Polycythemia Vera Patients Research Articles

Evaluation of pulmonary artery stiffness and right ventricle functions in polycythemia vera patients by transthoracic echocardiography.

Polycythemia vera (PV) is known to be a subgroup of chronic myeloproliferative neoplasms and is recognized as a cause of pulmonary hypertension (PH). Pulmonary artery stiffness (PAS) is a relatively new noninvasive echocardiographic index developed to evaluate the structural features and functions of the pulmonary vascular bed. In this study, we aimed to evaluate right ventricular (RV) functions and PAS in PV patients and healthy controls. A group of 65 consecutive PV patients and 40 healthy controls were included in the study. RV global longitudinal strain (RVGLS) and RV free wall longitudinal strain were (RVFwLS) evaluated using two-dimensional (2D) strain echocardiography. RV volume, systolic and diastolic functions were evaluated with three-dimensional (3D) echocardiography. PAS was calculated using the maximum frequency shift (MFS) and acceleration time of the pulmonary artery flow trace. PAS values were significantly higher in the PV group than in the control group (25.2 ± 5.2 vs. 18.2 ± 4.2, p < .001). We found that tricuspid annular plane systolic excursion (TAPSE) (p < .001), RV fractional area change (p < .001) and RV ejection fraction (p < .001) measurements evaluated by 3D echocardiography were significantly lower in the PV group. In our study, PAS values were higher in PV patients than in the healthy control group. Patients with PV may have subclinical RV dysfunction, and PAS value can be used in the early diagnosis of PH and RV dysfunction in this patient group.

Real-world treatments and thrombotic events in polycythemia vera patients in the USA

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased risk of thrombotic events (TE) and death. Therapeutic interventions, phlebotomy and cytoreductive medications, are targeted to maintain hematocrit levels < 45% to prevent adverse outcomes. This retrospective observational study examined medical and pharmacy claims of 28,306 PV patients initiating treatment for PV in a data period inclusive of 2011 to 2019. Study inclusion required ≥ 2 PV diagnosis codes in the full data period, at least 1 year of PV treatment history, and ≥ 1 prescription claim and medical claim in both 2018 and 2019. Patients having ≥ 2 hematocrit (HCT) test results in linked outpatient laboratory data (2018–2019) were designated as the HCT subgroup (N = 4246). Patients were characterized as high- or low-risk at treatment initiation based on age and prior thrombotic history. The majority of patients in both risk groups (60% of high-risk and 83% of low-risk) initiated treatment with phlebotomy monotherapy, and during a median follow-up period of 808 days, the vast majority (81% low-risk, 74% high-risk) maintained their original therapy during the follow-up period. Hematocrit control was suboptimal in both risk groups; 54% of high-risk patients initiating with phlebotomy monotherapy sometimes/always had HCT levels > 50%; among low-risk patients, 64% sometimes/always had HCT levels above 50%. Overall, 16% of individuals experienced at least 1 TE subsequent to treatment initiation, 20% (n = 3920) among high-risk and 8% (n = 629) among low-risk patients. This real-world study suggests that currently available PV treatments may not be used to full advantage.

Real-world patient characteristics and treatment patterns of polycythemia vera in Taiwan between 2016 and 2017: a nationwide cross-sectional study.

Polycythemia vera (PV) patients often experience constitutional symptoms and are at risk of thromboembolism as well as disease progression to myelofibrosis or acute myeloid leukemia. Not only is PV often overlooked but treatment options are also limited, however. To explore the patient characteristics and treatment pattern of PV patients in Taiwan, and compare with other countries reported in the literature. This is a nationwide cross-sectional study. The National Health Insurance Research Database in Taiwan, which covers 99% of the population, was utilized. Patients were identified during the cross-sectional period between 2016 and 2017, and their retrospective data were retrieved from 2001 to 2017. A total of 2647 PV patients were identified between 1 January 2016 and 31 December 2017. This study described the demographic information of these patients, including number of patients by risk stratification and by sex, age at diagnosis, age at cross-sectional period, rate of bone marrow aspiration/biopsy at diagnosis, comorbidities, number of postdiagnosis thrombosis, number of disease progression, and death. The mortality rate of PV patients (4.1%) over 60 of age was higher than the general population of the same age group (2.8%). This study also compared the different treatment patterns between sexes and risk groups. Hydroxyurea was deferred to an older age, but conversely was prescribed at higher dose to younger patients. Alarmingly, a high proportion of patients did not receive phlebotomy or hydroxyurea for at least 2 years. Furthermore, discrepancies in prevalence, age at diagnosis, sex ratio, incidence of thrombosis and mortality were also found when compared with data reported in other countries. The clinical landscape of PV in Taiwan between 2016 and 2017 was examined. Distinctive patterns of phlebotomy and hydroxyurea were identified. Overall, these findings highlight the importance of understanding the patient characteristics and treatment patterns of PV in different regions to better inform clinical practice and improve patient outcomes.

Mutation Status Defines Subtypes of Essential Thrombocythemia and Relation to Polycythemia Vera in Iraqi Patients

Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are a part of the BCR-ABL1-negative myeloproliferative neoplasms (MPNs) that harbor mutation in Janus kinase 2 (JAK2), CALR, or MPL gene. Objectives: The objective of this study was to investigate the impact of JAK2 and CALR mutations on the clinical course and hematological phenotype of ET patients and to evaluate the biological and clinical features of ET and PV sharing the same type of mutation in JAK2V617F. Materials and Methods: This was a cross-sectional study that included 94 patients diagnosed with MPN, of them 47 had PV and 47 had ET. JAK2V617F mutation was assessed using either allele-specific PCR or JAK-2 quantitative real-time PCR kit. JAK2-negative patients were further assessed for the existence of CALR mutations using SNP biotechnology MPN screening kit. Results: JAK2 mutation was identified in 29 ET patients, whereas CALR mutations were confirmed in 18 patients. JAK2-mutated ET patients were significantly older than those with CALR mutations. Seventy-six were reported to have a mutation in JAKV617F, of them 47 were diagnosed as PV and 29 as ET. JAK2V617F-mutated PV patients had significantly higher levels of hemoglobin, hematocrit, and WBC than JAK2-mutated ET patients. On the other hand, JAK2-mutated PV patients exhibited lower platelet count than ET harboring the same mutation. Conclusion: JAK2-mutated ET represents a distinct clinical entity that has a hematological and clinical phenotype ranging between JAK2-mutated PV and CALR-mutated ET. The analysis of the mutational status is essential in discriminating subtypes of MPN and confirming the diagnosis in ET and PV patients.

The Combination of JAK2V617F Allele Burden and WT1 Expression can Be Helpful in Distinguishing the Subtype of MPN Patients.

Classical Philadelphia-negative myeloproliferative neoplasm (MPN) includes Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF). The JAK2V617F mutation is part of the major criteria for diagnosis of MPN. WT1 is reported to be highly overexpressed in most hematological malignancy. Our aim was to explore the combination value of JAK2V617F allele burden and WT1 expression in distinguishing the subtype of MPN patients. Allele specific real-time quantitative fluorescence PCR (AS-qPCR) was conducted to detect JAK2V617F allele burden. WT1 expression was assessed by RQ-PCR. Our study is a retrospective study. JAK2V617F allele burden and WT1 expression were different in MPN subgroups. The expression of WT1 in PMF and PV is higher than in ET. JAK2V617F allele burden in PMF and PV is also higher than in ET. ROC analysis indicated that combination of JAK2V617F allele burden and WT1 expression to discriminate ET and PV, ET and PMF, PV and PMF is 0.956, 0.871, 0.737 respectively. Furthermore, their ability to distinguish ET patients with high Hb levels from PV patients with high platelet counts is 0.891. Our data revealed that combination of JAK2V617F allele burden and WT1 expression is useful in distinguishing the subtype of MPN patients.

Descriptive study in polycythemia rubra vera and evaluation of management outcome

Background: Polycythemia Vera (PV) is a myeloproliferative neoplastic disorder involving uncontrolled red blood cell production resulting in elevated red blood cell (RBC) mass. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of PV. It can occur in all age groups, but the median age of diagnosis is 60 years. Thrombosis considered as the most common cause for morbidity and mortality. Aim of study: To review the clinical characteristics of a sample of PV patients and their current treatment in addition to assessment of frequency of development of thrombotic events while on treatment. Patients and method: A hospital based retrospective study was conducted in the hematology outpatient's clinic from different centers in Iraq over a period of 11months (from January 2020 till November 2020). Patient's age more than 18 years old with duration of the disease more than 6 months and all of them were positive for JAKII V617F mutations were included in this study while excluding those who were negative for this mutation. The patients were divided in to low and high risk based on age and leukocyte counts and history of previous thrombosis and presence of cardiovascular risk factors. The response and resistance to treatment with hydroxyurea were evaluated according to ELN definition. Result: Thirty patients were enrolled in this study. The median age was 60.6±11 years, ranging between 35-78 years. The mean duration of disease was 54± 5.5 months. Headache was the predominant symptom observed in 96.7%, pruritus was experienced in 63.3%.Splenomegaly was seen in 46.7% .Thrombosis at time of diagnosis happened in 13.4%of cases. The most common complication that occurred in this study group was thrombosis in 20% of patients ,16.6% progressed to myelofibrosis and 63.3% of patients were controlled by treatment. Conclusion: The demographic and some of characteristic of Iraqi PV patients are similar to those from other countries. A good number of patients were controlled with hydroxyurea. Thrombosis is still the commonest complication in patients with PV and occurred mainly in the first 4 years since diagnosis of polycythemia Vera. Median time for development of myelofibrosis was more than 10 year.

Splenic Infarction in Patients with Philadelphia-negative Myeloproliferative Neoplasms.

Objective We retrospectively analyzed the prevalence and clinical features of splenic infarctions in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph- MPNs). Patients Patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic/early primary myelofibrosis (pre-PMF), or PMF from January 1996 to October 2020 in Chungnam National University Hospital, Daejeon, Korea, were reviewed. Results A total of 347 patients (143 ET, 129 PV, 44 pre-PMF, and 31 PMF patients; 201 men and 146 women) with a median age of 64 (range 15-91) years old were followed up for a median of 4.7 (range 0.1-26.5) years. Fifteen (4.3%) patients exhibited splenic infarctions at the diagnosis. These were most common in PMF patients (12.9%), followed by pre-PMF (9.1%) and PV (5.4%) patients. Multifocal infarcts (60.0%) were most common, followed by solitary (33.3%) and extensive infarcts (6.7%). The cumulative incidence of thrombosis in patients with splenic infarctions tended to be higher than in those lacking infarctions (10-year incidence 46.7% vs. 21.0% in PV; p=0.215; 33.3% vs. 17.9% in pre-PMF; p=0.473) patients, but statistical significance was lacking. Palpable splenomegaly (hazard ratio 14.89; 95% confidence interval 4.00-55.35; p<0.001) was the only independent risk factor for splenic infarction. During follow-up, 5 (1.4%) patients developed splenic infarctions. Conservative treatment adequately controlled the symptoms; no serious complications were noted in any patient. Conclusion Splenic infarctions occurred most frequently in patients with PMF; it was rare in patients with ET. The clinical courses were generally mild.

Philadelphia-negative chronic myeloproliferative neoplasm follow-up: when the phone rings. Changes during the COVID-19 pandemicand patient satisfaction. Experience in 30 health centers in Spain.

The SARS-CoV-2 pandemic has favored the expansion of telemedicine. Philadelphia-negative chronic myeloproliferative neoplasms (Ph-MPN) might be good candidates for virtual follow-up. In this study, we aimed to analyze the follow-up of patients with Ph-MPN in Spain during COVID-19, its effectiveness, and acceptance among patients. We present a multicenter retrospective study from 30 centers. Five hundred forty-one patients were included with a median age of 67years (yr). With a median follow-up of 19months, 4410 appointments were recorded. The median of visits per patient was 7 and median periodicity was 2.7months; significantly more visits and a higher frequency of them were registered in myelofibrosis (MF) patients. 60.1% of visits were in-person, 39.5% were by telephone, and 0.3% were videocall visits, with a predominance of telephone visits for essential thrombocythemia (ET) and polycythemia vera (PV) patients over MF, as well as for younger patients (< 50yr). The proportion of phone visits significantly decreased after the first semester of the pandemic. Pharmacological modifications were performed only in 25.7% of the visits, and, considering overall management, ET patients needed fewer global treatment changes. Telephone contact effectiveness reached 90% and only 5.4% required a complementary in-person appointment. Although 56.2% of the cohort preferred in-person visits, 90.5% of our patients claimed to be satisfied with follow-up during the pandemic, with an 83% of positive comments. In view of our results, telemedicine has proven effective and efficient, and might continue to play a complementary role in Ph-MPN patients' follow-up.

Metabolic Biomarkers Affecting Cell Proliferation and Prognosis in Polycythemia Vera

Background Polycythemia vera (PV) is a malignant clonal hematological disease of hematopoietic stem cells characterized by proliferation of peripheral blood cells, and JAK2 mutation is one of the main causes of PV peripheral blood cell proliferation. Abnormal cell metabolism is a new feature of malignant proliferation of tumor cells, but the role of metabolism in the pathogenesis and prognosis of PV remains unclear. Methods Metabolic profiling of peripheral blood sera from 32 patients with PV and 20 HCs was performed using liquid chromatography-mass spectrometry (LC-MS). Partial least-squares with latent structure discriminant analysis (PLS-DA) was used for data analysis. Results To assess whether there were significant changes in the metabolic profiles of PV patients and healthy controls, we performed a multifactorial analysis of the metabolic profiles of the two groups. Figure 1 shows the score plots of the PLS-DA in positive and negative modes. Both data from positive and negative modes suggested that the serum metabolites of PV patients were significantly changed. Subsequently, we identified endogenous metabolites between PV patients and HCs. These potential biomarkers were eventually identified as fatty acids, acylcarnitine, sphingolipids, amino acids, etc. To clarify the abnormal metabolic pathways in PV, we performed enrichment analysis of the metabolic pathways of the biomarkers. The results showed there were 9 important metabolic pathways associated with PV, namely: D-glutamine and D-glutamate metabolism, sphingolipid metabolism, pyruvate metabolism, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, tryptophan metabolism, lysine degradation, arginine biosynthesis and glycolysis/gluconeogenesis (Figure 2). Therefore, fatty acid metabolism, glucose metabolism, sphingolipid metabolism and amino acid metabolism were significantly altered in PV. To explore the effect of JAK2-associated metabolic abnormalities on cell proliferation in PV patients, we screened for endogenous metabolites associated with JAK2, and found 7 metabolites that differed significantly between the JAK2 mutated and unmutated groups. The levels of Cer(d18:2/22:6-2OH(7S, 17S)), SM(d18:0/PGF1α), CerP(d18:1/16:0), glutamic acid, lactic acid, melibiose and xylose were significantly higher in the JAK2-mutated group than in the JAK2-unmutated group. Among them, Cer(d18:2/22:6-2OH(7S, 17S)) (r=0.817; P<0.001) and SM(d18:0/PGF1α) (r=0.463; P=0.021) levels were positively correlated with JAK2 mutational burden. Then we evaluated the relationship between JAK2 mutation and blood cell count in PV patients. PLT and HCT levels were significantly higher in JAK2 mutated PV patients than in JAK2 unmutated PV patients (P=0.006; P=0.044) and found a significant positive correlation between JAK2 mutational burden and WBC and PLT levels (r=0.62, P=0.001; r=0.55, P=0.007). Finally, we found that Cer(d18:2/22:6-2OH(7S, 17S)) levels were positively correlated with WBC (r=0.650, P<0.001), and SM(d18:0/PGF1α) levels were positively correlated with WBC and PLT (r=0.444, P=0.011 and r=0.623; P<0.001, respectively). Therefore, we speculate that Cer(d18:2/22:6-2OH(7S, 17S)) and SM(d18:0/PGF1α) are closely associated with JAK2 mutations and may contribute to the proliferation of peripheral blood cells in PV patients. According to the prognostic point system, PV patients can be divided into low-risk group (n=11) and intermediate/high-risk group (n=21). Compared to the low-risk group, the levels of 8 endogenous metabolites in the intermediate/high-risk group were significantly elevated. We next used binary logistic regression to analyze the combined biomarkers and then determine the ROC curve. A set of potential biomarkers containing four endogenous metabolites with an AUC > 0.77 was found to provide an AUC of 0.952, with a sensitivity of 90.905% and specificity of 90.909% at the optimal cutoff point. Therefore, elevated levels of Cer(d18:2/22:6-2OH(7S, 17S)), SM(d18:0/PGF1α), CerP(d18:1/16:0) and octadec-13-enoylcarnitine could be used as potential metabolic biomarkers of poor prognosis in patients with PV. Conclusion Metabonomics provides an important tool for the study of the pathogenesis of PV and the relationship between JAK2 gene mutation. Furthermore, the potential biomarkers of this study may provide a reference for the prognosis of PV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Features and Outcomes of Polycythemia Vera Patients with Different JAK2 V617F Mutational Status and Allele Burden

Polycythemia vera (PV) is the most common myeloproliferative neoplasms (MPNs) characterized by the overproduction of morphologically and functionally normal blood cells. Whereas, the clinical usefulness of JAK2 V617F allele burden is still under investigation. We retrospectively reviewed the clinical parameters and haematologic information of 276 patients with PV, including 247 JAK2 mutated and 29 JAK2 unmutated patients, and 38 patients with idiopathic erythrocytosis in the First Affiliated Hospital of Zhejiang University School of Medicine and the Fourth Affiliated Hospital of Zhejiang University School of Medicine(ChiCTR2200061208). JAK2 V617F allele mutational burden was performed in 183 PV patients by RQ-PCR. The expression of WT1 gene was performed in 28 PV patients .JAK2 mutated PV exhibited higher leukocyte counts[12.4(5.0-36.8)×109/L vs 7.1(4.7-17.1)×109/L, P<0.001], neutrophil counts[11.3(3.9-26.6)×109/L vs 4.4(2.2-6.3)×109/L, P<0.001], monocyte counts[0.7(0.3-2.2)×109/L vs 0.6(0.3-0.9)×109/L, P=0.004], eosinophil counts[0.26(0.02-0.96)×109/L vs 0.12(0.04-0.28)×109/L, P<0.001], basophil counts[0.13(0.01-0.62)×109/L vs 0.05(0.02-0.06)×109/L, P<0.001], red blood cell distribution width values[15.2(12.3-23.1)fL vs 12.4(11.7-15.5)fL, P<0.001], platelet counts[616(153-1436)×109/L vs 230(158-375)×109/L, P<0.001], lactate dehydrogenase values[320(144-547) U/L vs 196(117-261) U/L, P<0.001], onset ages[61(26-89) years vs 52(17-72) years, P=0.003], a higher frequency of splenomegaly(41.3% vs 6.9%, P<0.001), lower body mass index[22.91(15.57-32.58) kg/m2 vs 24.83(19.62-34.90) kg/m2, P=0.019] , lymphocyte counts[1.6(0.8-8.7)×109/L vs 2.2(1.3-3.9)×109/L, P=0.015], mean corpuscular hemoglobin values[30.0(22.2-38.6)pg vs 31.5(28.9-36.8)pg, P=0.008], mean corpuscular hemoglobin concentration values[327(294-362)g/L vs 345(324-361)g/L, P<0.001] and serum cholesterol level[3.81(1.84-6.44) mmol/L vs 5.04(3.67-6.41) mmol/L, P=0.001] than JAK2 unmutated patients. PV patients exhibited higher leukocyte counts[13.8(5.0-36.8)×109/L vs 7.5(3.8-11.3)×109/L, P<0.001], neutrophil counts[10.2(2.2-26.6)×109/L vs 4.8(2.1-7.5)×109/L, P<0.001], monocyte counts[0.7(0.3-2.2)×109/L vs 0.5(0.1-1.0)×109/L, P=0.001], eosinophil counts[0.23(0.02-0.96)×109/L vs 0.12(0.03-0.58)×109/L, P=0.001], basophil counts[0.09(0.01-0.62)×109/L vs 0.04(0-0.12)×109/L, P<0.001], red blood cell distribution width values[14.3(11.7-23.1)fL vs 12.5(11.7-15.4)fL, P<0.001], platelet counts[493(153-1436)×109/L vs 233(137-428)×109/L, P<0.001], lactate dehydrogenase values[294(117-547) U/L vs 203(134-301) U/L, P<0.001], onset ages[60(17-89) years vs 45 (20-83) years, P<0.001], a higher frequency of splenomegaly(37.7% vs 7.9%, P<0.001), lower body mass index[23.11(15.57-34.90) kg/m2 vs 25.97(18.40-39.18) kg/m2, P=0.001], mean corpuscular hemoglobin concentration values[332(294-362)g/L vs 342(314-377)g/L, P<0.001] and serum cholesterol level[4.12(1.84-6.44) mmol/L vs 5.00(2.78-7.83) mmol/L, P=0.001] than idiopathic erythrocytosis patients. Among the 276 PV patients, 183 were measured with JAK2 V617F allele burden. The analysis of spearman rank correlation showed that JAK2 V617F allele burdens were positively correlated with white blood cell counts(r=0.5516, P<0.0001), neutrophil count(r=0.8358, P<0.0001), lactate dehydrogenase levels(r=0.6915, P<0.0001). Moreover, the expression level of WT1 gene was positively correlated with JAK2 V617F allele burden(r=0.6653, P=0.0001), white blood cell counts(r=0.4276, P=0.0184), neutrophil count(r=0.4238, P=0.0220), platelet counts(r=0.3914, P=0.0324) and lactate dehydrogenase levels(r=0.6500, P=0.0001). In conclusion, the JAK2 V617F allele burden and the expression level of WT1 gene were correlated with hematologic parameters and clinical outcomes of PV patients. These two tests are recommended for all patients with PV, irrespective of hemoglobin level. The research was supported by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; the Key Project of Jinhua Science and Technology Plan, China, No. 2020-3-011;the 2019-2022 Key Medical Discipline (Hematology) Fund of Jinhua, China. Correspondence: Jian Huang househuang@zju.edu.cn. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Polycythemia Vera Molecular Response and Its Correlation with Disease Progression: A Systematic Review and Meta-Analysis

Background: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) driven primarily by JAK2V617F and is associated with an excess risk of thrombosis and progression to myelofibrosis (MF) and acute leukemia (AML). Advances in treatment of PV and earlier diagnosis has reduced fatal thrombotic events, but with longer thrombosis-free survival, the natural progression to MF is an increasingly common cause of morbidity. More than 50% of PV patients (pts) have MF after 30 years from diagnosis, independent of age, making this a particularly important issue for young pts1. Because of disease chronicity, short-term monitoring biomarkers are needed to dynamically predict risk of disease progression on the long-term and allow appropriate implementation and modification of therapy. Whole blood (WB) JAK2V617F allele frequency (MAF) is frequently measured in clinical trials to assess molecular response to treatment, yet no study has established whether serial changes in MAF are predictive of progression. Despite limitations of WB MAF monitoring 2, the readily accessible WB samples and feasibility of testing, along with the need for a clinical biomarker in PV, merits a study to determine whether MAF change correlates with disease progression. Objective & Methods: We conducted a systematic review and meta-analysis to examine the correlation of molecular response with thrombosis or progression to MF and AML in PV pts. We searched the main scholarly engines: Pubmed, Scopus and Embase for "Polycythemia vera" and terms including "JAK2V617F" and "molecular response". Title and abstracts were screened by 2 reviewers independently based on predefined criteria and selected for full-text review if criteria are met or further information was required. Studies were included if they reported serial MAF measurements in PV patients, and excluded for other JAK2V617F MPNs or lack of serial MAF assessment. Pearson correlation analysis was conducted on the subset of studies that reported rates of thrombosis, MF and or AML to determine the correlation of MAF reduction with clinical outcomes. Results: The search resulted in 563 abstracts to screen. A total of 59 studies were selected for full-text review and ultimately only 20 studies met inclusion criteria where MAF was serially assessed in PV patients. In all studies, MAF was monitored on cytoreductive therapy, and these included 12 on interferon (IFN), 8 on hydroxyurea (HU), and 2 on ruxolitinib (RUX). The median follow-up times were between 16-116 months. In most studies (n=18, 90%), there was an overall decrease in MAF on cytoreductive treatment (Figure 1). There was a poor correlation between molecular response rates and hematological response rates (n=11 studies, r2=0.20). Of the 20 studies, only 7 reported clinical outcomes of thrombosis and/or progression: 2 were prospective and 5 were retrospective. In our analysis, MAF reduction correlated with decreased rates of MF (n = 7 studies, r2=0.69) (Figure 2), irrespective of treatment (IFN: r2 =0.83, HU: r2 =0.72), but results were not statistically significant (p=0.08). On the other hand, there was no correlation between MAF reduction and progression to AML (n= 3 studies, r2=0.17), or the incidence of thrombotic events (n = 6 studies, r2=0.15), but fewer studies reported these outcomes. Discussion: This systematic review highlights the lack of high-level evidence available to determine if molecular response in PV is associated with reduced risk of progression. The correlation observed between MAF reduction and MF rates requires validation in larger, ideally prospective studies. Until then, reduction in WB MAF should not be the determinant of a treatment's long-term likelihood of success. Alternative biomarkers are needed to capture the biology of malignant MPN stem cells and better predict the long-term outcomes of patients with PV.

Efficacy and Safety of Long-Term Ropeginterferon Alfa-2b Treatment in Patients with Low-Risk and High-Risk Polycythemia Vera (PV)

Introduction: Patients with "low-risk” (LR) PV are managed conservatively despite higher risk of vascular events and impaired quality of life compared to a population without PV. Acknowledging new evidence (LOW-PV study, Barbui et al 2021), recent treatment guidelines (European LeukemiaNet [ELN] 2021) recommend ropeginterferon alfa-2b (BESREMi®) as a cytoreductive treatment in LR PV patients meeting specific criteria as well as in high-risk (HR) PV patients. Final data from the phase 3 PROUD-PV and CONTINUATION-PV trials (NCT01949805; NCT02218047) demonstrated the long-term efficacy and safety of ropeginterferon alfa-2b compared with hydroxyurea/best available treatment (HU/BAT); here we report results in the ropeginterferon alfa-2b arm by risk stratum. Methods: PV patients were randomized 1:1 and received ropeginterferon alfa-2b or HU/BAT for ≥6 years. In the ropeginterferon alfa-2b arm, subgroup analyses were performed post-hoc by risk stratum (LR: age ≤60 years and no history of thrombosis; all others HR). Complete hematologic response (CHemR) and molecular response defined by modified ELN criteria were assessed in the full analysis set for CONTINUATION-PV (N=95); safety analyses included all data regardless of roll-over (N=127). Results: CONTINUATION-PV enrolled 46 LR and 49 HR patients in the ropeginterferon alfa-2b arm. At baseline, mean age was 50.7 vs 63.7 years respectively, and median duration since PV diagnosis was 1.9 months vs 1.5 months. HR patients had higher platelet and leukocyte counts at baseline and more frequently presented with clinically significant splenomegaly or PV-related symptoms. Median JAK2V617F allele burden was similar for LR and HR patients (37.0% vs 39.4%), however LR patients were less likely to harbor additional non-driver mutations (11.4% vs 24.4%). The median 4-weekly ropeginterferon alfa-2b dose was comparable in LR and HR patients throughout the study (in the 6th year, 499 µg and 489µg respectively) as was the use of an extended 3-4 weekly dose regimen (6th year: 59.5% vs 65.4%). LR patients achieved a significantly higher CHemR rate than HR patients during long-term treatment (Month 72: 73.2% vs 38.3% in LR and HR respectively [RR: 2.41; 95% CI: 1.50 to 3.90; p=0.0003]). Higher CHemR among LR patients was confirmed in a sensitivity analysis including discontinued patients (last observation carried forward [LOCF]; 80.4% in LR vs 65.3% in HR patients at Month 72) indicating that in the HR group, more patients discontinued despite CHemR. In general, discontinued patients were older than those who completed the study (mean age 62.8 years vs 55.2 years) but did not have a longer duration of PV or markedly greater symptom burden at baseline. Importantly, regardless of risk stratum, most patients receiving ropeginterferon alfa-2b did not require any phlebotomy for the entire 6th year (85.7% of LR patients and 75.0% of HR patients entering the 6th year [p=0.3]). LR patients had a higher molecular response rate than HR patients (LOCF at Month 72: 84.4% vs 49.0% respectively, RR: 2.15 [95% CI: 1.37 to 3.37]; p=0.0009) and achieved molecular response more rapidly (median time to first response: 12 months [95% CI: 12 to 18] vs 18 months [95% CI: 12 to 24]; Log-rank test p=0.03). The median JAK2V617F allele burden was 5.6% for LR and 17.9% for HR patients at Month 72 (p<0.0001). During the entire PROUD-PV/CONTINUATION-PV studies (≥6 years exposure), adverse drug reactions (ADRs) to ropeginterferon alfa-2b led to withdrawal of treatment in 1 (1.8%) LR patient (due to sarcoidosis), and in 13 (18.3%) HR patients (due to thrombocytopenia [n=1], elevated transaminases [n=1], psychiatric disorders [n=2], autoimmune disorders [n=6], hypothyroidism [n=2] and dyspnea/pneumonitis [n=1]). LR patients were also less likely than HR patients to experience ADRS of grade ≥3 severity (5.4% vs 23.9%). Conclusion: These results demonstrate the benefit of ropeginterferon alfa-2b therapy in both HR and LR patient populations. LR patients may have a greater potential benefit: higher hematologic and molecular response rates can be safely achieved, and the patients are more likely to remain on long-term treatment. These data provide further evidence for an early treatment start as recently outlined by the updated ELN guidelines.

Patterns of Childbirth in Women with Myeloproliferative Neoplasms

Pregnancy and childbirth in women with myeloproliferative neoplasms (MPN) are subjects of increasing interest. MPNs are most commonly diagnosed in elderly individuals, however 10-20% of patients with MPN are of fertile age at diagnosis. Elevated risks of obstetric complications are described in MPN; miscarriage, stillbirth, preterm birth, and reduced live birth rates. Population-based data are limited, and data on fertility and reproductive patterns are lacking. We have previously performed a population-based study, including all pregnancies 1973-2017 from week 22 (week 28 before 2008) in patients with MPN in Sweden, comparing pregnancy outcomes to those of matched population controls. In 342 identified pregnancies in women with MPN we could confirm an increased risk of preterm birth in MPN compared to controls (12% vs 4%), while the rate of thrombosis (1%) and stillbirth (0.6%) was lower than previously anticipated in the MPN cohort. To further explore the childbearing potential of women with MPN we performed a study where women with a diagnosis of an MPN 1973-2018, aged 15-44 at diagnosis, were matched by age and year of birth to four population controls, free of MPN. Matching date was at MPN diagnosis, and follow up started 40 weeks after MPN diagnosis/matching date, thus excluding patients and controls that were pregnant at diagnosis. Patients and controls were followed until childbirth or censored at death, emigration, diagnosis of other hematologic malignancy, when turning 45 years old, or at the end of study, December 31st 2018, whichever occurred first. National health registers were used; Swedish Cancer Register and Patient Register to identify MPN patients, Register of Total population for identification of controls and migration data, and Multi-Generation Register to identify live births. Stillbirths were collected from the Medical Birth Register and miscarriages were collected from the Patient register. A flexible parametric model was applied, adjusting for matching variables, calendar period (1973-1988, 1989-2003 and 2004-2018) and age category at diagnosis (15-25, 26-35 and 36-44 years). Primary outcome was live childbirth after MPN diagnosis. We identified 1,141 women with MPN and 4,564 controls with a mean age of 34 years at MPN diagnosis. Exclusion prior to start of follow up occurred in 730 women leaving 4,975 women left for analysis, 953 with MPN and 4,022 controls. Cause of exclusion was childbirth within 40 weeks of MPN diagnosis in 61 women with MPN and 189 controls. Regarding type of MPN, 24% were polycythemia vera patients, 54% essential thrombocythemia, 11% primary myelofibrosis and 12% MPN unclassifiable. Patients and controls were followed for 0-27.3 years, together collecting 25,532 person-years, and gave birth to 1,116 children. At MPN diagnosis mean number of previous live childbirths was 1.3 in women with MPN and 1.4 in controls, 61% of the women with MPN were parous at diagnosis and 67% of controls. Among those diagnosed 1989 and later, during the last 2 years prior to diagnosis, 2.5% of MPN patients and 1.9% of controls experienced at least one miscarriage. Compared to childbirth patterns in controls, MPN patients had 28% lower rate of giving birth to a living child, hazard ratio was 0.72 with 95% confidence interval of 0.61-0.85, using a proportional hazards model. Birth rate per 1000 person-years was estimated using a non-proportional model, Figure 1. The HR of childbirth after MPN diagnosis in relation to follow-up time is shown in Figure 2. Of the women reaching age 45 during the study period, 17% of the MPN patients never had a child (before or after MPN diagnosis), the corresponding number in controls was 13%. The mean total number of children per women of those reaching age 45 during the study period, was 1.8 in the MPN cohort and 2.0 in population controls. There were one stillbirth in the MPN patients and 6 in the controls during follow-up. This large population-based cohort study demonstrates a significantly lower hazard ratio of live childbirth in women with MPN compared to population controls. Reasons for this may be related to reduced possibility of having children, where difficulties conceiving, maintaining pregnancy, and obstetric complications may play a role, as well as related to the complex and highly personal decision to have children, affected by desire to have a child, life situation, health concerns, and expectations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Polycythemia Vera Patients with >20% Reduction in Whole Blood JAK2V617F Allele Frequency Have Improved Myelofibrosis-Free Survival but Not Overall Survival

Polycythemia Vera Patients with >20% Reduction in Whole Blood JAK2V617F Allele Frequency Have Improved Myelofibrosis-Free Survival but Not Overall Survival

Preferential Use of Coagulation Pathways Differs between Classical Myeloproliferative Neoplasms: Results of Global Coagulation Assays with Respect to Clinical and Genetic Features

Introduction Classical Myeloproliferative Neoplasms (MPN) are hematopoietic stem cell diseases characterized by inflammation, promotion of atherosclerosis, hypercoagulability, fibrosis, and clonal evolution. Our previous studies led us to the construction of a model, called "the circulating wound", for the likely exploitation of tissue factor (TF)-dependent thrombin generation and the consequent amplification of pro-fibrotic mechanisms mediated by Protease Activated Receptors (PARs). The indirect demonstration of PARs hyperactivation is the marked reduction of platelet fibrinogen receptors (PFRs) in patients with MPNs, following the rapid conversion of functional fibrinogen to fibrin. Acetylsalicylic acid (ASA), endowed with hypoprothrombinemic and hyperfibrinolytic properties, could restore the expression of PFRs. The aim of the present study is to verify the existence of imbalances in hemostatic function in rotational thromboelastometry (ROTEM), with respect to the different classical forms of MPN, their cell counts, the presence of genetic mutations in Next Generation Sequencing (NGS), PFR expression, the use of ASA and the history of vascular events. Methods We enrolled 53 patients affected by MPNs, naïve from any therapy, with the only exception of ASA (taken by 50% of patients). We used the samples to run assays of genetics (30-gene panel in NGS - SOPHiA Myeloid Solution™, SOPHiA Genetics, Switzerland), cytofluorimetric determination of PFRs, global coagulation by rotational tromboelastometry (ROTEM® Delta, Werfen, Spain) for INTEM, EXTEM, FIBTEM parameters. Results We found that ROTEM parameters show significant divergence depending on disease type, cell number and some mutations. The results should be read in terms of "efficiency" or "preferential use" of one pathway over another, as the instrument (as expected) mostly yields values in the ranges. Essential thrombocythemia (ET) and CALR mutation exhibit preserved efficiency of both classical coagulation pathways, with significantly more contracted clot formation times (CFTs). In contrast, primary myelofibrosis (PMF) and polycythemia vera (PV) show greater imbalances in the hemostatic system. PV patients have longer CFTs (EXTEM 114 sec, p= 0.008, INTEM 82 sec, p=0.027) and selective contraction of parameters in INTEM for higher counts of platelets (Plt), white blood cells (WBC) and hemoglobin (Hb). PMF - in contrast - seems to exploit the extrinsic pathway (EXTEM) more - see figure. Multivariate analysis gives Hb levels the largest contribution to the alterations, while only Plt retain statistical significance in PMF and ET. Selected mutations are associated with changes in ROTEM parameters. Among the DTA mutations, the presence of DNMT3A shows a significant reduction in clotting time (CT) in EXTEM, while ASXL1 is associated with reduced maximum lysis (ML). EZH2 could be responsible for CFT elongations in the INTEM assay. In addition, increased expression of PFRs is associated with bleeding history and sustained FIBTEM CT under ASA prophylaxis. Conclusions In more indolent MPNs (such as ET, especially if CALR mutated) the balance and efficiency of the classical pathways are preserved. In PMFs, the hemostatic system is unbalanced toward the extrinsic pathway, confirming the link between increased fibrosis and plasma-dependent hypercoagulable states. The experiment also provides further evidence of the robustness of the "circulating wound" model. Rheological characteristics and endothelial stress in PV appear to result in increased involvement of the intrinsic pathway. Interestingly, mutations involving genes that regulate DNA methylation are confirmed to interfere with hemostatic balance. Finally, excessive restitution of PFR expression by ASA appears to be related to the history of bleeding events, making their cytofluorimetric determination a potential tool for monitoring antiplatelet prophylaxis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ropegiterferon Alfa-2b-Njft for Treatment Myeloproliferative Neoplasms: A Single Institution Experience

Background: While interferon alfa has been used for decades as a cytoreductive agent in myeloproliferative neoplasms (MPNs), tolerability and need for frequent parenteral administration have limited its widespread adoption. Ropeginterferon Alfa-2b-njft (ropeg) is monopegylated extended half-life interferon alpha product that received FDA approval for treatment of polycythemia vera (PV) in November 2021. A phase III clinical trial has demonstrated efficacy and tolerability of this novel agent as compared to hydroxyurea (HU) in PV patients with indication for cytoreductive therapy. Real-world experience (RWE) assessment of a newly available pharmaceutical can yield important insights regarding barriers to access, clinical feasibility, and usage in populations not yet evaluated in clinical trial. In this single institution cohort, we report the first RWE using ropeg for patients with MPNs, including essential thrombocythemia (ET), in the United States. Methods: Patients presenting to an MPN clinic at an academic medical center were evaluated for initiation of ropeg based individualized assessment, with patients engaged in shared decision-making regarding risks and benefits. Patients were screened for autoimmune, neuropsychiatric, or endocrine disorder on basis of history and limited laboratory investigation as appropriate, including thyroid stimulating hormone, triglycerides, and anti-nuclear antibody testing. The treating physician and pharmacist provided pre-treatment counseling including review of potential toxicities, administration teaching, and financial considerations. Patients on HU were started on a dose 50mcg every 2 weeks via subcutaneous injection with subsequent HU tapering; patients not on HU were started 100mcg every 2 weeks. Ropeg dosing was increased to target hematologic response. Complete blood counts and comprehensive metabolic panels were ordered every 2 weeks until hematologic response achieved, with less frequent monitoring thereafter. Results: Between December 2021 to June 2022, 13 patients with JAK2 V617F positive MPNs have been started on ropeg. Four patients were unable to start ropeg due to payor denial of coverage and ineligibility for manufacturer patient assistance programs. Patients were predominantly female (10/13, 77%) with average age of 60.9 years (range 36-73 years). Seven patients had PV (transformed from ET in 2 cases), 5 patients had ET, and 1 patient had post-ET myelofibrosis. Mean pre-treatment hematocrit, platelet count, and WBC were 42.5% (range 34.3% - 51.5%), 630 *109/L (range 127-2065*109/L), and 7.0*109/L (range 2.5 - 13*109/L) respectively. At treatment start, 7 patients were on HU (either alone or in combination with therapeutic phlebotomy (TP)), 1 was on TP alone, 1 was on ruxolitinib, 1 was on peginterferon alfa-2a, and 3 were on no cytoreductive treatment. Reasons for switching to ropeg included poor tolerance or efficacy of prior therapy (6/13, 46%), patient interest in potential disease modifying properties of interferon (6/13, 46%), and, in the case of patient on peginterferon alfa-2a, ease of administration (1/13, 7.6%). Patients received medication through insurance approval with copay assistance (11/13, 85%) or through the manufacturer patient assistance program (2/13, 15%). Average time to receipt of medication from prescription submission was 25 days. At mean follow-up time of 12.9 weeks, all patients remain on treatment. One patient required treatment interruption due to severe fatigue, two patients deferred scheduled doses due to cold-like symptoms. While efficacy data is immature, one patient with PV and 2 patients with ET obtained a hematologic response (hematocrit <45% without phlebotomy in 3 months and platelet count <450), with mean response time 6.9 weeks (range 5.7 -7.7). Two patients experienced rebound in hematocrit after HU stop and are requiring TP as bridging therapy. Conclusions: Medication access, patient counseling, and symptom and laboratory monitoring must be addressed in translating clinical trial findings to clinical practice with ongoing evaluation of drug efficacy and safety. In a single institution analysis, 13 patients with MPNs, including 5 patients with ET, were started on ropeg with good initial tolerance at mean follow-up of 12.9 weeks. Lengthy insurance approval process and payor coverage denials limit medication access.

Dysregulated Autophagy in Platelets from JAK2V617F-Positive Polycythemia Vera and Essential Thrombocythemia Underlies Bioenergetic Failure As a Possible Mechanism for Thrombohemorrhagic Complications

Background: JAK2V617F-positive polycythemia vera (PV) and essential thrombocythemia (ET) are the most common Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). ET/PV patients have high levels of inflammation and are at increased risk of thrombosis. Platelets from patients with ET/PV are characterized by hyperreactivity (low activation threshold), contributing to the increased incidence of thrombosis in the MPNs. We previously described that platelets from PV patients accumulate dysmorphic mitochondria. Autophagy is a housekeeping and an inducible cellular process that eliminates damaged proteins and organelles (such as mitochondria and endoplasmic reticulum), providing biosynthetic and bioenergetic substrates for the cell. Dysregulated autophagy has been described in cancer, aging, and neurodegenerative, cardiac, and muscular diseases. We hypothesized that impairment of the platelet autophagic flux in ET/PV Jak2V617F alters platelet metabolism and function at the early and late stages of platelet activation. Methods: Platelets from sex and age-matched healthy subjects and patients with PV were analyzed. Platelets were incubated for two hours with chloroquine (CQ) [50 and 100 µM] to inhibit autophagy. CQ blocks the late stage of the autophagy process; therefore, functional autophagy was assessed by quantifying the accumulation of autophagic-related proteins by western blot. Oxidative stress (4-hydroxynonenal protein adducts) was measured by western blot. Platelet bioenergetics was studied by the Seahorse extracellular flux analyzer. Semi-quantitative metabolomics was performed using the Vanquish UHPLC system. Clot retraction was assessed by measuring the weight of serum extruded from the clot. Results: Platelets from healthy patients showed basal and inducible autophagy characterized by the accumulation of autophagic markers such as LC3II (p<0.0024), GABARAP, the autophagic cargo receptor p62 and the mitochondrial marker TOM20 (p<0.021). However, ET/PV platelets showed dysfunctional basal and inducible autophagy. Moreover, PV platelets and platelets treated with CQ had higher levels of ROS-damaged proteins (p<0.0001) compared to healthy platelets. Platelets from PV patients exhibited hyperreactivity by flow cytometry (PAC-1 binding, p<0.05) and under flow conditions (p<0.03). Moreover, platelets from ET/PV patients showed marked bioenergetic failure characterized by increased mitochondrial depolarization, higher intracellular calcium, depressed mitochondrial respiration, and lower levels of ADP and ATP. Pharmacological inhibition of autophagy of platelets from healthy individuals with CQ recapitulated the bioenergetic and functional profiles of platelets from patients with ET/PV. Bioenergetically, autophagy inhibition resulted in depressed basal (p<0.03) and ATP-linked respiration (p<0.01). Functionally, pharmacological inhibition of the autophagic flux led to significantly decreased clot retraction, as observed with the platelets from patients with ET/PV. Conclusion: Our results suggest that impairment of autophagy in platelets from ET/PV patients might exert a negative bioenergetic effect on platelet function, promoting platelet hyperreactivity and dysfunctional clot retraction, which would likely favor the formation of unstable clots. Our findings may explain why patients with Jak2V617F ET and PV are at increased risk for both thrombosis and hemorrhage and suggest that targeting autophagy might lower this risk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety of Cytoreductive Therapy in Younger Patients with Polycythemia Vera: A Systematic Review and Meta-Analysis

Background: Treatment recommendations for polycythemia vera (PV) are age-based and reserve cytoreductive agents for patients (pts) older than 60, with some exceptions such as thrombosis history (Marchetti M, et al. Lancet Haematol 2022; Ali H, et al. NCCN Guidelines Version 2.2022). Effective, potentially life-prolonging cytoreductive treatment such as interferon-alpha (IFN) and hydroxyurea (HU) is often deferred in younger pts due to a presumption that treatment toxicity exceeds its potential benefit (Abu-Zeinah G, et al. Leuk 2021). In this systematic review, we examine the safety of cytoreductive agents in PV pts younger than 60, and discuss the implications of our findings to the clinical care of younger PV pts. Methods: We used the databases PubMed, Scopus, Web of Science and Embase to identify relevant articles with search terms "polycythemia vera" and one of: hydroxyurea, hydroxycarbamide, interferon, ruxolitinib, cytoreductive. Inclusion criteria were predefined as: prospective studies including clinical trials, and retrospective studies including case series with at least 20 pts; pts with a diagnosis of PV; median age 18-60 years (yr) at enrollment; and the use of IFN, HU, or ruxolitinib (RUX). Data on treatment discontinuation for toxicity (DCT), frequency of grade 3-4 adverse events (AEs), and duration of follow-up were collected. Toxicity data were pooled using random-effects models with weights assigned based on study size and duration (patient-years). The derived annual DCT rate assumes linear correlation of toxicity with treatment time, and the pooled analysis assumes Poisson distribution of DCT probability. Results: The search resulted in 691 articles. Titles and abstracts were independently screened by two reviewers with 91% concordance and 102 articles were ultimately selected for full-text review. Of those, 18 met inclusion criteria and were selected for data extraction. JBI quality scores were calculated and ranged between 0.6 and 1. The median age of PV patients in these studies was between 47 and 59 yr. On IFN (n= 760, 12 studies), the reported DCT ranged from 4.6-37% over median durations of 0.4-6.3 yr (Table 1). The pooled DCT was 13% (95% CI 2.7-23%) and annual DCT rate for IFN was 3.2% (95% CI 0-6.4%). Of note, there was significant heterogeneity in reported DCT between studies (Cochran's Q = 29, p<0.001, and I2 = 70%), perhaps related to differences in dosing. Commonly reported causes for IFN DCT include fatigue, flu-like symptoms, and pneumonia. On HU (n= 1169, 6 studies), the reported DCT ranged from 2.6-17% over median durations of 2-14 yr (Table 1). The pooled DCT for HU was 15% (95% CI 6.9-24%) and annual DCT rate was 3% (95% CI 1-5%). There was no significant heterogeneity in reported HU DCT between studies (Q = 6.4, p=0.3, and I2 = 27%). Commonly reported causes for HU DCT included gastrointestinal symptoms and skin ulcers. Only one study was available for RUX and reported a DCT of 23.5% over 2.9 yr. Discussion: PV-related complications and mortality is higher than expected in younger pts (Abu-Zeinah K, et al. Leuk Lymphoma 2022; Abu-Zeinah G, et al. Leuk 2021), but cytoreductive treatment is often deferred - until patients are older or experience symptoms, thrombosis, or progression - because of toxicity concerns. In this systematic review focused on younger PV cohorts, we found the annual rate of DCT with IFN or HU to be relatively low at 3-3.2%. Additional long-term data is required because most patients in these studies were treated for less than 10 yr. Nevertheless, given the excess risks of thrombosis, progression and death in PV patients compared to age-matched controls; and the potential for IFN or HU to safely reduce those risks, we continue to advocate for earlier intervention in young PV pts. Treatment recommendations should account for these findings, particularly as PV is being diagnosed more frequently at a younger age. Acknowledgements: Mr. Sa'ad Laws for library and systematic review support. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: The "RAMP” Multicenter Prospective Study

Ruxolitinib (RUX) is beneficial in myelofibrosis (MF) and polycythemia vera (PV) patients (pts). However, little is known about patient adherence (ADH) to this chronic therapy. Poor ADH may increase treatment failure, with serious welfare and economic consequences (Osterberg L, N Engl J Med 2005). The Adherence to Refills and Medications Scale (ARMS) (Kripalani S, Value Health 2009) and the Distress Thermometer and Problem List (DTPL) (Donovan KA, Psycho-oncology 2014) measure drug ADH and psychological distress, respectively. After IRB approval, the RAMP (Rux Adherence in MF and PV) multicenter prospective observational study included 189 consecutive pts with MF (n. 141, 75%) or PV (n.48, 25%), that received RUX according to routine practice in 9 Hematology Centers. The ARMS included 12 questions, 6 evaluating intentional and 6 unintentional ADH. The DT describes pts’ level of distress using a scale of 0 (no distress) to 10 (extreme distress). Also, pts can select problems from a list (39 areas divided in 5 subgroups). First tests administration occurred at the earliest convenient time (week, wk0), irrespective of the time of RUX start, and again after 4 (wk4), 8 (wk8), 12 (wk12), 24 (wk24) and 48 weeks (wk48). The aims of the RAMP study are to evaluate: 1) baseline level of RUX ADH and distress, and characteristics associated to low ADH; 2) modifications of ARMS/DTPL scores over time; 3) impact of ARMS/DTPL scores on IWG-MRT defined spleen response in MF. Between June 2020 and March 2022, 189 pts completed ≥1 ARMS and DTPL test; median age, 70 yrs (33-89); 59.2% males. The first questionnaire was completed within 1 yr from RUX start in 127 pts (67.2%) (EARLY-ADH), and after >1 yr of RUX therapy in 62 pts (32.8%). At wk0, the mean ARMS and DT scores were 13.2 (SD, 1.95) and 2.9 (SD, 2.79), respectively. Based on the DT ≥4 cutoff, 76 pts (38.1%) had high distress (Table 1). Overall, 11.1%, 4.5%, 28.5% and 55.9% of pts had no emotional/physical problems, only emotional, only physical and both problems, respectively. 77.8% of pts with both emotional/physical problems also had high distress (compared to 41.5% in pts with low distress, p=0.002). Overall, 95 pts (50.3%) had HIGH-ADH (ARMS score of ≥14) and 94 (49.7%) had LOW-ADH (score <14). LOW-ADH was intentional in 49 (52.1%), unintentional in 20 (21.3%) and both in 25 pts (26.6%). LOW-ADH was comparable in PV (45.8%) and MF (51.8%) pts (p=0.48); however, unintentional LOW-ADH was more frequent in PV than in MF pts (43.8% vs 25.5%, p=0.02). In multivariate regression analysis, LOW-ADH was associated to male sex (odd ratio, OR: 3.2, p=0.007), high distress (OR: 3.7, p=0.003), and RUX duration >1yr (OR: 2.23, p=0.003). Male sex and high distress remained associated with LOW-ADH in MF pts (OR:3.7p=0.002; OR: 3.6, p=0.002 respectively) and only in those who completed the ARMS/DTPL > 1 yr after RUX start (OR: 3.7, p=0.002; OR: 3.7, p=0.003, respectively). Overall, 146 (77.2%) pts completed both tests at w24. Full completers with HIGH-ADH tended to increase over time (from 47.3% at wk0 to 52.4% at wk24), while pts with high distress decreased (from 44.3% to 36.2%). Pts with high distress more frequently also showed LOW-ADH (p=0.05). Over time, 25% of pts with baseline LOW-ADH acquired a HIGH-ADH, while distress improved in 27% of pts. MF pts who maintained high ADH and low distress over time were more likely to obtain or maintain spleen response at 24 weeks (Mc Nemar test, p=0.02 and p=0.04) (Table 2). At wk24, pts reporting sexual dysfunctions (13.7% vs 7.5%, p=0.04) and insomnia (24.6% vs 15.1%, p=0.01) significantly decreased compared to wk0, along with emotional distress (60.9% vs 29.5%, p<0.001). ARMS/DTPL results at wk48 will also be provided to explore long-term ADH/distress. The RAMP study highlights that LOW-ADH to RUX remains an unmet clinical need in MF and PV. The association between LOW-ADH and spleen response supports that ADH evaluation in real-life practice may improve MF therapy and prognosis. LOW-ADH is more frequently intentional in MF, and unintentional in PV; thus, differentiated corrective interventions are needed in the two diseases. Male pts and those on RUX for >1 yr are at higher risk for LOW-ADH and should be monitored more closely. As ADH increased over time, it is possible that periodic ARMS administration may be beneficial in itself. Since high distress correlates with LOW-ADH, DTPL evaluation and targeted support may also improve treatment success. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Direct and Indirect Costs of Patients with Myeloproliferative Neoplasm Diseases

Background: Myeloproliferative neoplasms (MPNs) are clonal blood diseases characterized by an overproduction of blood cells and include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Over the course of illness, these disorders can impose substantial economic burden, in both direct and indirect healthcare costs, due to lost work productivity and medical leave. The objective of this study was to measure work loss (short-term and long-term disability [STD/LTD]) and direct and indirect costs for patients with MPNs among US employees. Methods: In this retrospective cohort study, MarketScan administrative claims databases were used to identify employed patients (aged 18-64 years) with ≥1 diagnosis of an MPN (cohorts for MF, PV, and ET identified separately) from 1/1/2009 to 12/31/2019. The latest date meeting all eligibility criteria in the selection window was set as the index. Patients were required to have 6 months of continuous database enrollment (with medical, pharmacy, and work loss data available) before (pre-index period) and 12 months after (follow-up period) the index date. Patients with evidence of pregnancy during follow-up, a diagnosis of acute myeloid leukemia (AML; all cohorts), myelodysplastic syndrome (MDS; PV and ET cohort only), or MF (PV and ET cohort only) at any point during the study were excluded. A control cohort of patients without evidence of MPN, AML, or MDS during the entire study period and meeting the same enrollment criteria as the MPN cohorts was also selected (index date randomly assigned). Direct matching on age and sex followed by propensity score matching (1:3 ratio) methods were used to adjust for differences in other patient demographics and comorbidities before measuring outcomes. The proportion of patients with STD or LTD, number of days lost from work, and associated indirect and direct healthcare costs (overall and by service category) were reported for the MF, PV, and ET cohorts and compared with matched controls during the 12-month follow-up period; subsets of each MF, PV, and ET cohort who experienced a thrombotic event (TE) were also analyzed. Results: The number of patients with MF, PV, and ET included in the analysis were 173, 4,477, and 6,061, respectively. After matching, patients with an MPN were well balanced with controls (defined as standard mean difference of <0.1) on all demographic and clinical characteristics. Median age was 54, 51, and 48 years for MF, PV, and ET patients, respectively. Total direct healthcare costs and those of each of the components (ie, inpatient, outpatient, and pharmacy) were significantly higher among all 3 MPN cohorts compared with controls (Figure). The largest mean cost difference was observed in the MF cohort ($67,456 higher), followed by the ET cohort ($22,279 higher) and the PV cohort ($10,970 higher). The MPN cohorts also had a significantly larger proportion of patients with an STD claim, a larger number of days lost from work due to STD, and higher associated indirect costs related to STD compared with controls. Patients in the MF cohort had an 8.1% higher chance of filing a STD claim, followed by the ET cohort (7.5% higher) and the PV cohort (3.3% higher). Results were consistent but less pronounced for LTD due to the small proportion of patients with LTD during the 12-month follow-up period, which may not be long enough to observe the diseases' impact (Table). In the subsets of patients with ET and PV with a TE, the mean total direct healthcare costs were substantially larger than those observed for the full ET and PV cohorts (ET: $74,279 higher and PV: $45,219 higher), and the difference in the percentage of patients filing a STD claim was also substantially larger (ET: 20.5% higher and PV: 11.6% higher). Conclusions: This real-world analysis found high economic burden among employed patients with MPNs. Patients with MF, PV, and ET were significantly more likely to take disability leave and had higher direct and indirect costs compared with matched controls. The presence of TEs more than tripled direct costs and nearly tripled use of disability leave for patients with PV or ET compared with the full PV or ET cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal