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Turkish Journal of Haematology :... Dec 2023Ropeginterferon alfa-2b (RopegIFN) enables effective cytoreduction in polycythemia vera (PV). Recent analyses suggest that long-term RopegIFN therapy fulfills treatment...
Ropeginterferon alfa-2b (RopegIFN) enables effective cytoreduction in polycythemia vera (PV). Recent analyses suggest that long-term RopegIFN therapy fulfills treatment goals important to patients with PV including good quality of life, the slowing of disease progression, and long event-free survival. Data support the use of RopegIFN in both early PV therapy and second-line and beyond.
Topics: Humans; Quality of Life; Polycythemia Vera
PubMed: 38050364
DOI: 10.4274/tjh.galenos.2023.2023.0419 -
Annals of Hematology Oct 2023Somatic JAK2 mutations are the main molecular cause of the vast majority of polycythemia vera (PV) cases. According to a recent structural model, the prevalent acquired...
Somatic JAK2 mutations are the main molecular cause of the vast majority of polycythemia vera (PV) cases. According to a recent structural model, the prevalent acquired V617F mutation improves the stability of the JAK2 dimer, thereby enhancing the constitutive JAK2 kinase activity. Germline JAK2 mutations usually do not largely alter JAK2 signaling, although they may modulate the impact of V617F. We found an unusual germline JAK2 mutation L604F in homozygous form in a young PV patient, along with a low allele burden JAK2 V617F mutation, and in her apparently healthy sister. Their father with a PV-like disease had L604F in a heterozygous state, without V617F. The functional consequences of JAK2 L604Fmutation were compared with those induced by V617F in two different in vitro model systems: (i) HEK293T cells were transfected with plasmids for exogenous JAK2-GFP expression, and (ii) endogenous JAK2 modifications were introduced into HeLa cells using CRISPR/Cas9. Both mutations significantly increased JAK2 constitutive activity in transfected HEK293T cells. In the second model, JAK2 modification resulted in reduced total JAK2 protein levels. An important difference was also detected: as described previously, the effect of V617F on JAK2 kinase activity was abrogated in the absence of the aromatic residue F595. In contrast, JAK2 hyperactivation by L604F was only partially inhibited by the F595 change to alanine. We propose that the L604F mutation increases the probability of spontaneous JAK2 dimer formation, which is physiologically mediated by F595. In addition, L604F may contribute to dimer stabilization similarly to V617F.
Topics: Humans; Female; HEK293 Cells; HeLa Cells; Germ-Line Mutation; Mutation; Germ Cells; Janus Kinase 2
PubMed: 37639050
DOI: 10.1007/s00277-023-05423-y -
Frontiers in Oncology 2023Polycythemia vera (PV) and essential thrombocythemia (ET) are diseases driven by canonical mutations in JAK2, CALR, or MPL gene. Previous studies revealed that in...
INTRODUCTION
Polycythemia vera (PV) and essential thrombocythemia (ET) are diseases driven by canonical mutations in JAK2, CALR, or MPL gene. Previous studies revealed that in addition to driver mutations, patients with PV and ET can harbor other mutations in various genes, with no established impact on disease phenotype. We hypothesized that the molecular profile of patients with PV and ET is dynamic throughout the disease.
METHODS
In this study, we performed a 37-gene targeted next-generation sequencing panel on the DNA samples collected from 49 study participants in two-time points, separated by 78-141 months. We identified 78 variants across 37 analyzed genes in the study population.
RESULTS
By analyzing the change in variant allele frequencies and revealing the acquisition of new mutations during the disease, we confirmed the dynamic nature of the molecular profile of patients with PV and ET. We found connections between specific variants with the development of secondary myelofibrosis, thrombotic events, and response to treatment. We confronted our results with existing conventional and mutation-enhanced prognostic systems, showing the limited utility of available prognostic tools.
DISCUSSION
The results of this study underline the significance of repeated molecular testing in patients with PV and ET and indicate the need for further research within this field to better understand the disease and improve available prognostic tools.
PubMed: 37671053
DOI: 10.3389/fonc.2023.1224590 -
Annals of Hematology Oct 2023Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative neoplasms (MPNs) characterized by thrombotic and hemorrhagic complications,...
Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative neoplasms (MPNs) characterized by thrombotic and hemorrhagic complications, leading to a high risk of disability and mortality. Although arterial hypertension was found to be the most significant modifiable cardiovascular (CV) risk factor in the general population, little is known about its role in MPNs as well as a possible role of renin-angiotensin system inhibitors (RASi) in comparison with other anti-hypertensive treatments. We investigated a large cohort of 404 MPN adult patients, 133 diagnosed with PV and 271 with ET. Over half of the patients (53.7%) reported hypertension at MPN diagnosis. The 15-year cumulative incidence of thrombotic-adverse events (TAEs) was significantly higher in patients with hypertension (66.8 ± 10.3% vs 38.5 ± 8.4%; HR = 1.83; 95%CI 1.08-3.1). Multivariate analysis showed that PV diagnosis and hypertension were independently associated with a higher risk of developing TAEs (HR = 3.5; 95%CI 1.928-6.451, p < 0.001 and HR = 1.8; 95%CI 0.983-3.550, p = 0.05, respectively). In multivariate analysis, the diagnosis of PV confirmed a significant predictive role in developing TAEs (HR = 4.4; 95%CI 1.92-10.09, p < 0.01), also considering only MPN patients with hypertension. In addition, we found that the use of RASi showed a protective effect from TAEs both in the whole cohort of MPN with hypertension (HR = 0.46; 95%CI 0.21-0.98, p = 0.04) and in the subgroup of thrombotic high-risk score patients (HR = 0.49; 95%CI 0.24-1.01, p = 0.04). In particular, patients with ET and a high risk of thrombosis seem to benefit most from RASi treatment (HR = 0.27; 95%CI 0.07-1.01, p = 0.03). Hypertension in MPN patients represents a significant risk factor for TAEs and should be adequately treated.
Topics: Adult; Humans; Angiotensins; Antihypertensive Agents; Thrombocythemia, Essential; Polycythemia Vera; Renin Inhibitors; Renin; Thrombosis; Hypertension; Cefdinir
PubMed: 37603060
DOI: 10.1007/s00277-023-05417-w -
Journal of Hematology Oct 2023Multiple myeloma (MM) is classically associated with organ dysfunction leading to hypercalcemia, renal insufficiency, anemia and bone disease, known as the CRAB...
Multiple myeloma (MM) is classically associated with organ dysfunction leading to hypercalcemia, renal insufficiency, anemia and bone disease, known as the CRAB criteria. More than 70% of patients with MM present with anemia. Few rare case reports, however, have demonstrated the presentation of MM associated with polycythemia. We present an interesting case of a 65-year-old female who was initially diagnosed with monoclonal gammopathy of undetermined significance (MGUS) which progressed to smoldering myeloma and later developed into MM. The patient also had coexisting polycythemia vera (PCV). We discuss the typical patient presentations as well as the expanded diagnostic criteria for MM. The pathophysiology explaining the coexistence of polycythemia and MM will be explored as well.
PubMed: 37936979
DOI: 10.14740/jh1167 -
Biomedicines Jul 2023Patients with polycythemia vera (PV) are at significant risk of thromboembolic events (TE). The PV-AIM study used the Optum de-identified Electronic Health Record...
Patients with polycythemia vera (PV) are at significant risk of thromboembolic events (TE). The PV-AIM study used the Optum de-identified Electronic Health Record dataset and machine learning to identify markers of TE in a real-world population. Data for 82,960 patients with PV were extracted: 3852 patients were treated with hydroxyurea (HU) only, while 130 patients were treated with HU and then changed to ruxolitinib (HU-ruxolitinib). For HU-alone patients, the annualized incidence rates (IR; per 100 patients) decreased from 8.7 (before HU) to 5.6 (during HU) but increased markedly to 10.5 (continuing HU). Whereas for HU-ruxolitinib patients, the IR decreased from 10.8 (before HU) to 8.4 (during HU) and was maintained at 8.3 (after switching to ruxolitinib). To better understand markers associated with TE risk, we built a machine-learning model for HU-alone patients and validated it using an independent dataset. The model identified lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) as key markers of TE risk, and optimal thresholds for these markers were established, from which a decision tree was derived. Using these widely used laboratory markers, the decision tree could be used to identify patients at high risk for TE, facilitate treatment decisions, and optimize patient management.
PubMed: 37509564
DOI: 10.3390/biomedicines11071925 -
Annals of Hematology Jun 2024Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between... (Meta-Analysis)
Meta-Analysis
Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.
Topics: Polycythemia Vera; Janus Kinase 2; Humans; Alleles; Gene Frequency; Amino Acid Substitution; Mutation, Missense
PubMed: 38652240
DOI: 10.1007/s00277-024-05754-4 -
SAGE Open Medicine 2023The study describes the clinical and laboratory profile of the patients with polycythemia vera at Komfo Anokye Teaching Hospital in Kumasi, Ghana.
OBJECTIVES
The study describes the clinical and laboratory profile of the patients with polycythemia vera at Komfo Anokye Teaching Hospital in Kumasi, Ghana.
METHODS AND DESIGN
This was a retrospective hospital-based cohort study conducted from September 2020 to August 2022. Hematology clinic entry book was used to identify the patient's unique hospital code. Using these unique codes, retrospective data were collected using an Excel spreadsheet from the Hospital Lightwave health information management system (LHIMS) database.
RESULTS
A total of 20 participants were recruited over the period of 2 years. The overall mean age was 51.53 ± 16.39 years. The hematological profile of the male participants revealed a mean hemoglobin of 18.25 ± 1.373 g/dl, mean hematocrit of 52 ± 3.47%, and a mean platelet of 345.5 ± 180.82. Comparatively, the mean hemoglobin, hematocrit, and platelet for the female participants were higher with figures of 19.26 ± 1.43 g/dl, 53 ± 3.61%, and 816 ± 935.32, respectively. Headache, tiredness, numbness, splenomegaly, and abnormal labs were the most common reasons why participants sought medical attention. Majority (60%) of the study participants had Janus Kinase 2 mutation. New-onset hypertension was identified in 45% of the study participants during follow-up. Thromboembolism was seen in 10% of the study population.
CONCLUSION
Polycythemia vera is an uncommon disease in Ghana mostly found in older males above 50 years. It is important to recognize it early to initiate therapy aimed at preventing common complications such as hypertension and thromboembolism. Polycythemia vera should be considered a differential diagnosis for patients with secondary hypertension.
PubMed: 37529706
DOI: 10.1177/20503121231187747 -
Human Molecular Genetics Aug 2023Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key...
Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16 h 11% O2/8 h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.
Topics: Humans; Mice; Animals; Friedreich Ataxia; Neurodegenerative Diseases; Disease Models, Animal; Polycythemia; Hypoxia; Oxygen; Ataxia
PubMed: 37260376
DOI: 10.1093/hmg/ddad091 -
Federal Practitioner : For the Health... Aug 2023Pruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). Interventions for PV-associated...
BACKGROUND
Pruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). Interventions for PV-associated pruritus include phlebotomy, antidepressants, antihistamines, phototherapy, interferon α, myelosuppression, and signaling pathway-specific agents.
CASE PRESENTATION
A 40-year-old man presented with Janus kinase 2 (Jak2)-positive PV complicated by intractable pruritus that was not alleviated by multimodal therapy and lifestyle modifications. Following the initiation of naltrexone, the patient experienced immediate relief that has persisted for 2 years.
CONCLUSIONS
This case demonstrates a novel approach to the management of PV-associated pruritus. Notably, naltrexone is an affordable, accessible, and potentially effective option for patients with intractable PV pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy and pathophysiology of naltrexone in treating PV-associated pruritus.
PubMed: 38021098
DOI: 10.12788/fp.0396