JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

Características clínicas y epidemiológicas de las neoplasias mieloproliferativas Philadelphia negativas en el sistema público de salud de Chile

Background: Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are chronic hematological disorders characterized by the overproduction of one or more mature myeloid blood cell lineages. Classical Ph-MPN are polycythemia vera (PV), essential thrombocytopenia (ET) and primary myelofibrosis (PMF). Aim: To assess the epidemiological, clinical and diagnostic characteristics of Ph-MPN in Chile. Material and Methods: Retrospective review of medical records of all patients referred as MPN from 2012 to 2017. Patients with (9;21) translocation were excluded. Results: Data of 462 cases with a median age of 69 years from 10 public hospitals was reviewed. ET was the most frequently Ph-MNP found. The incidence of Ph-MPN was 1.5 x 100.000 cases. The JAK2 V617F mutation study was performed in 96% of patients and only 30% had a bone marrow biopsy. Thrombotic events were observed in 29% of patients. Bleeding events were observed in 7%. Five-year overall survival was 87%. Conclusions: ET is the most frequent Ph-MPN. The mean incidence was lower than reported in the literature, in part because of a sub diagnosis.

The 491st case: thrombocytosis, gastrointestinal hemorrhage, intestinal perforation / 中华内科杂志

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) featured by clonal proliferation of platelets, thrombosis and hemorrhage. Portal hypertension is a serious complication of ET associated with poor prognosis. We report a patient with ET complicated with acute upper gastrointestinal hemorrhage and intestinal perforation due to portal hypertension. She had an uneventful recovery after surgical and endoscopic treatment.

Clinical and molecular profile of a Brazilian cohort of patients with classical BCR-ABL1-negative myeloproliferative neoplasms

ABSTRACT Background: The classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). In developing countries, there are few reports that truly reveal the clinical setting of these patients. Therefore, we aimed to characterize a single center MPN population with a special focus on the correct diagnosis based on the recent review of the WHO criteria for the diagnosis of myeloid neoplasms. Methods: This retrospective study analyzed data from medical records of patients with classical BCR-ABL1-negative MPNs diagnosed from January 1997 to October 2017 and followed at the University Hospital of Ribeirão Preto Medical School. Results: A total of 162 patients were assessed, 61 with PV, 50 with ET, and 51 with PMF. The mutational status analysis revealed that 113 (69.3%) harbored the JAK2V617F mutation, 23 (14.1%), the CALR mutation, and 12 (7.4%) had a triple-negative status. None of the patients were found to have mutations on the thrombopoietin receptor gene (MPL), including some ET and PMF patients who were not tested. Among the PV patients, 57 (93.5%) were positive for the JAK2V617F mutation, one (1.6%) presented an in-frame deletion JAK2 exon 12 mutation and one (1.6%) presented a missense JAK2 exon 9 mutation, not previously described. The overall survival was lower in the triple-negative patients with PMF, when compared to the JAK2V617F or CALR-mutated (p= 0.002). Conclusion: The frequency of somatic mutations and survival in our cohort, stratified according to the respective disease, was consistent with the literature data, despite some limitations. Further prospective epidemiological studies of MPN cohorts are encouraged in developing countries.

Symptom load assessment of Ph chromosome/BCR-ABL fusion gene negative myeloproliferative tumor patients at different efficacy evaluation periods / 国际肿瘤学杂志

Objective@#To observe the disease type and the changes of symptom load during treatment of patients with Ph chromosome/BCR-ABL fusion gene negative myeloproliferative neoplasm (MPN).@*Methods@#A total of 84 patients with MPN diagnosed from May 2017 to January 2019 in People′s Hospital of Longhua District of Shenzhen were selected, and were divided into polycythemia vera (PV) group, essential thrombocyhemia (ET) group, and myelofibrosis (PMF) group according to their subtypes, with 28 cases in each group. The scores of MPN-SAF-TSS were compared among the three groups. Besides, the scores of the scale (myeloproliferative neoplasm symptom assessment form total symptom score, MPN-SAF-TSS) in different treatment periods (at the time of the visit, when the disease progressed, when the disease was stable, when the clinical improvement was made, when the partial remission was completed, at the time of remission and recurrence) were also compared.@*Results@#At the time of initial diagnosis, there were significant differences in the incidences of symptom burdens among the three groups of MPN patients with abdominal fullness (χ2=6.095, P=0.047), abdominal discomfort (χ2=7.342, P=0.025), poor mobility (χ2=13.029, P=0.001), inattention (χ2=6.099, P=0.047), pruritus (χ2=6.956, P=0.031), bone pain (χ2=7.807, P=0.020), fever (χ2=8.000, P=0.018) and weight loss (χ2=27.340, P<0.001). The incidences of poor mobility (85.71%, 24/28), inattention (67.86%, 19/28) and weight loss (82.14%, 23/28) in PMF group were significantly higher than those in PV group [42.86% (12/28), 39.29% (11/28), 35.71% (10/28)] and ET group [46.43% (13/28), 39.29% (11/28), 14.29% (4/28)] (all P<0.05). The incidences of abdominal discomfort (75.00%, 21/28) and bone pain (60.71%, 17/28) in PMF group were higher than those in PV group [39.29% (11/28), 25.00% (7/28)] (both P<0.05). The incidences of abdominal fullness (89.29%, 25/28) and fever (42.86%, 12/28) in PMF group were higher than those in ET group [60.71% (17/28), 10.71% (3/28)] (both P<0.05). The incidence of pruritus in PV group (71.43%, 20/28) was higher than that in ET group (42.86%, 12/28) and PMF group (39.29%, 11/28) (both P<0.05). Symptom load scores of patients with fatigue (χ2=368.594, P<0.001), abdominal fullness (χ2=261.312, P<0.001), abdominal discomfort (χ2=195.629, P<0.001), poor mobility (χ2=217.862, P<0.001), lack of concentration (χ2=280.664, P<0.001), night sweats (χ2=239.650, P<0.001), pruritus (χ2=254.418, P<0.001), bone pain (χ2=180.291, P<0.001), fever (χ2=231.613, P<0.001) and weight loss (χ2=227.831, P<0.001) were significantly different during different therapeutic periods. The fatigue symptom load score was higher when the disease progressed than that at the time of the visit (P<0.05), and the symptom score of abdominal fullness was lower than that at the time of visit (P<0.05). Symptom load scores of weakness and pruritus when the condition was stable was lower than those when the disease progressed (both P<0.05). When the clinical improvement was made, symptom load scores of weakness, abdominal discomfort, inattention, night sweats, weight loss were lower than those when the disease was stable (all P<0.05). Symptom load scores of abdominal fullness, poor mobility, inattention, night sweats and pruritus in partial remission period decreased compared to temporary improvement period (all P<0.05). Compared to the partial remission period, the symptom load scores of weakness, abdominal fullness, night sweats, pruritus, bone pain and weight loss in complete remission period were lower (all P<0.05). At last, symptom load scores of weakness, abdominal fullness, abdominal discomfort, poor mobility, inattention, night sweats, pruritus, bone pain, fever and weight loss in recurrence period were higher than those in complete remission period (all P<0.05).@*Conclusion@#There are several differences in the main clinical symptoms among patients with different MPN subtypes, and there are significant changes in the main clinical symptoms as the disease progresses or turns around.

Significance of calreticulin gene mutations classification in BCR-ABL1 negative myeloproliferative neoplasms / 白血病·淋巴瘤

Objective@#To investigate calreticulin (CALR) gene mutations classification in BCR-ABL1 negative myeloproliterative neoplasms (MPN), and its relationship with clinical manifestations.@*Methods@#Genomic DNA polymerase chain reaction (PCR) amplification product Sanger sequencing method was used to detect the mutation of exon 9 of CALR gene in 236 patients with BCR-ABL1 negative MPN (excluding polycythemia vera and negative CALR mutations) in Ruijin Hospital of Shanghai Jiao Tong University School of Medicine from November 2015 to November 2018. The mutations were classified into 52 bp deletion (type 1) mutation, 5 bp insertion (type 2) mutation and other mutation types according to PCR sequencing analysis. The clinical characteristics of the carriers with two kinds of mutations in 198 patients with essential thrombocythemia (ET) and 38 primary myelofibrosis (PMF) were compared. For the types of mutations that could not be determined, they were classified according to the α-helix propensity score of the mutant protein peptide chain or the degree of retention of the negatively charged amino acid residues, and the differences between the two classification methods were also compared.@*Results@#Among 236 patients, the CALR gene type 1 or type 2 mutation was detected in 206 cases (87.3%), including 173 ET patients (99 cases of type 1 mutation and 74 cases of type 2 mutation) and 33 PMF patients (28 cases of type 1 mutation and 5 cases of type 2 mutation). The CALR non-type 1 or non-type 2 mutation was detected in 30 cases, including 25 ET patients and 5 PMF patients. Among 173 ET patients with CALR gene mutation, the white blood cell count (WBC) of patients with type 1 mutation was higher than that of patients with type 2 mutation [(8.6±2.7)×109/L vs. (7.6±2.4)×109/L, t = 2.45, P = 0.015]. Among 33 PMF patients with CALR gene mutation, the age of patients with type 1 mutation was older than that of patients with type 2 mutation [(58±13) years old vs. (41±16) years old, t = 2.51, P = 0.018]. According to the α-helix propensity score of mutant protein peptide chain and the degree of retention of the negatively charged amino acid residues, 27 kinds of non-type 1 or non-type 2 mutations were classified by using sequencing method, and there were differences between the two methods. According to the α-helix propensity score of the mutant protein peptide chain, the proportion of type 1/type 1-like mutation in PMF patients was higher than that in ET patients [78.9% (30/38) vs. 56.6% (112/198), P < 0.01]. According to the degree of retention of negatively charged amino acid residues in the mutant protein peptide chain, the isoelectric point (pI) value of the mutant protein peptide chain was higher than that of the wild type sequence. The pI value of the type 1-like mutant protein peptide chain was higher than that of the type 2-like mutation (11.79±0.15 vs. 10.02±0.42, t = 11.51, P < 0.01).@*Conclusions@#Type 1 mutated ET patients may be closely related to the high risk of myelofibrosis transformation. The results of the classification of CALR mutations are different according to the α-helix propensity score of the mutant protein peptide chain and the degree of retention of the negatively charged amino acid residues. Further study is necessary to identify the pathogenesis of MPN caused by CALR mutation, and to determine the relationship between mutation type and prognosis of disease.

Clinical analysis of seven cases of intracranial hypertension with essential thrombocythemia / 中华神经科杂志

Objective To report the presentation,clinical course and prognosis of intracranial hypertension (IH) with essential thrombocythemia (ET).Methods Retrospective data analysis was conducted.Seven cases of IH with ET were reviewed between January 2010 and December 2016.The clinical features,and the relationship between IH and ET were analyzed.Results IH complicated with ET was more common among young and middle-aged women.Sub acute or chronic course was more common.IH was easily misdiagnosed as optic neuritis in the early stage.The median platelet count of seven patients was 559 × 109/L.Paroxysmal black haze (four cases) was the most common of the first symptom.The head MRI showed empty sella in six cases.CT venography/DSA showed venous sinus thrombosis in three cases.All the patients were given intracranial pressure lowering and other symptomatic treatment.Five cases were treated with anti ET.Results showed remission in six cases and death in one case.Conclusions In the early stage IH was often misdiagnosed.Female was more common than male in IH with ET.Dural sinus blockage was common.In addition to symptomatic treatment such as lowering intracranial pressure,the patients should also be treated with anti ET.

Advances in pathogenesis and treatment of essential thrombocythemia / 肿瘤研究与临床

Essential thrombocythemia is a kind of myeloproliferative neoplasms.In recent years,researchers have made big progress in pathogenesis and treatment of this disease due to discovery of JAK2 gene mutation.This article focused on the research of pathogenesis,clinical diagnosis and treatment of essential thrombocythemia.

Allogeneic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia with primary thrombocytosis: three cases report and literatures review / 中华血液学杂志

Objective@#To investigate the characteristics of the essential thrombocythemia (ET) cases transformed to the acute myeloid leukemia (AML) and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of this disease.@*Methods@#The clinical and laboratory characteristics of 3 ET cases before and after transformation and after allo-HSCT were retrospectively analyzed, meanwhile the related literatures were reviewed and discussed.@*Results@#Case 1 was a male patient of 44 years old, whose PLT was 500×109/L when firstly diagnosed ET. After 3 years the disease progressed into myelodysplastic syndrome (MDS) while WT1 expression increased from 77 (first visit) to 13 171 copies/10 000 ABL copies, at the same time chromosome changed dramatically. During the period of decitabine treatment the disease processed into AML. Case 2 was a male of 58 years old whose PLT was 2 100×109/L when firstly diagnosed ET. The disease progressed to AML after 9 years, whose WT1 expression increased from 130 (first visit) to 3 222 copies/10 000 ABL copies, and he relapsed shortly after intensive chemotherapy. Case 3 was a male of 60 years old whose PLT was 900×109/L when firstly diagnosed ET. The disease progressed to AML after 5 years, whose WT1 increased from 56 (first visit) to3 696 copies/10 000 ABL copies. Moreover leukemia spread to central nervous system (CNS) during chemotherapy. Before allo-HSCT, cases 1 did not achieve remission; case 2 relapsed after a short time of remission and case 3 transferred to CNS leukemia. All of the 3 cases underwent allo-HSCT successfully, and they all achieved completely remission, whose chromosome and gene mutation recovered negative. At the same time, CNS leukemia of case 3 disappeared. The median WT1 decreased to 50 copies/10 000 ABL copies. There was no severe complication during the median time of 5 months after allo-HSCT.@*Conclusions@#The patients transformed to AML had poor prognosis, allo-HSCT was the only method that can cure the disease now.

Clinical significance of JAK2、CALR and MPL gene mutations in 1 648 Philadelphia chromosome negative myeloproliferative neoplasms patients from a single center / 中华血液学杂志

Objective@#To explore the prevalences of JAK2, CALR and MPL gene mutations and the mutation types in patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) , and to compare their clinical characteristics of different mutation types with each other and mutation negative group.@*Methods@#The mutations of JAK2 V617F, JAK2 gene at exon 12, CALR gene at exon 9 and MPL gene at exon 10 in 1 648 Ph negative MPNs patients were detected by direct sequencing.@*Results@#① The JAK2V617F mutation was found in 471 (92.7%) of 508 PV patients, 819 (78.1%) of 1 049 ET patients and 74 (81.3%) of 91 PMF patients respectively, with the total mutation rate as 82.8% (1 364/1 648) . The JAK2 exon12 mutation was found in 9 (1.7%) of 508 PV patients, none was found in ET or PMF patients, with the total mutation rate as 0.5% (9/1 648) . The CALR mutation was found in 132 (12.6%) of 1 049 ET patients and 11 (12.1%) of 91 PMF patients respectively, with the total mutation rate as 8.7% (143/1 648) ; the MPL mutation was found in 9 (0.9%) of 1 049 ET patients and 1 (1.1%) of 91 PMF patients respectively, with the total mutation rate as 0.6% (10/1 648) . The co-occurrence of any two types of driver gene mutations was not detected by direct sequencing. ②The median onset age of patients with JAK2V617F[61 (15-95) y] was significant higher than of with JAK2 exon12 mutation[49 (33-62) y] or without mutations[42 (3-78) y] (P<0.001) , but not for patients with CALR[57 (17-89) y] or MPL mutation[59 (22-71) y] (P>0.05) . Patients with JAK2V617F had higher white blood cell count and hemoglobin level (P<0.05) when compared with patients with CALR mutation or without mutations, or only significantly higher white blood cell count when compared with patients with MPL mutation (P=0.013) . The platelet count of patients with CALR mutation was significantly higher than of with JAK2V617F[966 (400-2 069) ×109/L vs 800 (198-3 730) ×109/L, P<0.001]. ③Karyotype analysis was conducted in 1 160 patients with MPNs, the rates of karyotype abnormality of patients with and without CALR mutation were 9.8% (8/82) and 7.4% (80/1 078) (P=0.441) respectively; The rates of karyotype abnormality of patients with and without JAK2V617F mutation were 7.7% (75/971) and 6.9% (13/189) (P=0.688) respectively. The incidence of karyotype abnormality of patients with CALR mutation was higher than of with JAK2V617F[9.8% (8/82) vs 7.7% (75/971) ] without statistically significant difference (P=0.512) . The karyotype analysis of 7 cases of JAK2 exon12 mutation and 6 ones with MPL gene mutation revealed normal karyotype.@*Conclusions@#Driver gene mutations detection could ensure the diagnosis and prognosis judgment of MPN more reliable, different subtypes of MPNs had different profiles of driver gene mutations, the latter lead to unique clinical phenotype.

Clinical evaluation of the revised International Prognostic Score of Thrombosis for essential thrombocythemia (IPSET-thrombosis) in a cohort of 746 Chinese adult patients / 中华血液学杂志

Objective@#To evaluate the role of the revised International Prognostic Score of Thrombosis (IPSET-thrombosis) in predicting the occurrence of thrombotic events in Chinese patients with essential thrombocythemia (ET) and to develop a thrombosis predicting model more applicable to Chinese ET patients.@*Methods@#Medical records of 746 adult patients with an initial diagnosis of ET were retrospectively analyzed.@*Results@#The median age at diagnosis was 52 (18-87) years, with 305 males and 441 females. According to the revised IPSET-thrombosis model, the number of very low-, low-, intermediate-, and high-risk patients were 271 (36.3%) , 223 (29.9%) , 63 (8.4%) and 189 (25.3%) , respectively. The four groups exhibited significantly different thrombosis-free survival (χ2=72.301, P<0.001) . Thirty-six patients were reclassified as intermediate-risk according to the revised IPSET-thrombosis instead of low-risk as per the original IPSET-thrombosis. Nineteen intermediate-risk patients as per the original IPSET-thrombosis were upgraded to high-risk according to the revised IPSET-thrombosis. Fifty-one high-risk patients as per the original IPSET-thrombosis were reclassified as low-risk in the revised IPSET-thrombosis. It suggests that the revised IPSET-thrombosis potentially avoids over- or under-treatment. In low-risk patients as per the revised IPSET-thrombosis, the rate of thrombosis in patients with cardiovascular risk factors (CVF) was higher than that in those without (16.3% vs 5.2%, χ2=5.264, P=0.022) , and comparable with intermediate-risk patients as per the revised IPSET-thrombosis (16.3% vs 14.3%, χ2=0.089, P=0.765) . As a result, a new revised IPSET-thrombosis model more applicable to Chinese ET patients was developed in which patients with CVF in the low-risk group as per the revised IPSET-thrombosis were reclassified as intermediate-risk group.@*Conclusion@#For predicting the occurrence of thrombotic events, the revised IPSET-thrombosis model was better than the original IPSET-thrombosis model. The revised IPSET-thrombosis was optimized and a new revised IPSET-thrombosis model more applicable to Chinese ET patients was developed, and the new evidence for risk stratification and treatment of ET in Chinese was provided.

The relationship between JAK2 V617F mutation and coagulation function in patients with essential thrombocythemia / 白血病·淋巴瘤

Objective To investigate the frequency of JAK2 V617F mutation and JAK2 V617F mutation allele burden in patients with essential thrombocythemia (ET), and explore the relationship between mutation and hematological parameters and coagulation function. Methods The clinical and laboratory parameters of 90 ET patients were analyzed. JAK2 V617F mutation was detected by AS-PCR and the mutation allele burden of JAK2 V617F was detected by qPCR. The correlation between mutation frequency and mutation burden of JAK2 V617F and blood laboratory parameters were investigated in ET. Results JAK2 V617F mutation was found in 50 patients (55.6 %). RBC [(4.67±0.89)×109/L vs (4.04±0.99)×109/L, P =0.003], WBC (11.64±5.20)×109/L vs (9.11±4.11)×109/L, P = 0.014], HCT (0.41±0.07) vs (0.36±0.07), P =0.005) in the JAK2 V617F mutated group were higher than those in the wild-type group. PT in mutated patients was longer than that in wild-type group [(13.18±1.63) s vs (12.02±1.24) s, P = 0.000]. The JAK2 V617F mutation allele burden was (29.91 ±18.63) %. No significant correlation was found between JAK2 V617F mutation allele burden and hematological parameters such as WBC, RBC and Plt (all P>0.05), but the JAK2 V617F mutation allele burden had a significant correlation with FDP (r = 0.456, P = 0.001). Conclusions JAK2 V617F mutation occurs in significant percentage patients with ET. Detection of JAK2 V617F mutation allele burden at diagnosis may play an important role in the early prevention of vascular events.

Essential Thrombocytosis-Associated Thromboembolism in the Abdominal Aorta

Essential thrombocytosis (ET) is a myeloproliferative disorder characterized by an anomalous increase in platelet production. Many patients with ET are asymptomatic. Few studies have reported ET-associated thromboembolism in large vessels such as the aorta. We report a patient with ET who presented with peripheral embolism from an abdominal aortic thrombus and developed acute limb ischemia. The patient underwent aortic replacement successfully. The patient’s platelet count was controlled with hydroxyurea, and no recurrence was noted over 2 years of follow-up.

Advances in the Diagnosis of Myeloproliferative Neoplasms / 대한내과학회지

Philadelphia chromosome-negative classical myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In recent years, there have been major advances in our understanding of the molecular pathophysiology of these rare subgroups of myeloproliferative neoplasms. The World Health Organization diagnostic criteria were revised in 2008, and incorporated new somatic mutations of JAK2 V617F, found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis. Subsequently, other mutations (MPL W515 and CALR) were discovered and this led to substantial changes in the diagnosis and treatment guidelines. This article reviews the diagnostic criteria for Philadelphia chromosome-negative classical myeloproliferative neoplasms, and changes in the diagnostic algorithm for clinical practice in Korea.

Advances in Treatment for Polycythemia Vera and Essential Thrombocythemia / 대한내과학회지

Although there have been substantial advances in confirming diagnoses and defining the molecular characteristics of polycythemia vera (PV) and essential thrombocythemia (ET), treatments for these conditions remain elementary. The main goal is still mainly focused on reducing the risk of thrombosis. The prevention of hemorrhage, leukemia transformation, and progression to myelofibrosis has yet to be established. To reduce the risk of thrombosis, risk-adapted treatment is recommended. Phlebotomy is the most important and effective treatment modality for patients with erythrocytosis, while cytoreduction using hydroxyurea, busulfan, or interferon-α is an ancillary treatment for patients at high risk for thrombosis. Anagrelide is used to decrease platelet counts in patients with thrombocytosis by inhibiting the maturation of platelets from megakaryocytes. Recent trials have shown that ruxolitinib, a Janus kinase (JAK) inhibitor, has clinical benefits in patients with polycythemia vera who show an inadequate response, or unacceptable side effects, to therapeutic doses of hydroxyurea. Theoretically, JAK inhibitors may also delay the progression of leukemia transformation and myelofibrosis but there is still no evidence of this. The cost of JAK inhibitors for the treatment of patients with PV/ET is a difficult hurdle for its use as a first-line treatment.

JAK2 V617F, MPL, and CALR Mutations in Korean Patients with Essential Thrombocythemia and Primary Myelofibrosis

Mutations in the calreticulin gene, CALR, have recently been discovered in subsets of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). We investigated Korean patients with ET and PMF to determine the prevalence, and clinical and laboratory correlations of CALR/JAK2/MPL mutations. Among 84 ET patients, CALR mutations were detected in 23 (27.4%) and were associated with higher platelet counts (P=0.006) and lower leukocyte counts (P=0.035) than the JAK2 V617F mutation. Among 50 PMF patients, CALR mutations were detected in 11 (22.0%) and were also associated with higher platelet counts (P=0.035) and trended to a lower rate of cytogenetic abnormalities (P=0.059) than the JAK2 V617F mutation. By multivariate analysis, triple-negative status was associated with shorter overall survival (HR, 7.0; 95% CI, 1.6-31.1, P=0.01) and leukemia-free survival (HR, 6.3; 95% CI, 1.8-22.0, P=0.004) in patients with PMF. The type 1 mutation was the most common (61.1%) type among all patients with CALR mutations, and tended toward statistical predominance in PMF patients. All 3 mutations were mutually exclusive and were never detected in patients with other myeloid neoplasms showing thrombocytosis. CALR mutations characterize a distinct group of Korean ET and PMF patients. Triple-negative PMF patients in particular have an unfavorable prognosis, which supports the idea that triple-negative PMF is a molecularly high-risk disease.

Clinical analysis of essential thrombocythemia and pregnancy: treatment and outcomes / 中华围产医学杂志

Objectives To summarize the maternal and fetal outcomes of patients with essential thrombocythemia (ET), and tentatively propose possible solutions for different clinical scenarios.Methods We retrospectively studied the clinical data, treatment, outcomes and follow-up status in 18 consecutive cases of young women with ET visited Peking University People's Hospital, among whom 22 pregnancies occurred from March 2005 to January 2015.Rank-sum test, Chi-square test or Fisher exact test were applied for statistics.Results (1) Out of the total 22 pregnancies, 17 (77％) were successful (term live births) and five (23％) ended in miscarriages, among which four were spontaneous abortion in first trimester.(2) Six pregnancies did not received any therapy, while 16 received various treatments before and/or during pregnancy, including oral Aspirin(single/joint), Hydroxyurea, Interferon-α (IFN-α) and platelet apheresis.(3) Treatments before/during pregnancy improved the live birth rate significantly (15/16 vs 2/6, P=0.009).Platelet (PLT) count of the newborns were all normal till the time at follow-up.(4) The median PLT count in those patients before Aspirin therapy was 761 × 109/L[(448-1 213) × 109/L, and 639× 109/L[(283-1 908) × 109/L] thereafter, which showed no significant difference (Z=-0.405, P=0.686).(5) The PLT counts in those patients before combination therapy of Aspirin and IFN-α was 989 × 109/L[(435-1 504) × 109/L], and 498 × 109/L[(186-559) × 109/L] thereafter, which decreased significantly (Z=-2.366, P=0.018).Conclusions (1) First-trimester spontaneous abortion is the most common complication of ET in pregnancy.(2) A specific treatment strategy may improve the pregnant outcomes without long-term harmful effect up to now.(3) IFN-α and/or Aspirin might be the first-line therapy in women with ET during pregnancy.

Guidelines for the management of myeloproliferative neoplasms

Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are collectively known as 'Philadelphia-negative classical myeloproliferative neoplasms (MPNs).' The discovery of new genetic aberrations such as Janus kinase 2 (JAK2) have enhanced our understanding of the pathophysiology of MPNs. Currently, the JAK2 mutation is not only a standard criterion for diagnosis but is also a new target for drug development. The JAK1/2 inhibitor, ruxolitinib, was the first JAK inhibitor approved for patients with intermediate- to high-risk myelofibrosis and its effects in improving symptoms and survival benefits were demonstrated by randomized controlled trials. In 2011, the Korean Society of Hematology MPN Working Party devised diagnostic and therapeutic guidelines for Korean MPN patients. Subsequently, other genetic mutations have been discovered and many kinds of new drugs are now under clinical investigation. In view of recent developments, we have revised the guidelines for the diagnosis and management of MPN based on published evidence and the experiences of the expert panel. Here we describe the epidemiology, new genetic mutations, and novel therapeutic options as well as diagnostic criteria and standard treatment strategies for MPN patients in Korea.

Essential thrombocythemia: a rare disease in childhood

Essential thrombocythemia is an acquired myeloproliferative disorder characterized by the proliferation of megakaryocytes in bone marrow, leading to a persistent increase in the number of circulating platelets and thus increasing the risk for thrombotic and hemorrhagic events. The disease features leukocytosis, splenomegaly, vascular occlusive events, hemorrhages and vasomotor disorders. The intricate mechanisms underlying the molecular pathogenesis of this disorder are not completely understood and are still a matter of discussion. Essential thrombocythemia is an extremely rare disorder during childhood. We report on a case of essential thrombocythemia in a child and discuss the diagnostic approach and treatment strategy.

Molecular biology of Philadelphia-negative myeloproliferative neoplasms

Myeloproliferative neoplasms are clonal diseases of hematopoietic stem cells characterized by myeloid hyperplasia and increased risk of developing acute myeloid leukemia. Myeloproliferative neoplasms are caused, as any other malignancy, by genetic defects that culminate in the neoplastic phenotype. In the past six years, since the identification of JAK2V617F, we have experienced a substantial increase in our knowledge about the genetic mechanisms involved in the genesis of myeloproliferative neoplasms. Mutations described in several genes have revealed a considerable degree of molecular homogeneity between different subtypes of myeloproliferative neoplasms. At the same time, the molecular differences between each subtype have become clearer. While mutations in several genes, such as JAK2, myeloproliferative leukemia (MPL) and LNK have been validated in functional assays or animal models as causative mutations, the roles of other recurring mutations in the development of disease, such as TET2 and ASXL1 remain to be elucidated. In this review we will examine the most prevalent recurring gene mutations found in myeloproliferative neoplasms and their molecular consequences.