scholarly journals How I treat polycythemia vera

Blood ◽  
2019 ◽  
Vol 134 (4) ◽  
pp. 341-352 ◽  
Author(s):  
Jerry L. Spivak
Keyword(s):  
Polycythemia Vera ◽  
Clinical Course ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Past Century ◽  
Essential Thrombocytosis ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
The Past ◽  
Aggressive Clinical Course

Abstract Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same JAK2 mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.

An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive Polycythemia Vera and Essential Thrombocytosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 99-99 ◽  
Author(s):  
Alison R Moliterno ◽  
Gail J. Roboz ◽  
Martin Carroll ◽  
Selina Luger ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Adverse Events ◽  
Polycythemia Vera ◽  
Performance Status ◽  
Jak2 V617f ◽  
Spleen Size ◽  
Inclusion Criteria ◽  
Essential Thrombocytosis ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Secondary Endpoints

Abstract Polycythemia vera (PV) and essential thrombocytosis (ET) are clonal hematopoietic stem cell disorders characterized by the over production of phenotypically normal circulating blood cells. Most PV and approximately half of ET patients harbor the activating mutation JAK2 V617F. CEP-701 is an orally available, potent low nanomolar inhibitor of both the wild-type and mutated JAK2 tyrosine kinase, with its inhibitory effect demonstrated both in enzymatic and cellular assays and in vivo, where CEP-701 significantly inhibited the growth of JAK2 V617F-positive HEL.92 xenografts in mice. These findings suggest that CEP-701 is an attractive candidate for clinical evaluation in JAK2 V617F-positive myeloproliferative disorders. The purpose of this study is to test the safety and efficacy of CEP-701 administration in JAK2 V617F positive ET and PV patients. The primary endpoint is reduction in JAK2 V617F neutrophil allele burden; secondary endpoints are reduction in phlebotomy rates, improvement in hemoglobin, white cell and platelet counts, reduction in hydroxyurea (HU) dose, and reduction in spleen size. The secondary endpoints include the pharmacokinetics and pharmacodynamics of CEP-701 and the safety of CEP-701 treatment in patients with JAK2 V617F-positive PV and ET. This is a multicenter study with an anticipated enrollment of 40 PV and ET patients. Inclusion criteria include JAK2 V617F-positive PV and ET patients; patients with PV either have a neutrophil count greater than 7,000/ul or are receiving HU, while ET patients are receiving concomitant HU. Other inclusion criteria include an ECOG performance status of 0, 1 or 2, and 18 years of age or older. Exclusion criteria include the active use of anegrelide or interferon, or a recent history of venous or arterial thrombosis. This is an 18 week trial with an optional 1 year extension period; doses will escalate from 80 mg twice daily to a maximum of 120 mg twice daily. To date, 20 subjects, 11 PV and 9 ET, comprised of 11 females and 9 males, ages 34 to 74, have enrolled. Approximately 27% of the PV patients were taking HU. The most common adverse events have been gastrointestinal (GI) and constitutional in nature. No related serious adverse events have been observed. Five patients have discontinued study participation, all for adverse events: 1 due to disease progression, 1 leg cramps, and 3 GI. To date, 7 patients have completed 18 weeks of therapy and 6 of these patients will continue to receive CEP-701 on the extension phase of the trial. Five of 8 subjects with splenomegaly have responded with reductions in spleen size evident within 6 weeks of therapy initiation. Updated results on current and future patients will be presented at the meeting.

ANKL Is Strongly EBV-Related, Frequent In Chromosome Aberrations and Gene Mutations, LMP2A/LMP1-CDK6-MDM2-CD44-Positive and Might Be Sensitive To L-Asparaginase-Containing Regimen

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3012-3012
Author(s):  
Hongsheng Zhou ◽  
Yongjian Deng ◽  
Changxin Yin ◽  
Xiaolei Xue ◽  
Xiangzhao Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Chromosome Aberrations ◽  
Research Funding ◽  
Clinical Course ◽  
Molecular Cytogenetics ◽  
Sh2 Domain ◽  
Clinical Feature ◽  
Hematopoietic Stem ◽  
Aggressive Clinical Course

Abstract Background Aggressive natural killer leukemia (ANKL), previously being classified as large granular lymphocyte (LGL) leukemia or malignant histiocytosis, is a rare subset neoplasm with high aggressive clinical course. Until now, apart from clinical feature, the frequent chromosome aberrations, somatic genes mutations, signal pathway and the optimal treatment regimen are still poor understood. Patient and Methods A retrospective analysis was performed upon review of clinical database, including additional immunohistochemistry (IHC) staining and integrated mutation analysis on reserved samples. Twelve samples of extranodal NK/T-cell lymphoma-nasal type (ENKL-NT) were used in IHC analysis for control. Results A total of 26 cases were collected during 2001 to 2013, including 17 males and 9 females, median age of 28 years old (range 4-76 years old). Most patients presented with acute-onset high swinging fever (n=26), deteriorating jaundice (n=19) and pancytopenia (n=22) at diagnosis. The organ most frequently involved organs were bone marrow (n=25), liver (n=23), spleen (n=22) and gastrointestinal (n=6). Disseminated intravascular coagulopathy (DIC) was present in 15 out of 26 patients, significantly associated with liver involvement and jaundice (p<0.01). Epstein-Barr virus (EBV) viremia was present in 7 of 8 tested cases (5.12x10*,2-5.41x10*,6 copies/mL). The characteristic morphological appearance of ANKL in bone marrow smears were deep purple-red staining granules in cytoplasm and prominent vacuoles located in cytoplasm and/or nucleus. FACS demonstrated ANKL cells were CD2+cCD3+CD7+CD11b+/-CD11c+/-CD29+CD38+/-CD45+CD56+CD86+BCL-2+, CD3-TCR-cCD79a-cMPO-CD5-CD10-CD19-CD25-CD33-CD83-CD123-. Surprisingly, ANKL cells were negative for CD21, an established EBV receptor. Additional IHC on 14 reserved bone marrow samples revealed ANKL cells were strongly positive for LMP2A (n=14), LMP1 (n=11) and EBER (n=10). In ENKL-NT, LMP2A and LMP1 were moderately positive in 5 and 4 out of 12 cases, respectively. EBERs were detected in all ENKT-NT cases. Moreover, IHC analysis showed ANKL cells were strongly stained by CDK6 (n=13), MDM2 (n=14), CD44 (n=13), IFN-γ (n=14), slightly stained by CDK4 (n=2), negative for SH2 domain-containing inositol 5’-phosphatase-1 (SHIP-1), which is responsible for 2B4-mediated inhibition in NK cells. In ENKL-NT samples, CDK6 (n=11), MDM2 (n=9) and CD44 (n=8) were positive; furthermore, SHIP-1 was slightly positive in 4 samples. Chromosome aberrations were present in 7 patients, including dup1(q22q25), inv(3)(p21p25), del(3)(p13), t(3;11)(q21;q23), i(7)(q10), del(7)(q32), del(14)(q24), der(15)t(7;15)(q10;q10), -8, -12,+13,-18,+19,-22. Multiple somatic mutations were detected in 7 cases, including TET2 (D1938E, S69R, V292L, E1207D, G1391C, T1393K, Y1998X), FBXW7 (S427L,Q428K, D431E, R505C, Q508K, G517V, D775Y), CEBPA (E57D, N292K, S85I), FLT3 (M837I, E604X), KRAS (G77R, Q22H, G13D), PAX5 (P93T, A111S), PHF6 (R15S, S155X, V5F), DNMT3A (P602H, H613D), EGFR (E736X, S155X), IDH2 (K166M),SH2B3 (E190X), c-Kit (G812C), JAK1 (D775Y), NOTCH1 (A1701S). Only 1 out of 10 patients obtained partial remission after anthracycline-based or platinum-based regimens (CHOP, CHOP-Bleomycin, CDOP, EPOCH, HyperCVAD and ESHAP). Notably, two cases rapidly achieved durable complete remission after L-asparaginase-containing regimen (CHOP/PEG-L-asp and VDLP). Two patients received allogeneic hematopoietic stem cell transplantation, one maintained durable remission and another died of invasive pulmonary infection before engraftment. The median overall survival of 26 cases was only 7.5 days (range 2-330 days). Conclusions ANKL is Trojan story about EBV and NK cells, being presented with strong evidence of EBV infection/transformation, highly aggressive clinical course and prominent chromosome/genomic instability, which deserves more research efforts to dissect the role of EBV, molecular cytogenetics make-up, signaling pathway of LMP1/LMP2A-PI3K/AKT-CDK6-MDM2 and optimal regimen such as L-asp-contained protocol for this rare leukemia subset. Disclosures: Zhou: Guangzhou Pearl River of Science & Technology New Star (No. 2011J2200069 to HS.Zhou): Research Funding. Liu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding.

A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 195-200 ◽  
Author(s):  
William Vainchenker ◽  
Stefan N. Constantinescu
Keyword(s):  
Polycythemia Vera ◽  
Kinase Activity ◽  
Molecular Pathogenesis ◽  
Major Advance ◽  
New Classification ◽  
Jak2 Mutation ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Retroviral Transduction

Abstract Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.

The Clinical Phenotype of Patients with Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis Whom Only Manifest WHO Grade 1 Fibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3208-3208
Author(s):  
Krisstina L. Gowin ◽  
Amylou Constance Dueck ◽  
Srdan Verstovsek ◽  
Naval Daver ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Diagnostic Criteria ◽  
Clinical Characteristics ◽  
Clinical Phenotype ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Population Characteristics ◽  
Essential Thrombocytosis ◽  
Who Grade ◽  
Marrow Fibrosis

Abstract Introduction: The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) who manifest WHO grade 1 (on a 0-3 scale) for intramedullary fibrosis is poorly defined, and may represent MPN patients in a transitional state. We have specifically observed patients with existing PV and ET who manifest clinical progression towards a post PV/ET phenotype (IWG-MRT criteria) yet fail to progress to a 2+ marrow fibrosis. In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold as long as patients meet the diagnostic criteria. In this study, we retrospectively analyzed the clinical characteristics and outcomes of MPN patients with 1+ marrow fibrosis. Methods: MPN patients with WHO grade 1 (scale 0-3) fibrosis within two institutional databases were identified. The clinical characteristics, laboratory, and outcome data were collected. Data were compared between PMF and PV/ET patients. 2008 IWG-MRT criteria were applied to PV/ET patients with exclusion of fibrosis component. Results: 91 MPN patients with WHO grade 1 fibrosis were identified, PMF in 33 patients (36%), PV in 37 (41%), ET in 20 (22%), and MPN-U in 1 (1%). The population characteristics are reported in Table 1. The majority (56%) of patients exhibited one or more symptoms (weight loss, night sweats, early satiety, bone pain, fatigue). The presence of symptomatic disease was similar between groups, with 52% PMF versus 57% PV/ET exhibiting at least one symptom. Symptoms were more severe in the PMF group with DIPSS risk of intermediate 2 or higher being present in 39%(PMF) versus 29% (PV/ET). Erythrocyte transfusion dependence occurred in a small percentage of overall population (9%), and was seen primarily in the PMF group (6/8 patients). Incidence and severity of splenomegaly was higher in the PMF group, with 55% having splenomegaly versus 43% of the PV/ET group. A higher incidence of a leukoerythoblastic blood smears was seen in PMF (45%) than PV/ET (38%). Two or more prior medical therapies were utilized in 45/90 (49%) of patients, with the most common prior therapies including hydroxyurea (71%), pegylated interferon (28%), anagrelide (18%), Jak inhibitor (13%), lenalidomide (4%), and prednisone (4%). At the time of this analysis, 78/91 patients (86%) were alive. When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis (except for the 2+fibrosis requirement). Table 1 Patient characteristics UPN Age (yrs) Sex System Risk Activity Tx BRAFV600E (%) 1 56 F Multi High Inactive Yes 0 2 38 F Single High Inactive Yes 0 3 65 F Multi High Active Yes 2.59 4 48 M Single High Inactive Yes 0 5 41 F Single High Inactive Yes 0 6 28 M Multi High Inactive Yes 0 7 29 M Multi High Active No 1.00 8 47 F Multi High Active Yes 6.16 Discussion and Conclusion: PV and ET patients with WHO grade 1 marrow fibrosis manifest a phenotype that suggests progression to post-PV/ET myelofibrosis, and clinically overlap with PMF phenotype; however, these patients currently fail to meet 2008 IWG-MRT diagnostic criteria for this diagnosis on basis of sub-threshold fibrosis. MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from other criteria not restricted by degree of fibrosis. Disclosures Mesa: Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding.

scholarly journals The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 113
Author(s):  
Elena Genovese ◽  
Margherita Mirabile ◽  
Sebastiano Rontauroli ◽  
Stefano Sartini ◽  
Sebastian Fantini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Oxidative Dna Damage ◽  
Myeloproliferative Neoplasm ◽  
High Plasma ◽  
Driver Mutations ◽  
Poor Overall Survival ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.

Patients with Polycythemia Vera and Essential Thrombocytosis Have a Higher Risk of Prior or Concurrent Tumors Compared to Patients with Secondary Thrombocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3084-3084
Author(s):  
Krisstina Gowin ◽  
Caroline Irene Piatek ◽  
Siamak Saadat ◽  
Karren Cuadra ◽  
Pedram Razavi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Myeloproliferative Neoplasms ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Age At Diagnosis ◽  
World Health ◽  
Low Grade ◽  
Complication Rates ◽  
Essential Thrombocytosis ◽  
Hematopoietic Stem

Abstract Abstract 3084 Background Polycythemia vera (PV) and Essential thrombocytosis (ET) are chronic myeloproliferative neoplasms (MPNs) that arise from aberrant, clonal hematopoietic stem cells. MPNs are associated with an elevated risk of arterial and venous thrombosis as well as with transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). Diseases causing secondary, or reactive, elevation of the red cell or platelet counts are not considered clonal and do not predispose to the development of hematologic malignancies. Prior reports in patients of European descent suggest as many as 15% of patients with MPNs die of unrelated malignancies, but there is no data suggesting that these malignancies precede the MPN diagnosis. In a large, ethnically diverse population, we investigated whether tumors other than MF or AML (“unrelated tumors”) occurred more commonly among patients with ET and PV than among patients with secondary thrombocytosis. Methods We performed a retrospective chart review of all consecutive patients diagnosed with ET, PV or secondary thrombocytosis (ST) between April, 1992 and June, 2010. Laboratory data and the World Health Organization criteria were utilized to distinguish ET, PV and ST. In addition to demographic and MPN-specific diagnostic data and complication rates, we recorded the prior or concurrent, pathologically-confirmed diagnosis of unrelated tumors, their histology and treatment received. We performed a multivariate, exact logistic regression analysis adjusted for age at diagnosis of MPN, sex, ethnicity, JAK2 mutational status and MPN subtype to determine whether MPN patients are more likely to have had unrelated tumors than ST patients. Results Seventy-six patients with MPNs, 55 with ET and 21 with PV, were compared to 82 patients with ST. The median age at diagnosis in the MPN group was 53.5 years (range 19 –84); it was 46 years in the ST group (range 16 – 87). The majority (57.9%) of the patients with MPNs were Hispanic whites, 21% were Asian, 15.8% were non-Hispanic whites, and 5.3% were Black. Of the 82 patients with ST, 73.2% were Hispanic whites, 9.8% were Asian, 9.8% were Black and 4.9% were non-Hispanic whites. Thrombosis occurred in 12 (15.8%) of the MPN patients and in none of the ST patients. We observed a statistically significantly higher incidence of unrelated tumors in MPN patients (17.1%) as compared to ST patients (1.2%). The multivariate analysis revealed an odds ratio for unrelated tumors among MPN patients of 5.19 (95% CI 1.04 – 22.1, p = 0.038) compared to ST patients. Of the 13 unrelated tumors which were diagnosed among patients with MPN, 11 were diagnosed prior to the MPN diagnosis and included 5 breast cancers (2 treated surgically, 2 treated with surgery, radiation and chemotherapy, 1 treated with surgery and radiation only); 3 neural tumors including 1 meningioma, 1 pituitary macroadenoma, and 1 schwannoma (all treated with surgery alone); 2 hematologic malignancies including a low grade B-cell lymphoma and a rectal MALT lymphoma (1 treated with combination chemotherapy and 1 treated with Rituxan alone); and 1 prostate cancer (treated with hormonal therapy alone). Two patients developed unrelated tumors during the course of their MPN; these included 1 patient with gastrointestinal stromal tumor and 1 with multiple myeloma. Interestingly, the latter patient has maintained a normal platelet count without cytoreductive ET therapy for the 18 months since autologous transplant for his myeloma. Conclusions Patients with PV and ET have a significantly higher risk of having prior or concurrent tumors unrelated to progression of their MPN when compared to patients with ST. Disclosures: No relevant conflicts of interest to declare.

Polycythemia Vera: Redefinition in the Genomic Era

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1754-1754
Author(s):  
Alison R. Moliterno ◽  
Donna M. Williams ◽  
Michael A McDevitt ◽  
Brady L Stein ◽  
Jonathan M. Gerber ◽  
...  
Keyword(s):  
Risk Factors ◽  
Polycythemia Vera ◽  
Genomic Instability ◽  
Chromosomal Abnormalities ◽  
Snp Array ◽  
Myeloproliferative Neoplasm ◽  
Jak2 Mutation ◽  
Hematopoietic Stem ◽  
Younger Women ◽  
Chromosomal Changes

Abstract Abstract 1754 For more than 100 years since the initial descriptions, polycythemia vera (PV) was defined by an aggregation of clinical and laboratory features, reported to be more common in males than females, and diagnosed on average at age 60 (Modan Blood 1965, Berlin Sem Hematol 1975). The 2005 discovery of somatic mutations in the JAK2 gene introduced the molecular era of PV and required redefinition of this disease entity. We established a prospective, observational cohort of 556 patients evaluated in our center between 2005 and 2011, of which 273 had a PV phase at some point during their myeloproliferative neoplasm (MPN). Serial samples were obtained from each patient for genomic analyses, including neutrophil JAK2V617F allele burdens, clinical karyotypes, SNP-array karyotypes, JAK2 and ASXL1 sequencing and copy number variation, allele burden analysis in sorted hematopoietic stem cell (HSC) fractions, and whole exome sequencing. These data were used to define the relationship of genotype to clinical phenotype with regard to PV epidemiology, natural history and disease transformation. Thirty three percent of the cohort was evaluated within 1 year from PV diagnosis and the median MPN disease duration at the last update of the cohort was 9 years (range 1–52 years). As of 7/2012, of the 273 PV patient cohort, 47 had antecedent essential thrombocytosis (ET/PV), 176 had PV, 43 had developed post-PV myelofibrosis (PPVMF) and 7 had developed acute leukemia (AML) (PPVAML). 270 of the 273 PV patients had JAK2 mutations, either V617F (264, 97%) or exon 12 (6, 2%); the remaining 3 (1%) are molecularly undefined. Women outnumbered men (169/104; ratio 1.6), even when stratified by ET/PV (2.1), PV (1.6), PPVMF (1.4) and PPVAML (1.3). Age at PV diagnosis was significantly younger in women, 54 (range 8–88), compared to men, 56.5 (range 15–77) (p=0.022), and the proportion diagnosed before age 40 was 26% in women compared to 10.5% in men. PPVMF occurred on average after 9 years (range 2–53 years) of PV at a median age of 62.5 years. PPVAML occurred on average after 10 years (range 3–28 years) of PV, at a median age of 71 years, significantly higher than the age at PPVMF (p=0.038). Aside from JAK2V617F, acquired 9pUPD was the most common genomic lesion in PV, occurring in 57% within the first year after PV diagnosis, in 84% of PPVMF and 100% of PPVAML patients. Studied prospectively, the prevalence of 9pUPD increased from 0 to 40% in 11 patients transitioning from ET to PV, and increased from 59% to 75% in 30 PV patients from year 1 to year 6 after diagnosis, but stayed at 90% in 11 patients pre and post transformation to PPVMF. Chromosomal loss/gain was not highly prevalent during PV (2%) in contrast to PPVMF (64%) and PPVAML (100%). The most frequent chromosomal abnormalities in PPVMF were trisomy 9 (27%), 13q deletion (12%), 1q gain(12%), 20qdeletion (8%) and 11qdel (8%), whereas the most common chromosomal abnormalities in PPVAML were 5qdel or −5 (75%), and 7qdeletion (50%), both of which were often found in the setting of complex changes (75%). Genomic lesions identified in PV and PPVMF, including JAK2V617F, 9pUPD, 11qdel, and ASXL1 mutations, were detected at high allele burdens by quantitative allele assays in flow-sorted, pluripotent HSCs. We conclude that acquisition of a JAK2 mutation is implicated in the vast majority (99%) of PV patients, that PV occurs more often in women, and that younger women (<40) particularly are at higher risk than younger men. Genomic lesions in PV and PPVMF arise and accumulate in a primitive HSC population. 9pUPD is a common occurrence during transition from JAK2V617F+ ET to PV, and while highly prevalent, age and time dependent in PV, 9pUPD is not sufficient to generate PPVMF or PPVAML. In PPVMF, JAK2 mutations associate with specific recurrent chromosomal changes that are also found in normal individuals with advancing age (9pUPD, 13qdel, 20qdel, 11qdel; Nature Genetics 44, 2012). JAK2 mutations with 9pUPD enhance the acquisition of age-associated and therapy- associated genomic instability lesions, promoting the development of PPVMF and PPVAML. Given the molecular epidemiology of PV, it will be crucial recognize and reduce the risk factors that lead to the excess acquisition of PV in young women, to identify the risk factors that lead to 9pUPD, to study whether targeted therapy can prevent the development of 9pUPD, and to avoid genotoxic therapy that accelerates genomic instability in PV. Disclosures: Streiff: sanofi-aventis: Consultancy, Honoraria; BristolMyersSquibb: Research Funding; Eisai: Consultancy; Janssen Healthcare: Consultancy; Daiichi-Sankyo: Consultancy.

Diagnostic and Therapeutic MicroRNAs in Primary Myelofibrosis

2020 ◽  
Vol 14 (02) ◽  
pp. 91-109
Author(s):  
Roxana Manaila ◽  
Vlad Moisoiu ◽  
Erik Knutsen ◽  
Mihnea P. Dragomir ◽  
George A. Calin
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Symptom Control ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
In Vivo Studies ◽  
Driver Mutations ◽  
Transcriptional Level ◽  
Hematopoietic Stem ◽  
Medical Needs

Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2, CALR, or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature microRNAs (miRNAs) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger RNAs at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific miRNAs, as well as complex miRNA networks, to be dysregulated in PMF. Several of these miRNAs were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose miRNAs as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.

scholarly journals Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (7) ◽  
pp. 1062-1069 ◽  
Author(s):  
Elisa Rumi ◽  
Daniela Pietra ◽  
Cristiana Pascutto ◽  
Paola Guglielmelli ◽  
Alejandra Martínez-Trillos ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Effect ◽  
Clinical Course ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Genetic Subtypes ◽  
Key Points ◽  
Exon 9 ◽  
Exon 10

Key Points Patients with PMF may carry JAK2 (V617F), a CALR exon 9 indel, an MPL exon 10 mutation, or none of these genetic lesions. The genetic subtypes of PMF differ substantially as regards clinical course, disease progression, and overall survival.

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