SAN DIEGO–(BUSINESS WIRE)–AOP Orphan Pharmaceuticals GmbH (AOP Health), Vienna, Austria, announced the results of an analysis assessing the impact of an individually optimized dosing regimen of ropeginterferon alfa-2b on treatment response in patients with low-risk polycythaemia vera (PV)1 These new data show that some low-risk PV patients require and can tolerate high ropeginterferon alfa-2b doses, and that the optimal dose varies substantially between patients.
“The results of this analysis expand the depth of data and add the clinically relevant and important evidence which can support health care professionals in their treatment decisions”
The first author of the abstract, Professor Heinz Gisslinger from the Medical University of Vienna/Austria, and his research team conducted the present analysis in the cohort of low-risk PV patients from the large trial PROUD-PV and its extension CONTINUATION-PV. The goal was to examine the impact of various baseline characteristics such as body mass index as well as individually optimized dose levels of ropeginterferon alfa-2b on complete hematologic response (CHR), the state when blood cell counts have returned to normal, at 12, 24, and 72 months.1
“The results of this analysis expand the depth of data and add the clinically relevant and important evidence which can support health care professionals in their treatment decisions”, Gisslinger concludes.
1 Gisslinger H et al. Individualized dosing of ropeginterferon alfa-2b ensures optimal response in patients with low-risk polycythemia vera (PV). ASH 2023, Abstract #4563 (https://ash.confex.com/ash/2023/webprogram/Paper173499.html)
About Polycythaemia Vera Polycythaemia Vera (PV) is a rare cancer of the blood-building stem cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition increases the risk for circulatory disorders such as thrombosis and embolism, its symptoms lead to a reduced quality of life and on the long run may progress to myelofibrosis or transform to leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to blood-building stem cells in the bone marrow with a set of acquired mutations, the most important being a mutant form of JAK2 that make up the malignant clone.
Important PV treatment goals are to achieve healthy blood counts (hematocrit below 45%), improve quality of life and to slow or delay the progression of disease.
Splanchnic vein thrombosis (SVT) is a common manifestation of myeloproliferative neoplasms (MPN). The optimal anticoagulation strategies in MPN-SVT remain unclear due to the challenge of balancing the concurrent prothrombotic state of MPN with the risk for SVT complications, such as gastrointestinal bleeding.
Methods:
We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of anticoagulation in patients with MPN following SVT incidence. This study protocol was registered on PROSPERO (#CRD42023414120). On April 07, 2023, we comprehensively searched multiple databases from Cochrane Library, EMBASE, and PubMed/MEDLINE. Retrospective or prospective studies in English with at least ten adult patients with MPN-SVT were included. Study screening by title/abstract, full text, and data extraction were performed in duplicate. Primary outcomes included recurrence of venous thrombosis (SVT and non-SVT), arterial thrombosis, and major bleeding. The risk of bias was assessed with MINORS scale. Pooled risk ratio (RR) of recurrent thrombosis and major bleeding events with respective 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method with random-effects model. Pooled rates of recurrent thrombosis and major bleeding events with respective 95% CI were calculated by DerSimonian and Laird method using random-effects model. Inter study heterogeneity was evaluated using the Cochran Q test and I 2 statistic.
Results:
Of a total of 4624 studies that were identified on the initial abstract screen, full texts were obtained and reviewed for 192 records. We included five retrospective and one prospective study that provided outcome rates for 387 patients with MPN treated with anticoagulation following SVT. All patients receiving anticoagulation in the six studies included in this analysis were treated with vitamin K antagonists (VKA). Of note, one additional study evaluating MPN-SVT with rivaroxaban was not included in the analysis because of short follow-up compared to the other six studies. Most studies were conducted in Europe (n=4), one was international, and one was done in the United Kingdom. The median follow-up was 3.2 years (follow-up was not reported in one study) and median age of patients at SVT diagnosis was 47.5 years old. JAK2V617F positivity was reported in 311/387 (80.3%). Regarding quality assessment and bias risk, four of the studies had moderate and two high risk of bias by the MINORS scale.
Pooled incidence rates showed that subsequent venous thrombosis was the most common complication while on anticoagulation (Pooled rate 9.6%; 95% CI 5.6 – 15.8; I 2=27%), followed by major bleeding (Pooled rate, 9%; 95% CI, 3.7 – 20.3; I 2=72%). Four of the six studies provided data comparing management with anticoagulation vs. no anticoagulation in 288 patients. The rates of venous (SVT and non-SVT) and arterial thrombosis following SVT were similar between the anticoagulation vs. no anticoagulation group (venous: RR 0.90; 95% CI, 0.412 – 1.966; I 2 = 0%, Figure 1 and arterial: RR, 1.01; 95% CI, 0.36 – 2.80; I 2=0%). Similarly, there was no significant difference in the risk of major bleeding between the two groups (RR, 0.52; 95% CI, 0.23- 1.14; I 2=0%). (Figure 2)
Conclusion:
Risk of recurrent thrombosis and bleeding in patients with MPN-SVT are considerable. Anticoagulation with VKA in MPN patients following SVT was not associated with a reduction in the risk of subsequent venous or arterial thrombosis or increased risk of major bleeding. Further studies with larger populations are warranted to elucidate the optimal medical management for MPN-SVT.
Joan How, MD; Orly Leiva, BS; Anna Marneth, PhD; Baransel Kamaz, MD; Chulwoo Kim; Lachelle Weeks, MD, PhD; Mohammed Wazir; Maximilian Stahl, MD; Daniel DeAngelo; R. Coleman, Lindsley, Marlise Luskin, MD; Gabriela Hobbs, MD
BACKGROUND
Myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) are characterized by increased risk of arterial and venous thrombosis. Cardiovascular risk factors (CV RFs) including hypertension, hyperlipidemia, diabetes, smoking, and obesity likely contribute to thrombotic risk, but the exact incidence of these risk factors and the impact of CV RF modification in MPNs is less clear. The purpose of this study was to determine the prevalence of baseline CV RFs in MPN patients, investigate their association with genomic profiles, and evaluate their effect on long-term outcomes.
METHODS
We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana Farber Cancer Institute (N=977) from 2014-2023, and met WHO 2016 criteria for PV, ET, MF, or pre-fibrotic MF. CV RFs were identified through ICD-9 or 10 codes present prior to MPN diagnosis, and defined as hypertension, hyperlipidemia, diabetes, current smoking status, or BMI>30. Patient and treatment characteristics were described with summary statistics. Genomic profiles were compared between ET, PV, and MF patients with vs without a CV RF. Primary outcome was overall death. Secondary outcomes were venous thromboembolism, arterial thrombosis (including myocardial infarction and stroke), and transformation to MF or acute myeloid leukemia (AML). We calculated cumulative incidence functions of arterial/venous thrombosis as well as overall survival in patients with or without a CV RF. Hazard ratios (HR) were estimated for outcomes using Cox proportional hazards regression.
RESULTS
Our cohort contained 399 (39.6%) ET, 312 (31.0%) PV, and 237 (23.5%) MF or pre-fibrotic MF patients. The median age at diagnosis was 58.5 years, and 47.9% of patients were male. The overall prevalence of hyperlipidemia, hypertension, and diabetes at MPN diagnosis was 16%, 20%, and 8%. The average BMI at diagnosis in all MPNs was 27.28, with 64% and 23% of patients having a BMI of >25 and >30. Six percent of MPN patients were current smokers at time of diagnosis, compared to 39% former smokers and 56% never smokers.
ET and PV patients with ≥1 CV RF at MPN (N = 234, 32.9%) diagnosis were older (mean age 61.1 vs 52.1 years, p<0.001), and more likely to be male (50.9% vs 41.3%, p=0.02), non-White (12.4% vs 7.6%, p=0.015), and have a prior history of atherosclerotic disease (16.2% vs 4.4%, p<0.001), thrombosis (13.7% vs 5.0%, p<0.001), and heart failure (2.1% vs 0.4%, p=0.042). MF patients with ≥1 CV RF (N = 120, 50.6%) were also more likely to be older (mean age 67.5 vs 60.4 years, p<0.001), male (66.7% vs 53.9%, p=0.047), and have a prior history of atherosclerotic disease (19.2% vs 6.0%, p=0.003) (Table).
Results of targeted gene sequencing closest to MPN diagnosis were analyzed. A similar proportion of driver ( JAK2, CALR, MPL) and concomitant ( TET2, ASXL1, DNMT3A, SRSF2, SF3B1, U2AF1, ZRSR2) mutations were seen in MPN patients with or without a CV RF. However, patients with ET or PV with ≥1 CV RF had a lower variant allele fraction (VAF) of their driver mutation (mean 41.0% vs 48.1%, p = 0.004), which was primarily driven by JAK2 (mean 43.5% vs 52.0%, p=0.003).
In ET and PV, after adjusting for variables significant on univariate analysis, the presence of ≥1 CV RF was associated with higher risk of death from any cause (HR 1.73, 95% CI 1.08-2.76) and arterial thrombosis (HR 2.33, 95% CI 1.22-4.42). Among patients with MF, the presence of ≥1 CV RF was not associated with increased risk of death when adjusted for age, sex, and prior thrombosis (HR 1.36, 95% CI 0.84 – 2.20). MPN patients with ≥1 CV RF did not have increased rates of MF or leukemia progression (Fig).
DISCUSSION
In our study, CV RFs are common among patients with MPN. CV RFs were associated with adverse outcomes, including death and thrombosis among patients with ET or PV. We found no differences in the molecular profiles in MPN patients with or without CV RFs, although a lower JAK2 VAF was seen in patients without CV RFs, which will need to be explored further. MPN patients with a CV RF had significantly worse overall survival and cumulative arterial thrombosis rates, although the presence of CV RFs does not impact MF or leukemia progression. However, our results highlight the importance of addressing CV RFs in MPN care to improve morbidity and mortality.
Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.
Kirsi Manz, Jeanette Bahr, Till Ittermann, Konstanze Döhner, Steffen Koschmieder, Tim H. Brümmendorf, Martin Griesshammer, Matthias Nauck, Henry Völzke & Florian H. Heidel
Chronic myeloproliferative neoplasms (MPN) are characterized by hyperproliferation of myeloid cells leading to erythrocytosis, thrombocytosis, leukocytosis and splenomegaly. Thromboembolic events (TE) are among the most prevalent complications in patients with different subtypes of MPN such as polycythemia vera (PV) [1, 2], with arterial and venous thromboses being among the major causes of morbidity and mortality. Pathophysiologic mechanisms that contribute to TE complications, besides increased cell counts, include functional alterations of leucocytes, red blood cells, platelets and endothelial cells [3]. The rate of thromboembolic complications in MPN patients ranges from 1.1 to 4.4% per year, while this rate is significantly lower in the normal population (0.6 and 0.9% per year in the absence or presence of cardiovascular risk factors, respectively) [4, 5]. Therefore, prediction of occurrence of thromboembolic events for risk estimation is of great importance. While the risk of these patients to experience thromboembolic complications is clearly high, prognostic parameters beyond age and past history of thrombosis are currently lacking. This leads to challenges in clinical decision making regarding the indication of cytoreductive drugs and the prophylaxis and use of anticoagulants. Therefore, in our previous work, we used a machine learning algorithm to identify risk factors for this high-risk population of patients with PV for clinical use that can predict thromboembolic events [6]. Using the publicly available OPTUM database that consists of patient data provided by US insurance companies, we could define red cell distribution width (RDW), lymphocyte and platelet counts as independent prognostic parameters for thromboembolic events: Lymphocyte ratio (LYP) and RDW predicted the risk of occurrence of TEs of patients without a history of TEs within the next 12 months. In addition, predictive factors for patients with a history of TE complications included lymphocyte ratio and platelet count. Recently, neutrophil-lymphocyte ratio (NLR) was confirmed as predictive risk factor for venous thrombosis in an independent retrospective cohort of PV patients [7]. While these analyses require prospective validation in clinical trials, the predictive value of these parameters in a normal control population without myeloproliferation or hematopoietic cancers remains to be investigated.
In order to validate these findings in a control cohort of non-MPN patients, we retrieved data of the SHIP study conducted at Greifswald University Medicine. The Study of Health in Pomerania (SHIP) is a population-based epidemiological study consisting of currently 5 independent cohorts [8]. The SHIP investigates common risk factors, subclinical disorders and manifest diseases with highly innovative non-invasive methods in the population of northeast Germany. As this study is not focused on one specific disease it aims to investigate health in all aspects and complexity involving the collection and assessment of data relevant to the prevalence and incidence of common, population-relevant diseases and their risk factors.
We utilized data from different independent cohorts of the SHIP study: the baseline examination of SHIP-START (SHIP-START-0) between 1997 and 2001 (n = 4308), and the baseline examination of SHIP-TREND (SHIP-TREND-0) between 2008 and 2011 (n = 4420). After excluding missing datapoints, a total of 2491 datasets (derived from individual participants) from the SHIP-START-0 and 4358 from the SHIP-TREND-0 were included in the analyses. Data on all probands with baseline data on RDW, lymphocyte percentage, platelet count, body mass index (BMI), prior TE, neutrophil percentage, leukocytes and hematocrit was used for the study. Also, all documented medication was recorded and included for analysis. Of note, SHIP-START-0 data does not include differential blood counts, including lymphocyte and neutrophil percentage. Occurrence of TE in SHIP-START was defined as thrombosis, stroke or myocardial infarction or use of an antithrombotic agent while SHIP-TREND also included evidence of thrombophlebitis. Antithrombotic agents were defined as agents belonging to the Anatomical Therapeutic Chemical (ATC) classification system section B01 “antithrombotic agents”. This section includes oral anticoagulants such as vitamin K antagonists, platelet inhibitors (ASA and P2Y-antagonists) and direct oral anticoagulants (DOACs) among others. Single use of antithrombotic agents e.g. for in-flight prophylaxis was not considered. Cardiovascular risk factors included were elevated blood lipids, hypertension, diabetes mellitus, current smoking, BMI, and subjects’ age. Subjects with missing diabetes mellitus status and HbA1c > = 6.5% were counted as diabetic. In the absence of elevated blood lipid status, subjects with cholesterol > = 6 mmol/l and/or triglyceride > 1.9 mmol/l were assigned to elevated blood lipids. Descriptive statistics are provided as median and minimum – maximum, or as frequency and percentage, as appropriate. The non-parametric Mann Whitney U test was used to assess differences of continuous variables between two groups. Categorical variables were compared using the Fisher’s exact test. First, all candidate variables were adjusted for age and sex. Then, all significant age- and sex-adjusted variables were included in the backward variable selection procedure. Variable selection was performed 1000 times using bootstrapping methods. To report the most relevant variables, the final model consists of those selected in at least 80% of the bootstrapping runs. In both cohorts, 70% of the data were used to build and 30% were used to validate the model. To assess the predictive value of both models, accuracy and receiver operating characteristic (ROC) curve were calculated. Statistical significance was claimed at 5% (p < 0.05) and no correction for multiple testing was performed. The data was prepared using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and analyzed using R Version 4.2.2 [9].
Regarding baseline characteristics, TE events had occurred in 321 (12.9%) of the 2491 individuals of the SHIP-START cohort while the prevalence of TE events was 21.4% (932 events in 4358 individuals) in the SHIP-TREND cohort. Overall, established risk factors for TE such as male sex, higher age, higher body-mass-index (BMI), arterial hypertension, hypercholesterolemia, and diabetes mellitus were associated with significantly higher rate of TE events (Table 1). Of note, TE events were more frequently reported in non-smokers compared to smokers in both cohorts. In regard to laboratory parameters, higher RDW and lower platelet counts showed significant association with TE complications. In contrast, higher leukocyte counts, lower hematocrit and lower lymphocyte ratio showed exclusively significance in the SHIP-TREND cohort analysis.
Table 1 Baseline characteristics of both cohorts.
To assess for effects of the above risk factors on TE events, we used multivariable logistic regression models. When investigating the SHIP-START cohort of 2491 individuals, male sex (p < 0.0001), presence of hypertension (p = 0.0042), hypercholesterolemia (p < 0.0001) or diabetes mellitus (p = 0.0008), and higher age (p < 0.0001) were validated as TE risk factors. Regarding laboratory parameters, higher RDW (p = 0.0006) was the only predictor for TE complications.
Analysis of the SHIP-TREND cohort of 4358 individuals confirmed independent predictive value of higher age (p < 0.0001) and hypercholesterolemia (p < 0.0001) while elevated body mass index (BMI; p = 0.0003) scored as an additional predictive factor due to availability of the respective data points in this cohort. In contrast, male sex and hypertension were not confirmed as independent risk factors. Consistent with the SHIP-START cohort, higher RDW (p < 0.0001) was identified as predictive for TE events, along with lower platelet counts (p < 0.0028). Taken together, alterations of laboratory parameters such as red cell distribution width and platelet count at study entry were associated with occurrence of thromboembolic events in this retrospective assessment of individuals without evidence for hematologic malignancies.
When adjusting for age and sex (Fig. 1A, B), BMI, hypercholesterolemia, hypertension, diabetes mellitus and RDW consistently showed elevated odds ratios in both cohorts, using the basic model. Assessment for TE risk factors in the final model confirmed age, hypercholesterolemia and RDW as predictors of thromboembolic events in both cohorts. Here, RDW showed an OR of 1.28 (95% CI: 1.11–1.47) for SHIP-START and 1.25 (95% CI 1.12–1.38) for SHIP TREND (Fig. 1C, D). Of note, the SHIP-TREND model could also be validated using SHIP-START data. In order to select an optimal model, receiver operating characteristic (ROC) analysis was performed showing an AUC of 0.846 (95% CI: 0.805–0.886) for SHIP-START and an AUC of 0.847 (95% CI: 0.827–0.866) for SHIP-TREND (Fig. 1E, F). Accuracy of the SHIP-START model was 89.2% and of the SHIP-Trend model 86.8%.
Fig. 1: Effects of risk factors on TE events.
Age- and sex-adjusted odds ratios (A, B), final model odds ratios (C, D) and receiver operating characteristic (ROC) curve (E, F) for SHIP-START-0 data (E) and SHIP-TREND-0 data (F). BMI body mass index, HCL hypercholesterolemia, RDW red cell distribution width, PLT platelet count, LYP lymphocyte ratio, AUC area under curve, CI confidence interval.
Red cell distribution width is a marker for the variation of erythrocyte size (anisocytosis) and used in combination with other laboratory markers for differential diagnosis of hematological diseases such as anemia and bone marrow dysfunction. Changes in RDW have been reported for a variety of chronic inflammatory conditions such as diabetes, cardiovascular disease, infections and cancer and its predictive and prognostic value has been reported for cardiovascular disease as well as for overall mortality of the general population [10]. Likewise, differential blood counts have been described as biomarkers of inflammatory processes and cancers. Identification of RDW, platelet counts and lymphocyte ratio as biomarkers for thromboembolic events in PV patients is therefore not surprising, as JAK2-mutated cancers are associated with broad activation of cell signaling [11] and increase of pro-inflammatory cytokines [3, 12]. Recently, exome-analysis studies have shown age-related clonal hematopoiesis (CH) in healthy individuals, driven by mutations of genes recurrently mutated in myeloid neoplasms and associated with an increased risk of hematologic cancer and cardiovascular disease. Critically, both SHIP-cohorts reported in this analysis have not been investigated for the presence of clonal hematopoiesis. Therefore, we cannot exclude the influence of CH on the predictive value of RDW and occurrence of TE events. Moreover, cutoffs for RDW may vary and have not been generally defined in previous analyses. Critical limit values of these potential biomarkers may depend on the underlying condition, comorbidities (e.g. previous TE complications) or concomitant medication. Finally, in SHIP-TREND, we used a broad definition of TE events (including peripheral thrombosis and thrombophlebitis) and predictive biomarker values may vary with a definition restricted to deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Of note, the allocation of individuals into the “TE-event” cohort based on the use of anticoagulants may result in inclusion of individual participants using ASA and P2Y-antagonists as primary rather than secondary prophylaxis.
Taken together, we could confirm RDW as an independent predictive parameter for thromboembolic events in the general population. Development and prospective validation of predictive scoring systems combining predictive laboratory parameters are clearly warranted but are beyond the scope of this report.
The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.
Research shows that fedratinib and the earlier JAK inhibitor, ruxolitinib have similar efficacy in patients with MF. However, their toxicity profiles differ, and the potential for encephalopathy with fedratinib is an ongoing concern, resulting in a black box warning on the label. Now that the agent is FDA approved for the treatment of MF, oncologists are left with a decision of which JAK inhibitor to give to which patients and when to prescribe them.
How to continue using ruxolitinib now that fedratinib is available remains an unanswered question, said Kuykendall, assistant member, Moffitt Cancer Center; however, experts in treating myeloproliferative neoplasms (MPNs) can be a helpful resource for other oncologists.
Another resource for treatment decision-making is clinical data from the JAKARTA-2 trial, which studied fedratinib in patients with MF who were previously treated with ruxolitinib. Findings from a re-analysis of the study were presented at the 2019 ASCO Annual Meeting and showed that 46 of the 83 assessable patients achieved a spleen response (55%; 95% CI, 44%-66%), meeting the primary endpoint of the study.
The most common adverse events included diarrhea (n = 60), nausea (n = 54), vomiting (n = 40), constipation (n = 20), and others. Additionally, hematologic abnormalities including, grade 3/4 anemia (n = 96), thrombocytopenia (n = 68), and neutropenia (n = 23) were seen. Eighteen patients (19%) discontinued treatment due to adverse events.
These data suggest that fedratinib may be a second-line option for patients who are resistant or sensitive to ruxolitinib. The management of the gastrointestinal (GI)-related toxicities and checking of thymine levels to prevent encephalopathy, however, are newer management concerns that physicians must be aware of when administering fedratinib to patients with MF and is another point when consulting an MPN specialist may come in handy.
The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.