scholarly journals Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3551
Author(s):  
Julian Baumeister ◽  
Nicolas Chatain ◽  
Alexandros Marios Sofias ◽  
Twan Lammers ◽  
Steffen Koschmieder
Keyword(s):  
Acute Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Symptom Burden ◽  
Primary Myelofibrosis ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
Driver Gene ◽  
Major Hemorrhage ◽  
Symptomatic Disease

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

scholarly journals Rosai-Dorfman disease in the central nervous system with two isolated lesions originated from a single clone: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huawei Jin ◽  
Zhenhua Yu ◽  
Tian Tian ◽  
Guoping Shen ◽  
Weian Chen ◽  
...  
Keyword(s):  
Clonal Evolution ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Driver Gene ◽  
Whole Exome ◽  
Rosai Dorfman Disease ◽  
Single Clone ◽  
Tumor Mutational Burden ◽  
The Central Nervous System ◽  
Clonal Nature

Abstract Background Rosai–Dorfman disease (RDD) is a rare, benign, idiopathic non-Langerhans cell histiocytosis. Cases of RDD in the CNS are extremely rare but lethal. RDD is thought to represent a reactive process. Recent studies proposed a subset of RDD cases that had a clonal nature. However, its clone origin is poorly understood. Case presentation We present a rare case of RDD in the CNS with two isolated lesions. These two lesions were removed successively after two operations. No seizure nor recurrence appears to date (2 years follow-up). Morphological and immunohistochemical profiles of these two lesions support the diagnosis of RDD. Based on the whole-exome sequencing (WES) data, we found the larger lesion has a higher tumor mutational burden (TMB) and more driver gene mutations than the smaller lesion. We also found seven common truncal mutations in these two lesions, raising the possibility that they might stem from the same ancestor clone. Conclusions Overall, this is the first report about clonal evolution of RDD in the CNS with two isolated lesions. Our findings contribute to the pathology of RDD, and support the notion that a subset of cases with RDD is a clonal histiocytic disorder driven by genetic alterations.

scholarly journals CHRONIC MYELOPROLIFERATIVE NEOPLASMS: A COLLABORATIVE APPROACH

2010 ◽  
Vol 2 (2) ◽  
pp. e2010017
Author(s):  
Lisa Pieri ◽  
Paola Guglielmelli ◽  
Alessandro Maria Vannucchi
Keyword(s):  
Acute Leukemia ◽  
Clinical Course ◽  
Myeloproliferative Neoplasms ◽  
Clinical Manifestations ◽  
Primary Myelofibrosis ◽  
The Other ◽  
Collaborative Approach ◽  
Chronic Myeloproliferative Neoplasms ◽  
Key Issues ◽  
Oriented Approach

The classic chronic myeloproliferative neoplasms (MPN) include different entities that pose significant challenges for their optimal diagnosis, treatment and overall management. Polycythemia Vera and Essential Thrombocythemia are the most common among chronic myeloproliferative neoplasms (MPNs); major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as evolution to myelofibrosis or transformation to acute leukemia. However, survival is only minimally affected. Therapy aims at reducing the rate of thrombosis without increasing the risk of hematologic transformation which could be caused by exposure to cytotoxic drugs. On the other hand, survival is significantly reduced in primary myelofibrosis, and the clinical manifestations may be disabling. In the absence of therapies with the potential of curing the disease, a careful risk-oriented approach is employed for stratifying patients to the most appropriate, currently available, therapeutic options. In this brief review, we will discuss some of the key issues that can arise along the clinical course of MPNs and require an integrated, strictly patient-oriented, approach.

Risk of Mortality and Leukemic Transformation in Primary Myelofibrosis before and after Ruxolitinib Approval

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
John William Thomas ◽  
Mithun Vinod Shah ◽  
Pankit Vachhani ◽  
Omer Jamy ◽  
Ronald S. Go ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Hematologic Malignancies ◽  
The United States ◽  
Symptom Improvement ◽  
Advisory Committees ◽  
Study Results ◽  
Significant Difference ◽  
The Impact

Background: Primary myelofibrosis (PMF) has the worst prognosis of the classical BCR-ABL1 negative myeloproliferative neoplasms, with a median overall survival of six years. Factors affecting survival include age, symptom burden, cytopenias, mutation profile, and development of second malignancies including transformation to acute myeloid leukemia (AML). Ruxolitinib, a selective JAK1 and JAK2 inhibitor, was granted approval by the United States (US) Food and Drug Administration for treatment of intermediate and high-risk PMF in November 2011 based on reduction in spleen volume and demonstration of symptom improvement. The impact of ruxolitinib on PMF survival is unknown. In this study, we aimed to evaluate whether there has been a change in survival and patterns of second primary malignancies (SPMs) including AML transformation among PMF population in US after ruxolitinib approval. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 survival and Multiple Primary Standardized Incidence Ratio (MP-SIR) registries, we conducted a retrospective study with patients diagnosed with PMF between the years of 2007 and 2016. We divided these patients into two five-year cohorts, pre-ruxolitinib approval (2007-2011) and post-ruxolitinib approval (2012-2016), and compared relative survival rates (RSRs) and standardized incidence ratios (SIRs) of SPMs between the cohorts. SIRs were calculated as the ratio of observed to expected malignancy cases over the specified time periods. Median follow-up duration was five years for each cohort. RSRs and SIRs were compared between cohorts using two-proportion Z-tests. Results: We included 2164 patients diagnosed with PMF between 2007 and 2016 with data available in the SEER-18 survival and MP-SIR registries. Of these, 1051 (49%) patients were included in the pre-ruxolitinib cohort and 1113 (51%) patients were included in the post-ruxolitinib cohort. There was no significant difference in the four-year RSRs between the pre-ruxolitinib and post-ruxolitinib cohorts (55% vs. 56%, p = 0.719). A higher proportion of SPMs occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (60% vs. 40%, p < 0.001). Hematologic malignancies comprised a majority of all SPMs (AML 39% and non-Hodgkin lymphoma 16%). A higher incidence of AML transformation occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 121.48 vs. 72.22, p = 0.037). Non-hematologic malignancies were also more common in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 1.09 vs. 0.94, p < 0.001). The most common non-hematologic malignancies were cancers of the respiratory tract, urinary tract, and prostate gland, though their SIRs were not significant in either cohort. Conclusions: Our study results suggest that despite improvements in prognostication and the approval of ruxolitinib, the prognosis of PMF remains poor in the US. These results may be due to low uptake of ruxolitinib in practice or a lack of benefit from the drug itself. Additionally, for reasons that are unclear, SPM incidence has increased in the five years following the approval of this drug. Further studies should be conducted to determine the cause of these findings. Figure Disclosures Shah: Dren Bio: Consultancy. Vachhani:astellas: Speakers Bureau; agios, blueprint medicines, jazz pharmaceuticals, daiichi sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

TP53 Mutation Is Rare In Primary Myelofibrosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5241-5241
Author(s):  
Wesley O. Greaves ◽  
Shalini Verma ◽  
Tigist Bisrat ◽  
Hamed Rahimi ◽  
Abhaya Paladugu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Sanger Sequencing ◽  
Tp53 Mutation ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Melting Curve ◽  
Primary Myelofibrosis ◽  
Hrm Analysis ◽  
Exon 4

Abstract Abstract 5241 Introduction TP53 is the most frequently mutated tumor suppressor gene in human cancers and is usually associated with an aggressive disease course. TP53 mutation has been described in a variety of hematopoietic neoplasms, and has been suggested to play a role in leukemic transformation of myeloproliferative neoplasms (MPN). However, the incidence as well as the clinical and pathogenetic implications of TP53 mutation in each sub-category of MPN, including primary myelofibrosis, have not been described. In this study, we investigated the presence and potential clinical significance of TP53 mutations in a large series of primary myelofibrosis cases. Patients and Methods We retrieved archival bone marrow DNA from 51 consecutive patients diagnosed with primary myelofibrosis at The University of Texas MD Anderson Cancer Center between the years 2005 and 2007. Diagnosis was based on morphologic, immunophenotypic, cytogenetic and molecular evaluation of bone marrow in conjunction with clinical data. Only 2 patients had blast counts >10% (11 and 14%). Twenty nine of 50 (58%) patients showed JAK2 p.V617F mutation and all patients were negative for BCR-ABL1 translocation on routine clinical testing. DNA samples were assessed for sequence variation in exons 4 through 9 of TP53 by both high resolution melting curve (HRM) analysis using LightCycler® 480 System (Roche, Indiana IN) and bidirectional Sanger sequencing using 3730XL DNA Analyzer (Life technologies, Carlsbad CA). Results The mean overall survival was 5.7 years. Five patients developed acute leukemia, all of whom died of disease. By Sanger sequencing, only one (1.9%) case showed an amino acid-altering mutation in TP53: c.707A>G (TAC to TGC) in codon 236 (p.Y236C) of exon 7. In addition, 8 cases showed silent mutations/single nucleotide polymorphisms of unknown significance - c.36G>A (CCG to CCA) in exon 4 (n=3) and c.213A>G (CGA to CGG) in exon 6 (n=6). The p.R72P polymorphism in exon 4 which has been described in other hematopoietic neoplasms was present in 1 patient. All cases with a mutant sequence by Sanger sequencing also showed a variant melting curve pattern by HRM analysis. The patient with TP53 mutation died 2 years after presentation from progressive myelofibrosis without developing acute leukemia. Conclusion TP53 mutation is very rare in primary myelofibrosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Diagnosis and classification of hematologic malignancies on the basis of genetics

Blood ◽  
2017 ◽  
Vol 130 (4) ◽  
pp. 410-423 ◽  
Author(s):  
Justin Taylor ◽  
Wenbin Xiao ◽  
Omar Abdel-Wahab
Keyword(s):  
B Cell ◽  
Clinical Management ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
B Cell Lymphomas ◽  
Acute Leukemias

Abstract Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia. Among patients with MDS, detection of mutations in SF3B1 define a subgroup of patients with the ring sideroblast form of MDS and a favorable prognosis. For patients with MPNs, detection of the BCR-ABL1 fusion delineates chronic myeloid leukemia from classic BCR-ABL1− MPNs, which are largely defined by mutations in JAK2, CALR, or MPL. In the B-cell lymphomas, detection of characteristic rearrangements involving MYC in Burkitt lymphoma, BCL2 in follicular lymphoma, and MYC/BCL2/BCL6 in high-grade B-cell lymphomas are essential for diagnosis. In T-cell lymphomas, anaplastic large-cell lymphoma is defined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63. Genetic alterations affecting TP53 and the mutational status of the immunoglobulin heavy-chain variable region are important in clinical management of chronic lymphocytic leukemia. Additionally, detection of BRAFV600E mutations is helpful in the diagnosis of classical hairy cell leukemia and a number of histiocytic neoplasms. Numerous additional examples provided here demonstrate how clinical evaluation of genomic alterations have refined classification of myeloid neoplasms and major forms of lymphomas arising from B, T, or natural killer cells.

scholarly journals The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance

2020 ◽  
Vol 21 (23) ◽  
pp. 8885
Author(s):  
Elisa Rumi ◽  
Chiara Trotti ◽  
Daniele Vanni ◽  
Ilaria Carola Casetti ◽  
Daniela Pietra ◽  
...  
Keyword(s):  
Molecular Genetics ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Scoring Systems ◽  
Dynamic Structure ◽  
Primary Myelofibrosis ◽  
Driver Gene ◽  
Recent Effort ◽  
Biological Interactions ◽  
Hematopoietic Stem

Among classical BCR-ABL-negative myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF) is the most aggressive subtype from a clinical standpoint, posing a great challenge to clinicians. Whilst the biological consequences of the three MPN driver gene mutations (JAK2, CALR, and MPL) have been well described, recent data has shed light on the complex and dynamic structure of PMF, that involves competing disease subclones, sequentially acquired genomic events, mostly in genes that are recurrently mutated in several myeloid neoplasms and in clonal hematopoiesis, and biological interactions between clonal hematopoietic stem cells and abnormal bone marrow niches. These observations may contribute to explain the wide heterogeneity in patients’ clinical presentation and prognosis, and support the recent effort to include molecular information in prognostic scoring systems used for therapeutic decision-making, leading to promising clinical translation. In this review, we aim to address the topic of PMF molecular genetics, focusing on four questions: (1) what is the role of mutations on disease pathogenesis? (2) what is their impact on patients’ clinical phenotype? (3) how do we integrate gene mutations in the risk stratification process? (4) how do we take advantage of molecular genetics when it comes to treatment decisions?

Mixed phenotype acute leukemia and lineage switch from lymphoblastic leukemia to myeloid leukemia in the course of Philadelphia-negative myeloproliferative neoplasm – case reports and literature review

2020 ◽  
Vol 51 (2) ◽  
pp. 112-118 ◽  
Author(s):  
Agnieszka Ożańska ◽  
Marta Sobas ◽  
Donata Szymczak ◽  
Tomasz Wróbel
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Hematopoietic Stem ◽  
Lineage Switch ◽  
Mixed Phenotype

AbstractPhiladelphia-negative myeloproliferative neoplasms (Ph-neg MPNs) are characterized by clonal hematopoiesis derived from a mutated hematopoietic stem cell. Ph-neg MPNs rarely transforms into acute leukemia, and in most cases, the transformation leads to the development of acute myeloid leukemia (AML). The incidence of mixed-phenotype leukemia (MPAL) or acute lymphoblastic leukemia (ALL) with lineage switch is much rarer. The unidentified lineage of blast cells is due to the immaturity of their undifferentiated progenitors with co-expression of myeloid and lymphoid antigens. The prognosis of secondary acute leukemia transformed from Ph-neg MPN is very unfavorable, especially in MPAL or lineage switch from ALL to AML cases. Moreover, there are no therapeutic protocols for these specific leukemia subtypes. Therefore, we believe that all cases of MPAL or lineage switch leukemia should be reported. This article presents the case of a patient with JAK2-positive essential thrombocythemia (ET) transformed to MPAL, and a patient with triple-negative primary myelofibrosis (PMF) (negative for JAK2, CALR, and MPL) transformed to ALL with subsequent lineage switch to AML.

scholarly journals IRF4 expression is low in Philadelphia negative myeloproliferative neoplasms and is associated with a worse prognosis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Cosimo Cumbo ◽  
Francesco Tarantini ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Immacolata Redavid ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Suppressor Cells ◽  
Primary Myelofibrosis ◽  
Hematologic Malignancies ◽  
Leukemic Transformation ◽  
Free Survival ◽  
Inflammatory Status ◽  
Interferon Regulatory Factor 4 ◽  
Worse Prognosis

AbstractInterferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various hematologic malignancies. Its expression has been related to the negative regulation of myeloid-derived suppressor cells (MDSCs) and the polarization of anti-inflammatory M2 macrophages, thereby altering immunosurveillance and inflammatory mechanisms. An abnormal inflammatory status in the bone marrow microenvironment of myeloproliferative neoplasms (MPNs) has recently been demonstrated; moreover, in chronic myeloid leukemia a downregulated expression of IRF4 has been found. In this context, we evaluated the IRF4 expression in 119 newly diagnosed consecutive Philadelphia negative MPNs (Ph- MPNs), showing a low expression among the MPNs phenotypes with a more significant decrease in primary myelofibrosis patients. Lower IRF4 levels were associated with JAK2 + and triple negatives cases carrying the worst prognosis. Furthermore, the IRF4 levels were related to leukemic transformation and a shorter leukemia-free survival; moreover, the risk of myelofibrosis transformation in polycythemia vera and essential thrombocythemia patients was more frequent in cases with lower IRF4 levels. Overall, our study demonstrates an IRF4 dysregulated expression in MPNs patients and its association with a worse prognosis. Further studies could validate these data, to improve our knowledge of the MPNs pathogenesis and confirm the IRF4 role as a new prognostic factor.

Relevance of Weight Loss, Splenomegaly, and Hypocholesterolemia in the Treatment of Myeloproliferative Neoplasms— Implications for a JAK2 Inhibitor Era

2011 ◽  
Vol 07 (01) ◽  
pp. 61 ◽  
Author(s):  
Robyn M Scherber ◽  
Ruben A Mesa ◽  
◽  
Keyword(s):  
Weight Loss ◽  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Treatment Strategies ◽  
Primary Myelofibrosis ◽  
Hematologic Malignancies ◽  
Prognostic Features ◽  
Stem Cell Proliferation ◽  
Jak2 Inhibitor

Myeloproliferative neoplasms (MPNs) encompass a diverse yet homogenous classification of hematologic malignancies including primary myelofibrosis (MF), essential thrombocythemia (ET), and polycythemia vera (PV). Although clinically distinct, these three entities share similar clinical and prognostic features and are characterized by clonal stem cell proliferation with recurrent chromosomal abnormalities. MPNs can be accompanied by symptomatic worsening, particularly weight loss and splenomegaly. However, of these symptoms only splenomegaly is targeted by conventional therapy. With the key discovery of the JAK2V617F mutation, there has been renewed focus on effective treatment strategies aimed at counteracting the debilitating side effects accompanying this disease. In this brief article, we describe the clinical features, course, treatment approaches, and monitoring utility of progressive splenomegaly and cachexia in MPNs.

scholarly journals Epigenetic Effects of Benzene in Hematologic Neoplasms: The Altered Gene Expression

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2392
Author(s):  
Giovanna Spatari ◽  
Alessandro Allegra ◽  
Mariella Carrieri ◽  
Giovanni Pioggia ◽  
Sebastiano Gangemi
Keyword(s):  
Tumor Suppressor ◽  
Cpg Islands ◽  
Hematologic Malignancies ◽  
Genetic Alterations ◽  
Dna Hypomethylation ◽  
Negative Effects ◽  
Promoter Regions ◽  
Hematological Neoplasms ◽  
Altered Gene ◽  
Hematological Tumors

Benzene carcinogenic ability has been reported, and chronic exposure to benzene can be one of the risk elements for solid cancers and hematological neoplasms. Benzene is acknowledged as a myelotoxin, and it is able to augment the risk for the onset of acute myeloid leukemia, myelodysplastic syndromes, aplastic anemia, and lymphomas. Possible mechanisms of benzene initiation of hematological tumors have been identified, as a genotoxic effect, an action on oxidative stress and inflammation and the provocation of immunosuppression. However, it is becoming evident that genetic alterations and the other causes are insufficient to fully justify several phenomena that influence the onset of hematologic malignancies. Acquired epigenetic alterations may participate with benzene leukemogenesis, as benzene may affect nuclear receptors, and provoke post-translational alterations at the protein level, thereby touching the function of regulatory proteins, comprising oncoproteins and tumor suppressor proteins. DNA hypomethylation correlates with stimulation of oncogenes, while the hypermethylation of CpG islands in promoter regions of specific tumor suppressor genes inhibits their transcription and stimulates the onset of tumors. The discovery of the systems of epigenetic induction of benzene-caused hematological tumors has allowed the possibility to operate with pharmacological interventions able of stopping or overturning the negative effects of benzene.

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