermore, ASXL1 mutations were correlated with patients older than 65 years old, male, a lower level of platelet counts, and a higher risk of the international prognostic score system. These findings indicate that ASXL1 mutations have a significant adverse impact on the prognosis of PMF patients and may contribute to risk stratification and prognostic assessment for PMF patients.
... Polycythemia vera (PV) is characterized by trilineage myeloproliferation and extramedullary hematopoiesis, notably leading to elevated red blood cells and hematocrit, while essential thrombocythemia (ET) is characterized in part by dysregulated megakaryopoiesis. In addition to aberrant myeloid cell production, myelofibrosis (MF) is characterized by reactive fibrosis in the bone marrow (1,2). MPN patients show various symptoms including spleen and liver enlargement, fatigue, pruritus, fever, night sweats, and bone pain. ...
... MPN patients show various symptoms including spleen and liver enlargement, fatigue, pruritus, fever, night sweats, and bone pain. PV and ET can progress to MF and MF patients are at an increased risk of developing acute myeloid leukemia (AML) and have the poorest survival (2,3). For this reason, clinical assessment of treatment paradigms in MPN have largely been focused on MF patients (4,5). ...
Article
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The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.
... 3,5 Whereas PMF is characterized by the excessive proliferation of granulocytes, erythrocytes and megakaryocytes associated with extensive bone marrow scarring and extramedullary haematopoiesis. 6 The morphologic features on bone marrow trephine from PV, ET and PMF patients are presented in Table 1. The most common causes of morbidity and mortality in patients with MPN are thromboembolism and haemorrhage. ...
Article
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Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Unlike monogenic disorders, a more complicated series of genetic mutations are believed to be responsible for MPN with various degrees of thromboembolic and bleeding complications. Thrombosis is one of the early manifestations in patients with MPN. To date, the driver genes responsible for MPN include JAK2, CALR, MPL, TET2, ASXL1 and MTHFR. Affords have been done to elucidate these mutations and the incidence of thromboembolic events. Several lines of evidence indicate that mutations in JAK2, MPL, CALR, TET2 and ASXL1 gene and polymorphisms in several clotting factors (GPIa, GPIIa and GPIIIa) are associated with the occurrence and prevalence of thrombosis in MPN patients. Some polymorphisms within XRCC1, FBG, F2, F5, F7, F12, MMP9, HPA5, MTHFR, SDF-1, FAS, FASL, TERT, ACE and TLR4 genes may also play a role in MPN manifestation. This review aimed to provide an insightful overview on the genetic perspective of thrombotic complications in patients with MPN.
... Overt PMF is the least common [14] of MPN disorders, associated with dismal prognosis with an estimated survival of 2-5 years postdisease onset, slightly improved with current therapeutic approaches and cured with allogeneic stem cell transplantation [15][16][17]. The most common clinical hallmarks of PMF range from constitutional symptoms (fatigue, cachexia) to symptomatic anemia, thrombohemorrhagic events, hepatosplenomegaly with extramedullary hematopoiesis and increased susceptibility to infections and secondary cancers [18][19][20][21]. PMF is also considered a model where the neoplastic condition is present together with an elevated inflammatory status, and new therapies seem to target both aspects [22]. ...
Article
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Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hematopoietic stem-cell-derived clonal proliferation, leading to bone marrow (BM) fibrosis. Hematopoiesis alterations are closely associated with modifications of the BM microenvironment, characterized by defective interactions between vascular and endosteal niches. As such, neoangiogenesis, megakaryocytes hyperplasia and extensive bone marrow fibrosis, followed by osteosclerosis and bone damage, are the most relevant consequences of PMF. Moreover, bone tissue deposition, together with progressive fibrosis, represents crucial mechanisms of disabilities in patients. Although the underlying mechanisms of bone damage observed in PMF are still unclear, the involvement of cytokines, growth factors and bone marrow microenvironment resident cells have been linked to disease progression. Herein, we focused on the role of megakaryocytes and their alterations, associated with cytokines and chemokines release, in modulating functions of most of the bone marrow cell populations and in creating a complex network where impaired signaling strongly contributes to progression and disabilities.
... Pacientams, sergantiems mielofibroze, dažnai nustatoma JAK2, CALR ar MPL mutacijos, tačiau jos nėra būtinos, norint patvirtinti pirminės mielofibrozės diagnozę. Viena iš šios ligos komplikacijų yra ekstramedulinė hematopoezė [1]. Šiame straipsnyje apžvelgiamas ekstramedulinės hematopoezės atvejis, kurio diagnozei buvo naudotas magnetinio rezonanso tyrimas (MRT) ir diagnozės patikslinimui atlikta kaulų čiulpų biopsija. ...
Article
Pirminė mielofibrozė yra kraujo liga, kuriai būdingas nekontroliuojamas kamieninių ląstelių dauginimasis kaulų čiulpuose. Viena iš šios ligos komplikacijų yra ekstramedulinė hematopoezė. Tai procesas, kai kraujo ląstelės gaminasi už kaulų čiulpų ribų. Ekstramedulinę hematopoezę galima įtarti atlikus radiologinius tyrimus, tačiau diagnozę patvirtins biopsija. Straipsnyje pristatomas ekstramedulinės hematopoezės atvejis, kai diagnozei patikslinti buvo atlikti radiologiniai ir histologinis tyrimas.
... The need for more specific and more accurate prognostic models in PMF and SMF arises from the observation that only allogeneic stem cell transplantation (ASCT) is potentially curative and is able to prolong survival in patients; however, the incidence of mortality and severe adverse events justify this approach only in high-risk patients. 11 New prognostication models have been developed: the Mutation-enhanced International Prognostic Score System (MIPSS70) and the most recent MIPSS701 version 2.0 integrate clinical information with mutation and cytogenetic data to identify high-risk PMF patients aged # 70 years who are candidates for ASCT. 12,13 If cytogenetics is available, a genetically inspired prognostic scoring system (GIPSS) can be applied to predict patients' survival based on mutations and karyotype information. ...
Article
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Myelofibrosis (MF) belongs to the family of classic Philadelphia-negative myeloproliferative neoplasms (MPNs). It can be primary myelofibrosis (PMF) or secondary myelofibrosis (SMF) evolving from polycythemia vera (PV) or essential thrombocythemia (ET). Despite the differences, PMF and SMF patients are currently managed in the same way, and prediction of survival is based on the same clinical and genetic features. In the last few years, interest has grown concerning the ability of gene expression profiles (GEPs) to provide valuable prognostic information. Here, we studied the GEPs of granulocytes from 114 patients with MF, using a microarray platform to identify correlations with patient characteristics and outcomes. Cox regression analysis led to the identification of 201 survival-related transcripts characterizing patients who are at high risk for death. High-risk patients identified by this gene signature displayed an inferior overall survival and leukemia-free survival, together with clinical and molecular detrimental features included in contemporary prognostic models, such as the presence of high molecular risk mutations. The high-risk group was enriched in post-PV and post-ET MF and JAK2V617F homozygous patients, whereas pre-PMF was more frequent in the low-risk group. These results demonstrate that GEPs in MF patients correlate with their molecular and clinical features, particularly their survival, and represent the proof of concept that GEPs might provide complementary prognostic information to be applied in clinical decision making.
... With the application of intensity therapies such as chemotherapy, the survival rate of young people with hematologic malignancies continues to increase [1,2] while the survival rate of the elderly remains almost unchanged [3]. Older patients were poorly prepared due to comorbidities and cytogenetic abnormalities [4,5]. Also, older patients often show intolerance to standard treatments such as chemotherapy, and the prognosis is poor with non-transplant therapy. ...
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Apoptosis is a process of programmed cell death which mediated by proteases called caspases. Deregulated apoptosis is the basis of a variety of diseases, including cancer. The pathways of apoptosis can be divided into two independent signaling pathways, intrinsic or extrinsic. B-cell lymphoma 2 family proteins including BCL2 anti-apoptotic protein play an important role in the regulation of caspases in intrinsic pathways. Since that BCL2 is often overexpressed in cancer cells, a series of inhibitors targeting the BCL2 family antiapoptotic proteins have been developed to induce apoptosis in cancer cells. The highly selective BCL2 inhibitors, such as venetoclax (ABT-199, Venclexta™) and navitoclax(ABT-263), have shown good efficacy and safety in many hematologic malignancies. Considering that elderly patients with hematological malignancies still lack effective treatments, BCL2 inhibitors are undoubtedly an attractive new therapy due to their desirable safety and efficacy. This article reviews the application and research progress of BCL2 inhibitors in elderly patients with hematologic malignancies. Keywords: BCL2 inhibitors, hematologic malignancies, venetoclax, elderly patients
... Myelofibrosis (MF) is a clonal hematological malignancy which is pathologically characterized by bone marrow fibrosis, extramedullary hematopoeisis, and an overactive JAK-STAT pathway and clinically characterized by splenomegaly, cytopenias, and constitutional symptoms including fever, night sweats, and weight loss [1]. These constitutional symptoms can be debilitating, compromising quality of life in MF patients [2]. ...
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Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.
... Anemia is a frequent manifestation of MF. Its current treatments include androgens, erythropoiesis stimulating agents (ESA), immunomodulatory agents such as thalidomide and lenalidomide, and prednisone [9], but they are not effective in many patients, especially in those with transfusion dependence. Therefore, new therapies for the anemia of patients with MF are needed. ...
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Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
... Primary myelofibrosis (PMF) is a chronic myeloproliferative disease (Ph-negative) that is a myeloproliferative neoplasm (MPN) with the main characteristics of a significantly enlarged spleen, enhanced oxidative stress, advanced bone marrow fibrosis and extramedullary haematopoiesis [1]. PMF usually occurs in middle-aged and elderly individuals, and the median age is approximately 67 [2]; its annual incidence is approximately 0.6∼1.3/ ...
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Objection Primary myelofibrosis (PMF) is a familiar chronic myeloproliferative disease with an unfavorable prognosis. The effect of infection on the prognosis of patients with PMF is crucial. Immune system dysregulation plays a central role in the pathophysiology of PMF. To date, very little research has been conducted on the molecular mechanism of immune compromise in patients with PMF. Methods To explore potential candidate genes, microarray datasets GSE61629 and 26049 were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between PMF patients and normal individuals were evaluated, gene function was measured and a series of hub genes were identified. Several significant immune cells were selected via cell type enrichment analysis. The correlation between hub genes and significant immune cells was determined. Results A total of 282 DEGs were found, involving 217 upregulated genes and 65 downregulated genes. Several immune cells were found to be reduced in PMF, such as CD4⁺ T cells, CD4⁺ Tems, CD4⁺ memory T cells. Gene Ontology (GO) enrichment analysis of DEGs reflected that most biological processes were associated with immune processes. Six hub genes, namely, HP, MPO, MMP9, EPB42, SLC4A1, and ALAS2, were identified, and correlation analysis revealed that these hub genes have a negative correlation with immune cell abundance. Conclusions Taken together, the gene expression profile of whole blood cells in PMF patients indicated a battery of immune events, and the DEGs and hub genes might contribute to immune system dysregulation.
... Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by clonal proliferation of myeloid stem cells, bone marrow fibrosis, cytopenias, splenomegaly secondary to extramedullary hematopoiesis, and increased pro-inflammatory cytokine production with associated constitutional symptoms. 1 MF can arise de novo, called primary MF (PMF), or secondary to an antecedent MPN such as essential thrombocytosis (ET) or polycythemia vera (PV), termed post-ET MF or post-PV MF, respectively. 2 Patients with MF have a propensity towards leukemic transformation, termed MPN blast phase (MPN-BP). ...
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Julian A Waksal, Douglas Tremblay, John Mascarenhas Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: John Mascarenhas Email John.Mascarenhas@mssm.eduAbstract: Myelofibrosis (MF) is a clonal hematologic malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms with a propensity towards leukemic transformation. Constitutive activation of the JAK/STAT pathway is a well-described pathogenic feature of MF. Allogeneic stem cell transplant is the only curative therapy, but due to high morbidity and mortality this option is not available for most patients. There are two approved targeted therapy options for MF, ruxolitinib and fedratinib. In this review, we discuss the clinical utility of fedratinib in the myelofibrosis treatment paradigm. Fedratinib has shown impressive pre-clinical and clinical efficacy in patients with untreated MF as well as in those with ruxolitinib intolerance and those with relapsed/refractory MF. Here, we review the pre-clinical and clinical trials that led to the approval of fedratinib, and the ongoing late-phase trials. We highlight several areas regarding the clinical utility of fedratinib that remain unanswered. We discuss the limitations of fedratinib and address areas that are understudied and require further clinical evaluation and research. The approval of fedratinib has provided a significant expansion to the very limited treatment armamentarium available to patients with MF.Keywords: myelofibrosis, fedratinib, targeted therapy, JAK inhibitor
... However, there is also a possibility of increased infectious risk with this immunosuppressive treatment due to effects on cytokine release, T-cells, and natural killer cells [11]. This is complicated by the fact thatabrupt cessation of ruxolitinib may lead to severe withdrawal symptoms that include possible hemodynamic compromise and septic shocklike syndrome [12]. One discussion of JAKi use in COVID-19 notes only slightly increased infection rates in JAKi-treated patientsand minimal pulmonary toxicities [13]. ...
... In asymptomatic patients with a low or intermediate risk of disease according to the IPSS/DIPPS/DIPSS classifications, there is no evidence to support the value of disease-modifying therapy and observation alone is recommended. In contrast, cytoreductive treatment is indicated for patients with an intermediate or high risk of disease, and hydroxyurea or ruxolitinib are usually the first-line drugs of choice [22]. Although our patient had a low risk according to IPSS/DIPPS, there are studies demonstrating a good clinical response and safety profile in low-risk PMF patients treated with pegylated interferon, with high rates of splenic response, an improvement in constitutional symptoms, and the resolu- tion of leukocytosis and thrombocytosis, particularly in special populations including young and pregnant patients. ...
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Introduction: Myeloproliferative neoplasms are the most common cause of splanchnic vein thrombosis in the absence of cirrhosis or nearby malignancy. Case presentation: A 31-year-old male presented to the emergency department with epigastric pain associated with mild thrombocytosis and elevated levels of aminotransferases, lactate dehydrogenase, and C-reactive protein. Contrast-enhanced abdominal computed tomography revealed splanchnic venous thrombosis that involved the portal, splenic, and superior mesenteric veins, without signs of chronic liver disease. Anticoagulation with warfarin was immediately started. Diagnostic work-up was remarkable for the presence of the JAK2 V617T mutation and hypercellular bone marrow, with increased myeloid cells and atypical megakaryocytes, consistent with primary myelofibrosis in a prefibrotic stage. No other hypercoagulable conditions were identified. Discussion: We present a rare case of primary myelofibrosis in the prefibrotic stage presenting as portal-splenic-superior mesenteric vein thrombosis. This demonstrates that extensive splanchnic vein thrombosis may be the onset manifestation of myeloproliferative neoplasms, even in early stages and in the absence of concomitant hypercoagulable conditions. The presence of the JAK2 mutation is an important prothrombotic risk factor that can, per se, contribute to large venous thrombosis.
... Detailed information of individual patients were unavailable, including dose of medication; laboratory data such as hemoglobin level, white blood cell or PLT counts, percentage of circulating blasts; and the performance status or constitutional symptoms of patients. In addition the prognostic relevance of cytogenetics was highlighted in a recent study [20]. However, we were unable to perform cytogenetic analysis in this study. ...
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Previous studies have reported the survival benefit after ruxolitinib treatment in patients with myelofibrosis (MF). However, population-based data of its efficacy are limited. We analyzed the effects of ruxolitinib in MF patients with data from the Korean National Health Insurance Database. In total, 1199 patients diagnosed with MF from January 2011 to December 2017 were identified, of which 731 were included in this study. Patients who received ruxolitinib (n = 224) were matched with those who did not receive the drug (n = 507) using the 1:1 greedy algorithm. Propensity scores were formulated using five variables: age, sex, previous history of arterial/venous thrombosis, and red blood cell (RBC) or platelet (PLT) transfusion dependence at the time of diagnosis. Cox regression analysis for overall survival (OS) revealed that ruxolitinib treatment (hazard ratio (HR), 0.67; p = 0.017) was significantly related to superior survival. In the multivariable analysis for OS, older age (HR, 1.07; p < 0.001), male sex (HR, 1.94; p = 0.021), and RBC (HR, 3.72; p < 0.001) or PLT (HR, 9.58; p = 0.001) transfusion dependence were significantly associated with poor survival, although type of MF did not significantly affect survival. Considering evidence supporting these results remains weak, further studies on the efficacy of ruxolitinib in other populations are needed.
... This differentiation was probably missed as many patients did not undergo BM biopsy. The revised 2016 WHO classification system categorized 'prefibrotic' MF from 'overtly fibrotic' PMF and it is prognostically relevant to differentiate between the two [39]. The presence of the JAK2 V617F mutation was important in spite of its insignificant and marginal influence on OS in ET, PV and PMF in this study, and this could be possibly related to the 'prefibrotic' MF. ...
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Background Prognostication of myeloproliferative neoplasm (MPN) has always been challenging, even with the advent of Janus kinase 2 (JAK2 V617F) molecular studies. The survival pattern of patients diagnosed with MPN in developing countries is still undetermined.Materials and methodsThe national MPN registry conducted from 2009 to 2015 in Malaysia provided a comprehensive insight into the demographics, clinical characteristics and laboratory parameters of patients diagnosed with MPN nationwide. The study analysed the survival patterns and mortality outcomes and risk among 671 patients diagnosed with essential thrombocythaemia (ET), polycythaemia vera (PV), primary myelofibrosis (PMF) and unclassified MPN (MPN-U). Mortality status was traced and confirmed until the end of December 2018, with right censoring applied to patients alive beyond that.ResultsThe analysed cohort consisted of 283 (42.2%) ET, 269 (40.1%) PV, 62 (9.2%) PMF and 57 (8.5%) MPN-U incident cases with diagnosis made between 2007 and 2015. The majority of patients were male (52.3%) and Malay (48.9%), except for ET, in which the majority of patients were female (60.1%) and of Chinese origin (47.0%). Female patients were found to have significantly better overall survival (OS) rates in ET (p = 0.0285) and MPN-U (p = 0.0070). Patients with JAK2 V617F mutation were found to have marginally inferior OS over time. Multivariable Cox regression identified patients with increased age [hazard ratio (HR) 1.055, 95% CI 1.031; 1.064], reduced haemoglobin (HB) level (HR 0.886, 95% CI 0.831; 0.945, p = 0.0002), being male (HR 1.545, 95% CI 1.077; 2.217, p = 0.0182), and having MPN-U (HR 2.383, 95% CI 1.261; 4.503, p = 0.0075) and PMF (HR 1.975, 95% CI 1.054; 3.701, p = 0.0335) at increased risk for worse mortality outcomes.Conclusion Myeloproliferative neoplasm reduces patient survival. The degree of impact on survival varies according to sub-type, sex, bone marrow fibrosis and HB levels. The JAK2 V617F mutation was not found to affect the survival pattern or mortality outcome significantly.
... Aside from HCT, there are limited treatment options for very high-and high-risk patients and 10year survival is estimated at <13%. The use of JAK2 inhibitors is considered mostly palliative, and the treatment of clinical features includes the use of androgens, hydroxyurea and ruxolitinib (113). However, IFNs may provide a means of increasing the survival of patients with PMF. ...
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Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.
... Since our patient's Hb and Hct levels were normal, PV became less suspicious. In PMF, although sharing a common JAK2, CALR, or MPL mutation, anemia is typically present and increases over time accompanied by mild to moderate leukocytosis, mild to marked thrombocytosis, abnormal cytokine expression, cachexia, and hepatosplenomegaly [7,8]. With clinical signs and symptoms suggestive of ET, supported by positive JAK2 V617F mutation, the diagnosis of ET was established. ...
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Acute limb ischemia (ALI) is rarely observed in young populations. The hypercoagulable state is a notable cause of ALI other than artery disease progression and cardiac embolization. A hypercoagulable state occurs in essential thrombocytosis because of the overproduction of hematopoietic cells secondary to the mutation of the JAK2, CALR, or MPL genes. We report a rare case of a 37-year-old woman presenting with Rutherford IIA ALI in the left lower extremity. Laboratory data revealed she had a platelet count reaching up to 1.38 mil/μL, with other blood profiles being normal. A JAK2 mutation examination was later performed and proved positive. After careful management with catheter-directed thrombolysis, surgical thrombectomy, and cytoreductive therapy using hydroxyurea, the symptoms subsided and eventually restored the patient to physical activity in less than one month.
Article
Accelerated and blast phase myeloproliferative neoplasms present many challenges despite the advent of more novel and targeted therapeutic approaches. Outcome following transformation is frequently dismal, and the only curative approach remains allogeneic stem cell transplantation, applicable to a relatively small proportion of cases. Historically, potential risk factors for transformation from chronic phase disease have been based loosely on increasing age, long disease duration, use of sequential DNA-damaging agents, cytogenetic anomalies and advancing disease burden and limited genomic profiling which frequently reveals disparate signatures. Overall, the risk of these transformation events remains unpredictable, can occur in young individuals even without detectable high risk genomic profiles. Enhanced prognostic approaches would optimise monitoring and early intervention with potential to improve overall outcomes. Within this review we will summarise advances on disease biology, prognostication and molecular annotation and how this may ultimately lead to more rationale, stratified and forward-thinking therapeutic approaches.
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Myeloproliferative neoplasms (MPN) are a group of blood cancers in which the bone marrow (BM) produces an overabundance of erythrocyte, white blood cells, or platelets. Philadelphia chromosome-negative MPN has three subtypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The over proliferation of blood cells is often associated with somatic mutations, such as JAK2, CALR, and MPL. JAK2V617F is present in 95% of PV and 50–60% of ET and PMF. Based on current molecular dynamics simulations of full JAK2 and the crystal structure of individual domains, it suggests that JAK2 maintains basal activity through self-inhibition, whereas other domains and linkers directly/indirectly enhance this self-inhibited state. Nevertheless, the JAK2V617F mutation is not the only determinant of MPN phenotype, as many normal individuals carry the JAK2V617F mutation without a disease phenotype. Here we review the major MPN phenotypes, JAK-STAT pathways, and mechanisms of development based on structural biology, while also describing the impact of other contributing factors such as gene mutation allele burden, JAK-STAT-related signaling pathways, epigenetic modifications, immune responses, and lifestyle on different MPN phenotypes. The cross-linking of these elements constitutes a complex network of interactions and generates differences in individual and cellular contexts that determine the phenotypic development of MP
Article
Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the BCR-ABL-negative classical myeloproliferative neoplasms (MPNs). These clonal myeloid diseases are principally driven by well-described molecular events; however, factors leading to their acquisition are not well understood. Beyond increasing age, male sex, and race/ethnicity differences, few consistent risk factors for the MPNs are known. PV and ET have an incidence of 0.5 to 4.0 and 1.1 to 2.0 cases per 100,000 person-years, respectively, and predict similar survival. PMF, which has an incidence of about 0.3 to 2.0 cases per 100,000 person-years, is associated with the shortest survival of the MPNs.
Article
Purpose To provide up to date guidance, practice recommendations and highlight barriers to medication adherence in the long-term management of chronic myeloproliferative neoplasms (MPNs). Aim Current drug therapy for MPN is not curative and has not been shown to prolong survival. The main indication for treatment is the prevention of thrombosis and medication adherence remains a challenge in this group of patients. Identifying potentially modifiable barriers to medication adherence including primary nonadherence and non-persistent adherence enables timely interventions to be put in place and improve overall medication adherence. Methods A systematic review of peer-reviewed literature and expert opinions was performed using electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) that were searched for articles reporting MPN and medication adherence. Discussions A case vignette is discussed throughout the article and expert opinion with international peer reviewed guidelines that are authored to support clinical decision making at the point of care were utilised. The evidence base was combined with more practical/clinical (data based) insight from real world clinical practice. Adoption of a broad range of digital health care activities and services in the health care system (telehealth applications) by the advanced practice providers (Non-Medical Prescribers-NMPs) in MPN clinics included medication prescribing and management, oral drug compliance and adherence evaluations, interventions, chronic care management, counselling and patient education on treatments. Conclusion Current drug therapy for MPN is neither curative nor has it been shown to prolong survival, and medication adherence remains a challenge in this group of patients. The longevity of the patients’ disease course may contribute to the high risk of non-adherence in this patient cohort. Poor adherence to long-term therapies severely compromises the effectiveness of treatment. Adherence interventions should be tailored to the needs of the patient in order to achieve maximum impact. Interventions aimed at improving adherence provide the best experience and outcome for the patient and their families and can have a profound impact on the quality of life and mitigation of disease consequences.
Article
Introduction: Myelofibrosis is a clonal hematologic malignancy with clinical manifestations that include cytopenias, debilitating constitutional symptoms, splenomegaly, bone marrow fibrosis and a propensity towards leukemic progression. While allogeneic hematopoietic stem cell transplantation can be curative, this therapy is not available for the majority of patients. Ruxolitinib and fedratinib are approved JAK2 inhibitors that have produced meaningful benefits in terms of spleen reduction and symptom improvement, but there remain several unmet needs. Areas covered: We discuss novel therapies based upon published data from phase II or III clinical trials. Specifically, we cover novel JAK inhibitors (momelotinib and pacritinib), and agents that target bromodomain and extra-terminal domain (pelabresib), the antiapoptotic proteins BCL-2/BCL-xL (navitoclax), MDM2 (navtemadlin), phosphatidylinositol 3-kinase (parsaclisib), or telomerase (imetelstat). Expert opinion: Patients with disease related cytopenias are ineligible for currently approved JAK2 inhibitors. However, momelotinib and pacritinib may be able to fill this void. Novel therapies are being evaluated in the upfront setting to improve the depth and duration of responses with ruxolitinib. Future evaluation of agents must be judged on their potential to modify disease progression, which current JAK2 inhibitors lack. Combination therapy, possibly with an immunotherapeutic agent might serve as key components of future myelofibrosis treatment options.
Article
Introduction: Transformation to acute myeloid leukemia (AML) of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative neoplasms (MPN) represents a challenging medical concern and an unmet clinical need, since it charts a very poor outcome and a low rate of response to standard treatments with the exception of allogeneic hematopoietic stem cell transplantation (HSCT). Recent novel insights into the molecular disease pathways and the genomic features characterizing the transformation of Ph-MPN have led to new therapeutic individualized approaches with the potential to modify the clinical management of these difficult-to-treat patients. Areas covered: Literature review (MeSH headings/PubMed) of risk factors of MPNs progression and treatment options for transformed disease with traditional standard approaches, and novel and investigational agents was performed. One or combinations of related subject headings like transformed MPN, epigenetics, molecular alterations, HSCT, ruxolitinib, azacytidine, decitabine, gliterinib, novel agents, personalized therapy was screened. Informative papers were selected by the appropriate actual evidence and suggesting strategies for improving outcomes in the future. Expert opinion: Current and emerging treatments for transformed Ph-MPN, are presented. Novel targeted or experimental agents to be used both before HSCT, to induce blast-free state, or to modify the disease prognosis and improve survival and quality of life are critically reviewed.
Chapter
Benign or malignant diseases confined to the liver can be associated with inflammation, including lymphoid or plasmacytic infiltrate, and can rarely mimic neoplastic hematopoietic disorders. These differential diagnoses have received limited attention in the literature. Understanding the patterns of liver histology caused by lymphoma and various non-neoplastic inflammatory pathologies is essential, as the differential diagnosis varies depending on whether an inflammatory infiltrate primarily involves portal tracts, primarily involves sinusoids, or forms a discrete mass lesion. The differential diagnosis for pathologic enlargement of the spleen is broad. As a hematopoietic organ, the spleen is a site of primary lymphoma, but also manifests pathologic abnormalities in a variety of infectious diseases, hematologic disorders, and systemic inflammatory disorders that may mimic primary or secondary involvement by a hematopoietic malignancy.
Article
Résumé La myélofibrose est un syndrome myéloprolifératif chronique BCR-ABL1 négatif. On distingue la myélofibrose primitive, et la myélofibrose secondaire à une maladie de Vaquez ou à une thrombocytémie essentielle. Ces entités se caractérisent par une prolifération clonale des cellules souches hématopoïétiques, la présence d’une fibrose médullaire, et le plus souvent des mutations somatiques caractéristiques (JAK2, CALR ou MPL). Bien que pouvant être asymptomatiques, les patients présentent en général une splénomégalie, des signes généraux, une anémie, une thrombopénie ou une thrombocytose. La maladie peut aussi se révéler par une complication comme une thrombose ou une manifestation hémorragique. La myélofibrose primitive est peu fréquente, mais est associée à une survie médiocre et à un risque de transformation en leucémie aiguë. Bien que des progrès considérables aient été faits dans la compréhension de cette pathologie, les traitements demeurent majoritairement palliatifs. Le ruxolitinib, inhibiteur de JAK2, ne permet pas d’éliminer le progéniteur myéloïde clonal, et son effet n’est donc que suspensif. De nouveaux agents et de nouvelles stratégies sont à l’étude, afin de ralentir la progression de la maladie et d’améliorer la survie, mais l’allogreffe de cellules souches hématopoïétiques reste actuellement le seul traitement curatif.
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Background Primary myelofibrosis (PMF) is associated with morbidity and mortality. Ruxolitinib gained US FDA approval for treatment of intermediate/high-risk PMF in November 2011. We evaluated differences in survival and second primary malignancy (SPM) incidence among US PMF patients in the years before and after ruxolitinib approval. Methods We conducted a retrospective study utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)-18 database for PMF patients. We divided patients into five-year cohorts pre- (2007-2011) and post-ruxolitinib (2012-2016) approval and compared relative survival rates (RSRs) to the standard population and standardized incidence rates (SIRs) of SPMs between cohorts. Results We included 2020 patients diagnosed with PMF from 2007-2016 in this study. There was no difference in the four-year RSRs between cohorts (54% vs. 57%, p = 0.776). More patients developed SPMs in the post-ruxolitinib cohort (8% vs. 6%, p = 0.041). The majority of SPMs were hematologic with higher incidence of AML transformation in the post-ruxolitinib cohort (SIR 125.29 vs. 70.55). Conclusions PMF prognosis remains poor in the years following ruxolitinib’s approval. SPM incidence including AML transformation is higher in the years after approval. Further studies are needed to determine the true impact of ruxolitnib on population outcomes.
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Tyrimo pagrindimas. Išsėtinė sklerozė (IS) pasireiškia daugialypiais simptomais, tokiais kaip nuovargis, pusiausvyros bei pažintinių funkcijų sutrikimai. Kasdienis nuovargis didina griuvimo riziką, mažina aktyvumą, motyvaciją. Atsižvelgiant į ligos kompleksiškumą, siekta išsiaiškinti, ar kompleksinė kineziterapijos programa turi įtakos pusiausvyros, griuvimo rizikos, nuovargio bei pažintinių funkcijų rodikliams IS sergantiems asmenims. Tikėtina, kad minėtų rodiklių kaita gali priklausyti nuo paros laiko, kuriuo atliekami pratimai. Tikslas – įvertinti asmenų, sergančių IS, pusiausvyros, griuvimo rizikos, nuovargio bei pažintinių funkcijų kaitą, taikant kompleksinę kineziterapijos programą, priklausomai nuo procedūrų atlikimo laiko. Metodai. 20 tiriamųjų, Kauno apskrities sergančiųjų išsėtine skleroze draugijos narių. Tiriamieji buvo suskirstyti į dvi poveikio grupes. Tiriamiesiems buvo taikoma kompleksinė kineziterapijos programa, kurią sudarė tempimo, liemens stabilizavimo bei sensomotoriką lavinantys pratimai ir dvigubos užduoties metodas. Kiekvienai tiriamųjų grupei taikyta 10 kineziterapijos procedūrų, kas antrą dieną. Pirmajai grupei kineziterapija taikyta ryte, antrajai – po pietų. Tyrimo pradžioje įvertinta pusiausvyra, griuvimo rizika, nuovargis bei pažintinės funkcijos. Baigus tyrimą, atliktas pakartotinis funkcijų vertinimas. Tyrimo rezultatai. Vertinant kompleksinės kineziterapijos programos efektyvumą priklausomai nuo procedūrų atlikimo laiko, pirmosios tiriamosios grupės dinaminės pusiausvyros, griuvimo rizikos, bendrojo bei protinio nuovargio, pažintinių funkcijų rodiklių pagėrėjimas buvo reikšmingesnis, nei antrosios grupės (p < 0,05). Išvados. Dinaminės pusiausvyros rezultatai geresni toje grupėje, kurioje kompleksinė kineziterapijos programa taikyta ryte. Griuvimo rizikos sumažėjimas ryškesnis toje grupėje, kuri pratimų programą atliko ryte. Bendrasis ir protinis nuovargis sumažėjo tik rytinėje grupėje. Tiriamųjų pažintinės funkcijos pagerėjo toje grupėje, kuriai kineziterapijos programa vykdyta ryte.
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Extracellular vesicles (exosomes, in particular) are essential in multicellular organisms because they mediate cell-to-cell communication via the transfer of secreted molecules. They are able to shuttle different cargo, from nucleic acids to proteins. The role of exosomes has been widely investigated in solid tumors, which gave us surprising results about their potential involvement in pathogenesis and created an opening for liquid biopsies. Less is known about exosomes in oncohematology, particularly concerning the malignancies deriving from myeloid lineage. In this review, we aim to present an overview of immunomodulation and the microenvironment alteration mediated by exosomes released by malicious myeloid cells. Afterwards, we review the studies reporting the use of exosomes as disease biomarkers and their influence in response to treatment, together with the recent experiences that have focused on the use of exosomes as therapeutic tools. The further development of new technologies and the increased knowledge of biological (exosomes) and clinical (myeloid neoplasia) aspects are expected to change the future approaches to these malignancies.
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Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.
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Myeloproliferative neoplasms (MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The relationship between JAK2 p.(V617F) mutation and MPNs was first described in 2005. The purpose of this study was to determine the prevalence of JAK2 p.(V617F) mutation in Tunisian patients assessed for MPNs and try to set a genotype-phenotype correlation. A retrospective study was conducted between January 2015 and April 2019. We collected the clinical data of all patients with MPNs suspicion or atypical splanchnic vein thrombosis (SVT). JAK2 p.(V617F) mutation was detected by allele specific real-time quantitative fluorescence PCR (AS-qPCR). We gathered 974 patients who underwent molecular analysis, 55.5% of them were male and 44.5% were female. The median age of all studied patients was 56 years. JAK2 p.(V617F) was found in 349 (35.8%) of total enrolled cases. It was reported in 44%, 37%, 29% and 25% of all patients diagnosed as having respectively ET, PV, PMF and atypical SVT. JAK2 p.(V617F) was negative in 62.2% of patients addressed for suspicion of PV. There was a significant positive correlation between the JAK2 p.(V617F) mutation status, age, gender, white blood cell counts and platelet counts. To our best knowledge, this is the first vast investigation of JAK2 p.(V617F) variant in Tunisia and North Africa with the lowest mutation rate in entire cohort and MPNs subgroups, underlying a specific presentation of this mutation. It is considered as an essential marker of MPNs' diagnosis and prognosis and is associated with differences in the phenotype of these disorders, helpful for the follow-up of these patients.
Article
Introduction Driver mutations in Philadelphia chromosome‐negative myeloproliferative neoplasms are well known. In the past, whole‐genome sequencing identified nondriver mutations in other genes, potentially contributing to evolution of malignant clones. Methods Next‐generation sequencing was used to assess the presence of any mutations in 14 candidate genes at the point of diagnosis and the resultant impact on the clinical course of the disease. Results The study analysed 63 patients with myelofibrosis (MF). Nondriver mutations were detected in 44% of them. The most frequently affected genes were ASXL1 (27%), TET2 (11%) and SF3B1 (6%). The frequency of such mutations was highest in primary MF (59%) and lowest in the prefibrotic phase of primary MF (21%). Patients with prognostically unfavourable sequence variants in genes had significantly worse overall survival (53 vs 71 months; HR = 2.77; 95% CI 1.17‐6.56; P = .017). Conclusion In our study, multivariate analysis proved DIPSS to be the only significant factor to predict patient survival. DIPSS contains all of the important clinical and laboratory factors except genetic changes. Stratification of patients according to DIPSS is still beneficial although there are newer and improved scoring systems like GIPSS or MIPSS70. Assessing subclonal mutations in candidate genes during diagnosis may aid in the identification of high‐risk MF patients and is therefore relevant for making a prediction for overall survival more accurate.
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Mesleki etik , sağlık çalışanının mesleki uygulamalar sırasında nelere dikkat etmesi gerektiğine, hangi durumlarda nasıl davranılacağına dair yol gösterici olur. Mesleki açıdan etik ilkelere ve kodlara uygun davranmak ,bireylerin sağlığını geliştirmek ve korumak; sağlık çalışanlarının da iş doyumunu, motivasyonunu, kararlılığını, mesleki bütünlüğünü, bulunduğu pozisyonun güçlendirilmesini etkiler. Sağlık çalışanlarının sadece yeterli bilgiye sahip olmaları değil ,aynı zamanda mesleki uygulamalar sırasında da içinde bulunduğu duruma göre etik karar verebilmesi gerekir. Meslek Yüksekokulunda okuyan sağlık bölümü öğrencilerinin etik değerlerle ilgili görüşlerini araştırmak,davranışlarını değerlendirmek ve farkındalıklarını arttırmak amacıyla 17 soruluk bir anket hazırlanmış ve 220 kişiye uygulanmıştır.Anket sorularının frekansları değerlendirilerek yüzdelik oranları çıkartılmış ve sonuçlar, grafiklerle verilmiştir. Bu sonuçlara göre; ankete katılanların %86,9’unu 17-24 yaş aralığı oluşturmaktadır. %64,9’u kadın , %35,1 ‘i ise erkek öğrencilerden oluşmaktadır.Çalışmaya katılan öğrencilerin %60,4 ‘ü etik eğitim almadıklarından etik ikilemle karşılaştıklarında insiyatif kullanmak yerine bir üst yöneticiye ya da sorumlularına danışmayı tercih etmiştir. Çalışmamızda sağlık bölümü öğrencilerinin etik bilgilerinin ve etik değerlerle ilgili görüşlerinin yetersiz olduğu saptanmıştır. Bu sonuçlar doğrultusunda , sağlık bölümü öğrencilerinin sağlık sektöründe çalışmaya başladıklarında bilgi ve farkındalıklarını arttırmak ,etik ikilemle karşılaştıklarında ise neler yapabileceklerinin bilincinde olmaları için etik dersi almaları gerektiği sonucuna varılmıştır.
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Introduction: Myelofibrosis (MF) is characterized by anemia, splenomegaly, constitutional symptoms and bone marrow fibrosis. MF has no curative treatment to date, except for a small subset of patients that are eligible for allogeneic hematopoietic stem cell transplant. The discovery in recent years of the MF mutational landscape and the role of bone marrow microenvironment in disease pathogenesis has led to further insights into disease biology and consequentially rationally derived therapies. Areas covered: We searched PubMed/Medline/American Society of Hematology (ASH) abstracts until November 2020 using the following terms: myelofibrosis, mouse models, pre-clinical studies and clinical trials. The development of targeted therapies is aimed to modify the history of the disease. Although JAK inhibitors showed encouraging results in terms of spleen and symptoms response, long term remissions and disease modifying ability is lacking. Beyond JAK inhibitors, a range of agents targeting proliferative, metabolic, apoptotic pathways, the microenvironment, epigenetic modification and immunomodulation are in various stages of investigations. We review pre-clinical data, preliminary clinical results of these agents, and finally offer insights on the management of MF patients. Expert opinion: MF patients refractory or with suboptimal response to JAK inhibitors, may be managed by addition of agents with differing mechanisms, such as bromodomain (BET), lysine demethylase 1 (LSD1), MDM2, or Bcl-Xl inhibitors which could prevent emergence of resistance. Immunotherapies as long-acting interferons, and calreticulin directed antibodies or peptide vaccination are eagerly awaited. Historically, therapeutic challenges in MF have arisen due to the fact that rationally derived therapies that are based on murine models have limited impact on fibrosis and underlying disease biology in human studies, the latter illustrates the complex multi-faceted disease pathogenesis of MF. Together, we not only suggest individualized therapy in MF that is guided by genomic signature but also its early implementation potentially in prefibrotic MF.
Article
Introduction : Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50–100 × 10⁹/L) are reported. Patients and Methods : Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 10⁹/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. Results : Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). Conclusion : A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.
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Philadelphia-negative myeloproliferative neoplasms (MPN) are aggressive diseases characterized by clonal proliferation of myeloid stem cells. The clonal process leads to excessive red cells production, platelets production, and bone marrow fibrosis. According to the phenotype, MPN can be classified as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN patients have shortened survival due to the increased risk of thrombosis, hemorrhages, and transformation to acute myeloid leukemia (AML). Prognosis is variable, with a shorter life expectancy in myelofibrosis. Currently, drug therapy can reduce symptoms, splenomegaly, and risk of thrombosis. Still, some patients can be resistant or intolerant to the treatment. At the same time, allogeneic stem cell transplant (ASCT) is the only treatment modality with the potential to cure the disease. Nevertheless, the ASCT is reserved for high-risk leukemic progression patients due to the risk of treatment-related death and comorbidity. Therefore, there is a need for new drugs that can eradicate clonal hematopoiesis and prevent progression to more aggressive myeloid neoplasms. Thanks to the better understanding of the disease’s molecular pathogenesis, many new potentially disease-modifying drugs have been developed and are currently in clinical trials. This review explores the most promising new drugs currently in clinical trials.
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Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions.
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Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.
Article
Background Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a. Methods REFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVR35 at week 24 from baseline. Secondary endpoints were a 50% or greater reduction in total symptom score (TSS50) at week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (version 4.0), anaemia response assessed according to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to the European consensus grading system; and exploratory endpoints included overall survival and changes in inflammatory cytokines. Exploratory analyses investigated potential prognostic biomarkers of the benefit of navitoclax-based combination treatment, including bone marrow fibrosis and variant allele frequency, in patients with a suboptimal response to ruxolitinib. This study is registered with ClinicalTrials.gov (NCT03222609) and is ongoing. Findings Between Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9–32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVR35 at week 24 in the high molecular risk group, as did four (31%) of 13 in the non-high molecular risk group. Four (36%) of 11 patients in the high molecular risk group had TSS50 at week 24 compared with two (25%) of eight in the non-high molecular risk group; seven (39%) of 18 in the high molecular risk group had an improvement in fibrosis by at least one grade compared with five (36%) of 14 in the non-high molecular risk group; and four (28%) of 14 had reductions in variant allele frequency of 20% or greater in the high molecular risk group compared with two (17%) of 12 in the non-high molecular risk group. Patients with improvements in fibrosis of one grade or more and a reduction of 20% of more in variant allele frequency had improved overall survival (median overall survival not reached) compared with those who did not achieve fibrosis improvement or a reduction in variant allele frequency (median overall survival 28·5 months [95% CI 19·6–not estimable] for both), suggesting potential disease modification. Additionally, changes in concentrations of β-2-microglobulin (week 12: r=0·57; week 24: r=0·57), TIMP metallopeptidase inhibitor 1 (week 12: r=0·47; week 24: r=0·54), TNF receptor type II (r=0·55; week 24: r=0·40), and vascular cell adhesion molecule-1 (r=0·58; week 24: r=0·50) were positively associated with changes in spleen volume. Interpretation These biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. Funding AbbVie.
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International collaborations over the years have produced a series of prognostic models for primary myelofibrosis (PMF), including the recently unveiled mutation-enhanced international prognostic scoring systems for transplant-age patients (MIPSS70 and MIPSS70-plus). In the current study, we considered the feasibility of a genetically inspired prognostic scoring system (GIPSS) that is exclusively based on genetic markers. Among 641 cytogenetically annotated patients with PMF and informative for previously recognized adverse mutations, multivariable analysis identified “VHR” karyotype, “unfavorable” karyotype, absence of type 1/like CALR mutation and presence of ASXL1, SRSF2, or U2AF1Q157 mutation, as inter-independent predictors of inferior survival; the respective HRs (95% CI) were 3.1 (2.1–4.3), 2.1 (1.6–2.7), 2.1 (1.6–2.9), 1.8 (1.5–2.3), 2.4 (1.9–3.2), and 2.4 (1.7–3.3). Based on HR-weighted risk points, a four-tiered GIPSS model was devised: low (zero points; n = 58), intermediate-1 (1 point; n = 260), intermediate-2 (2 points; n = 192), and high (≥3 points; n = 131); the respective median (5-year) survivals were 26.4 (94%), 8.0 (73%), 4.2 (40%), and 2 (14%) years; the model was internally validated by bootstrapping and its predictive accuracy was shown to be comparable to that of MIPSS70-plus. GIPPS offers a low-complexity prognostic tool for PMF that is solely dependent on genetic risk factors and, thus, forward-looking in its essence.
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One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2–7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1–3.2) or SRSF2 (HR 2.4, 95% CI 1.3–4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3–16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9–32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4–11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.
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The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
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Current cytogenetic risk stratification in primary myelofibrosis (PMF) is two-tiered: 'favorable' and 'unfavorable'. Recent studies have suggested prognostic heterogeneity within the unfavorable risk category. In 1002 consecutive patients, we performed stepwise analysis of impact on survival from individual and prognostically ordered cytogenetic abnormalities, leading to a revised three-tiered risk model: 'very high risk (VHR)'-single/multiple abnormalities of -7, i(17q), inv(3)/3q21, 12p-/12p11.2, 11q-/11q23, or other autosomal trisomies not including + 8/ + 9 (e.g., +21, +19); 'favorable'-normal karyotype or sole abnormalities of 13q-, +9, 20q-, chromosome 1 translocation/duplication or sex chromosome abnormality including -Y; 'unfavorable'-all other abnormalities. Median survivals for VHR (n = 75), unfavorable (n = 190) and favorable (n = 737) risk categories were 1.2 (HR 3.8, 95% CI 2.9-4.9), 2.9 (HR 1.7, 95% CI 1.4-2.0) and 4.4 years and survival impact was independent of clinically derived prognostic systems, driver and ASXL1/SRSF2 mutations. The revised model was also effective in predicting leukemic transformation: HRs (95% CI) were 4.4 (2.0-9.4) for VHR and 2.0 (1.2-3.4) for unfavorable. The impact of driver mutations on survival was confined to favorable and that of ASXL1/SRSF2 mutations to favorable/unfavorable cytogenetic risk categories. The current study clarifies the prognostic hierarchy of genetic risk factors in PMF and provides a more refined three-tiered cytogenetic risk model.
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A total of 410 patients with blast phase myeloproliferative neoplasm (MPN-BP) were retrospectively reviewed: 248 from the Mayo Clinic and 162 from Italy. Median survival was 3.6 months, with no improvement over the last 15 years. Multivariable analysis performed on the Mayo cohort identified high risk karyotype, platelet count < 100 × 109/L, age > 65 years and transfusion need as independent risk factors for survival. Also in the Mayo cohort, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35 and 24%, respectively; treatment-specified 3-year/5-year survival rates were 32/10% for patients receiving allogeneic stem cell transplant (AlloSCT) (n = 24), 19/13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1/1% in the absence of both AlloSCT and CR/CRi (n = 200) (p < 0.01). The survival impact of AlloSCT (HR 0.2, 95% CI 0.1-0.3), CR/CRi without AlloSCT (HR 0.3, 95% CI 0.2-0.5), high risk karyotype (HR 1.6, 95% CI 1.1-2.2) and platelet count < 100 × 109/L (HR 1.6, 95% CI 1.1-2.2) were confirmed to be inter-independent. Similar observations were made in the Italian cohort. The current study identifies the setting for improved short-term survival in MPN-BP, but also highlights the limited value of current therapy, including AlloSCT, in securing long-term survival.
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Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.
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A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.
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Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study, we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia and red cell transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival and non-relapse mortality. The 5-year OS, relapse rate, and TRM for patients with Low/Int-1 risk MF was 78%, 5%, and 20%, respectively. The 5-year OS, relapse rate and TRM for patients with high risk MF was 35%, 28%, 40%, respectively. HCT-comorbidity index of 3 or greater was associated with higher non-relapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR=3.02, p=0.0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance following adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant.
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Performing a pre-transplant splenectomy in patients with myelofibrosis (MF) is a matter of debate, as while the procedure improves hematological recovery it may lead to severe morbidities. We retrospectively analyzed data from 85 patients consecutively transplanted in our center for MF, including 39 patients who underwent splenectomy before their transplant. A majority of them had primary MF (78%), were considered high risk patients (84% DIPSS intermediate-2 or higher), and were transplanted from HLA-matched sibling donors (56%) after a reduced-intensity conditioning regimen (82%). Half of all splenectomized patients presented surgical or post-surgical morbidities, most frequently thrombosis and hemorrhage. After adjustment using Cox models, pre-transplant splenectomy was not associated with non-relapse mortality or post-transplant relapse but with an improved OS and EFS. We conclude that some patients with huge splenomegaly may undergo pre-transplant splenectomy without there being a deleterious impact on post-transplant outcomes. OS and EFS improvement should in confirmed in controlled study.
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Key Points More than 80% of patients with PMF harbor DNA variants/mutations other than JAK2/CALR/MPL. Some of these variants/mutations adversely affect overall or leukemia-free survival independent of conventional risk stratification.
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Key Points More than half of patients with PV or ET harbor DNA mutations/variants other than JAK2/CALR/MPL. The presence of some of these mutations adversely affects overall, leukemia-free, or myelofibrosis-free survival.
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The World Health Organization (WHO) Classification of Tumours of the Haematopoietic and Lymphoid Tissues was last updated in 2008. Since then there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias - largely derived from gene expression analysis and next generation sequencing (NGS) that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that has have emerged since the last edition. The major changes in the classification and their rationale are presented here.
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Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
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Current prognostication in primary myelofibrosis (PMF) is based on the dynamic international prognostic scoring system (DIPSS)-plus, which employs clinical and cytogenetic variables. We recently reported DIPSS-plus independent prognostic significance for CALR (favorable) and ASXL1 (unfavorable) mutations. In the current study, 570 PMF patients were recruited for derivation (n=277) and validation (n=293) of a molecular prognostic model based on these two mutations. Survival was the longest in CALR(+)ASXL1(-) (median 10.4 years) and shortest in CALR(-)ASXL1(+) patients (median 2.3 years; HR 5.9, 95% CI 3.5-10.0). CALR(+)ASXL1(+) and CALR(-)ASXL1(-) patients had similar survival and were grouped together in an intermediate risk category (median survival 5.8 years; HR 2.5, 95% CI 1.5-4.0). The CALRsolASXL1 mutations-based prognostic model was DIPSS-plus independent (P<0.0001) and effective in identifying low/intermediate-1 risk patients with shorter (median 4 years) or longer (median 20 years) survival and high/intermediate-2 risk patients with shorter (median 2.3 years) survival. Multivariable analysis distinguished CALR(-)ASXL1(+) mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype. These observations signify immediate clinical relevance and warrant i) CALR and ASXL1 mutation screening in all patients with PMF and ii) molecular revision of DIPSS-plus.Leukemia accepted article preview online, 5 February 2014; doi:10.1038/leu.2014.57.
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To the editor: Treatment with the Janus-activated kinase (JAK) 1 and 2 inhibitor ruxolitinib decreases constitutional symptoms and spleen size in myelofibrosis. However, accumulating evidence suggests that the drug also exerts substantial immunosuppressive activity.[1][1],[2][2] A very recent
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Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL, and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2, and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.Leukemia accepted article preview online, 26 April 2013; doi:10.1038/leu.2013.119.
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Background The 2016 revised World Health Organization (WHO) classification system distinguishes prefibrotic (pre-PMF) from overtly fibrotic (overt PMF) primary myelofibrosis, based on the respective absence or presence of grade ≥2 bone marrow (BM) reticulin fibrosis (Blood. 2016;127:2391). The main objective of the current study was to determine the prognostic relevance of this distinction and compare clinical and genetic features between the two entities. Methods Study patients fulfilled the 2016 WHO criteria for the diagnosis of pre-PMF or overt PMF (Blood. 2016;127:2391). The degree of BM reticulin fibrosis was based on "real life" BM reports from Mayo Clinic hematopathologists and often in accordance with the European consensus scoring system (Haematologica 2005;90:1128). Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of BM examination that was graded for reticulin fibrosis. Results Patient characteristics: Analysis was conducted on 467 patients (median age 64 years; 62% males), including 63 with pre-PMF and 404 with overt PMF. 302 (65%) patients harbored JAK2 mutations, 90 (19%) CALR, 24 (5%) MPL and 51 (11%) were "triple-negative"; among the 90 CALR-mutated cases, 74 (82%) were classified as "type 1/type 1-like". Dynamic international prognostic scoring system (DIPSS)-plus risk distribution (JCO 2011;29:392) was 30% high, 38% intermediate-2, 16% intermediate-1 and 15% low; 29% displayed red cell transfusion-dependency, 29% constitutional symptoms, 70% palpable splenomegaly and 37% abnormal karyotype, including 13% with unfavorable karyotype. 308 patients were screened for ASXL1 mutations with 39% mutated, 305 for SRSF2 mutations with 16% mutated, 291 for U2AF1 with 18% mutated, 264 for SF3B1 with 6% mutated, 240 for EZH2 with 5% mutated and 118 for IDH1/2 with 7% mutated. BM reticulin fibrosis was reported as grade '0' in 5 (1%) patients, grade '1' in 58 (12%), grade '2' in 169 (36%) and grade '3' in 235 (50%). After a median follow up of 3 years, 273 (59%) deaths and 42 (9%) leukemic transformations were documented. Clinical, cytogenetic and molecular comparisons between pre-PMF vs overt PMF: Significant differences included higher hemoglobin level (p<0.0001), higher platelet count (p<0.0001), higher incidence of thrombocytosis (p<0.0001), lower circulating blast percentage (p=0.0002), lower incidence of constitutional symptoms (p=0.003), lower incidence of palpable splenomegaly and lower DIPSS-plus risk distribution (p=0.0004), in pre-PMF, compared to overt PMF. There were significantly more triple-negative patients with pre-PMF (22% vs 9% for overt PMF; p=0.02) but otherwise no significant difference in the distribution of ASXL1, SRSF2, U2AF1, SF3B1, EZH2 or IDH1/2 mutations or incidence of unfavorable karyotype. Survival analysis: In univariate analysis, all 8 variables included in DIPSS-plus were significantly associated with shortened survival (p<0.001 in all instances). Significant risk factors in univariate analysis also included overt PMF vs pre-PMF (p=0.002; HR 2.0, 95% CI 1.3-3.1), absence of CALR type 1/type 1-like (p<0.0001) and presence of ASXL1 (p<0.0001) or SRSF2 (p<0.0001) mutations. The significant difference in survival between pre-PMF and overt PMF was independent of DIPSS-plus (p=0.03), driver mutational status (p=0.001), ASXL1 (p=0.008) and SRSF2 (p=0.02) mutations; no significant difference in leukemia-free survival was noted (p=0.25). The survival difference between pre-PMF and overt PMF was most evident in high/intermediate-2 DIPSS-plus risk groups (Figure). Of note, we found no difference in survival when patients with grade '0' were compared to those with grade '1' reticulin fibrosis (p=0.96) and when those with grade '2' were compared with grade '3' (p=0.08). Conclusion The current study demonstrates the risk-adjusted prognostic relevance of the WHO distinction between pre-PMF and overt PMF. The two clinic-pathologic entities were otherwise similar in their spectrum of prognostically-relevant mutations or cytogenetic abnormalities, although pre-PMF clustered with thrombocythemic and triple-negative phenotype and overt PMF with adverse clinical features. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1,000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% “unfavorable” and 45% “favorable” karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pre-transplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (p=0.68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a non-transplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n=450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF. This article is protected by copyright. All rights reserved.
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Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed. Results Multivariable analysis identified the following as significant risk factors for OS: hemoglobin < 100 g/L, leukocytes > 25 × 10 ⁹ /L, platelets < 100 × 10 ⁹ /L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high–molecular risk mutation (ie, ASXL1, EZH2, SRSF2, IDH1/ 2), and presence of two or more high–molecular risk mutations. By assigning hazard ratio (HR)–weighted points to these variables, three risk categories were delineated for the MIPSS70 model; 5-year OS was 95% in low-risk, 70% in intermediate-risk, and 29% in high-risk categories, corresponding to median OS of 27.7 years (95% CI, 22 to 34 years), 7.1 years (95% CI, 6.2 to 8.1 years), and 2.3 years (95% CI, 1.9 to 2.7 years), respectively. In the MIPSS70-plus model, which included cytogenetic information, four risk categories were delineated, with 5-year OS of 91% in low-risk, 66% in intermediate-risk (HR, 3.2; 95% CI, 1.9 to 5.2), 42% in high-risk (HR, 6.4; 95% CI, 4.1 to 10.0), and 7% very high–risk categories (HR, 17.0; 95% CI, 9.8 to 29.2). Both models remained effective after inclusion of older patients in the analysis. Conclusion MIPSS70 and MIPSS70-plus provide complementary systems of risk stratification for transplantation-age patients with PMF and integrate prognostically relevant clinical, cytogenetic, and mutation data.
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The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (p=0.41). In multivariable analysis, the absence of type 1/like CALR (p<0.001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (p<0.001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (p<0.001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs 2.9 years; p<0.001). Triple-negative status did not disclose additional prognostic information for overall or leukemia-free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations. This article is protected by copyright. All rights reserved.
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Leukemia accepted article preview online, 01 November 2017. doi:10.1038/leu.2017.318.
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Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. In order to assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for post-splenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 x 10(9)/L, 25% leukocyte count >25 x 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple-negative 6%. At median follow-up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median post-splenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 x 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR-weighted scoring system with high (3-4 risk factors), intermediate (2 risk factors) and low (0-1 risk factors) risk categories; the corresponding post-splenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2-11.0), 1.3 (HR 2.9, 95% CI 1.8-4.6) and 2.9 years. Post-splenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia-free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF. This article is protected by copyright. All rights reserved.
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The 2016 revision of the World Health Organization (WHO) classification of myeloproliferative neoplasms defines 2 stages of primary myelofibrosis (PMF): prefibrotic/early (pre-PMF) and overt fibrotic (overt PMF) phase. In this work, we studied the clinical and molecular features of patients belonging to these categories of PMF. The diagnosis of 661 PMF patients with a bone marrow biopsy at presentation was revised according to modern criteria; clinical information and annotation of somatic mutations in both driver and selected nondriv