Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL.

ABSTRACT: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Although an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL) study collected prospective clinical data from 2510 patients with PV with a median follow-up of 44.7 months (range, 2-59 months) from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates), and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) and WBCs >11 × 109/L (HR, 2.35; 95% CI, 1.598-3.465; P < .0001). Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.066-3.554; P = .0300). The results support incorporation of WBC count into PV risk stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial was registered at www.clinicaltrials.gov as #NCT02252159.

A safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is not uncommonly seen in pregnancy, either with the first episode or with the exacerbation of known disease. The management of TTP in pregnancy can be challenging if there is refractoriness to the use of therapeutic plasma exchange (TPE) and high-dose corticosteroids. Caplacizumab, a vWF-directed humanized antibody fragment, is approved for the treatment of acquired TTP but there is sparse data on its use in pregnant patients. Antenatal and peripartum haemorrhage is a theoretical concern with the use of the medication in the obstetric population. However, as options for treatment of TTP in the patients who have refractory disease are significantly limited, off-label use of caplacizumab to achieve disease control and prevent maternofetal morbidity and mortality is a reasonable consideration. This article described the successful use of caplacizumab in a pregnant patient with acquired TTP and the associated favourable outcome. The patient suffered an exacerbation following initial TPE and became refractory to both plasma exchange and high-dose corticosteroids. Off-label use of caplacizumab resulted in hematologic recovery and successful delivery of a healthy neonate. This case represents a contribution to the sparse literature on the use of this effective medication in an often-challenging clinical situation.

JAK inhibition in myelofibrosis: how to sequence treatment in this new era of multiple options.

The management of myelofibrosis has improved following approval of the JAK1/JAK2 inhibitor, ruxolitinib. This agent laid the foundation for JAK inhibitor therapy, yet limitations have included myelosuppression and other adverse events (skin cancer, weight gain, and infection), as well as loss of response. Recently, two additional JAK inhibitors were approved for use in myelofibrosis. Fedratinib can be used front-line and has demonstrated impressive responses as a salvage option after ruxolitinib loss of response. Previously, patients with severe thrombocytopenia had limited treatment options; approval of pacritinib offers an option to address splenomegaly and/or symptoms in these patients. A significant unmet need has been the treatment of anemia; momelotinib (not approved at the time of writing) has demonstrated spleen, symptom, and anemia responses. The possibility of having four approved options for myelofibrosis may be soon realized. This speaks to progress in the past decade, though achieving clinical and molecular remissions remain paramount.

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Management of Myelofibrosis-Associated Anemia: Focus on Standard Agents and Novel Therapeutics in Phase 3 Clinical Trials.

PURPOSE OF REVIEW: The management of myelofibrosis is risk-adapted when considering transplant eligibility and symptom-directed, prioritizing the most burdensome symptoms for the patient. Unfortunately, myelofibrosis-anemia is common, multifactorial in its origin, and impactful regarding prognosis. While clinical trials are advised, not all patients have convenient access, and therefore, hematologists should be aware of the data supporting the use of conventional agents such as erythropoietin-stimulating agents, steroid treatments (danazol and prednisone), and immunomodulatory drugs (thalidomide and lenalidomide). This review summarizes the conventional approach to treating myelofibrosis-anemia and highlights recent data from 3 novel agents that are under phase 3 evaluation. RECENT FINDINGS: Momelotonib is a JAK1/2 and ACVR1 inhibitor that has demonstrated not only improvements in splenomegaly and symptoms, but also amelioration of anemia on the SIMPLIFY 1 and 2 clinical trial program. This may occur through suppression of hepcidin production. Luspatercept promotes late-stage hematopoiesis, and the phase 2 study has shown promise in ameliorating anemia as a monotherapy, and especially in combination with ruxolitinib. Finally, CP-0160, a BET inhibitor, has shown efficacy as an anemia-directed agent, when used as monotherapy and in combination. This agent reduces cytokine production and promotes erythroid differentiation. Results have been presented for patients previously treated with JAK inhibitors, as well as those who were naïve to JAK inhibitor therapy. Safety and effectiveness are reviewed for both conventional and selected novel agents used in the treatment of MF-anemia. A practical approach to treatment is presented, and data from ASH 2020 are presented.

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Thrombocytosis and Thrombosis: Is There Really a Correlation?

PURPOSE OF REVIEW: Thrombocytosis is common to all myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis. Despite the traditionally held belief amongst many clinicians that thrombocytosis correlates with thrombosis risk, there is little evidence in the literature to support that claim. Herein we critically analyze the literature to better understand the relationship between thrombocytosis and risk of thrombosis in MPN. RECENT FINDINGS: Both retrospective and prospective studies argue against associations between thrombocytosis and risk of thrombosis in patients with ET and PV. Rather, most studies suggest that the presence of extreme thrombocytosis is instead associated with an increased risk of hemorrhagic events, a paradoxical phenomenon with important clinical implications. Thrombosis risk has a multifactorial set of etiologies in MPNs. While qualitative abnormalities of the platelets may contribute, associations between platelet quantity and thrombosis risk are weak in MPN patients.

Long-term antithrombotic therapy after venous stent placement.

OBJECTIVES: To examine the prescribing patterns and outcomes of antithrombotic regimens after venous stent placement. METHODS: A total of 87 patients who received inferior vena cava or iliofemoral venous stents were included in the study. A retrospective review was performed to determine the antithrombotic regimens and the subsequent rates of in-stent restenosis, stent thrombosis, and bleeding. RESULTS: The prescribing patterns of specific antithrombotic regimens were highly variable. In-stent restenosis and stent thrombosis events were observed in 13 of 63 patients (21%) with available follow-up imaging, while major bleeding events were noted in 6 of 87 patients (7%). Triple therapy appeared to reduce the odds of in-stent restenosis/ stent thrombosis when compared to dual antiplatelet therapy (OR = 0.07, P = 0.01). CONCLUSIONS: Substantial variability exists in antithrombotic therapy following venous stenting at our institution. This study demonstrated a reduction of in-stent restenosis/thrombosis events when utilizing triple therapy compared to antiplatelet-only regimens. However, larger prospective trials are needed to more accurately determine the relative risks and benefits of each antithrombotic regimen.

From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms.

Thrombotic and hemorrhagic complications are prevalent in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis. Given the impact on morbidity and mortality, reducing the risk of thrombosis and/or hemorrhage is a major therapeutic goal. Historically, patients have been risk stratified on the basis of traditional factors, such as advanced age and thrombosis history. However, multiple factors contribute to the thrombotic tendency, including gender, mutational profile, inflammatory stress, and abnormal cell adhesion. Management includes cardiovascular risk reduction and use of antiplatelet therapy, depending on myeloproliferative neoplasm subtype and mutational status. Anticoagulation is a mainstay of therapy for those with venous thrombosis, but practice patterns remain heterogeneous. Cytoreduction is indicated for higher-risk patients, but efficacy may depend on the involved vascular bed. Management of special situations, such as unusual site thrombosis, bleeding, the perioperative period, and pregnancy, are especially challenging. In this article, risk factors and treatment strategies for myeloproliferative neoplasm thrombosis and bleeding, including special situations, are reviewed. Insights gained from recent studies may lead to the development of a more precise risk classification and tailored therapy.

From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms.

Thrombotic and hemorrhagic complications are prevalent in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis. Given the impact on morbidity and mortality, reducing the risk of thrombosis and/or hemorrhage is a major therapeutic goal. Historically, patients have been risk stratified on the basis of traditional factors, such as advanced age and thrombosis history. However, multiple factors contribute to the thrombotic tendency, including gender, mutational profile, inflammatory stress, and abnormal cell adhesion. Management includes cardiovascular risk reduction and use of antiplatelet therapy, depending on myeloproliferative neoplasm subtype and mutational status. Anticoagulation is a mainstay of therapy for those with venous thrombosis, but practice patterns remain heterogeneous. Cytoreduction is indicated for higher-risk patients, but efficacy may depend on the involved vascular bed. Management of special situations, such as unusual site thrombosis, bleeding, the perioperative period, and pregnancy, are especially challenging. In this article, risk factors and treatment strategies for myeloproliferative neoplasm thrombosis and bleeding, including special situations, are reviewed. Insights gained from recent studies may lead to the development of a more precise risk classification and tailored therapy.

Thrombosis in the Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

The myeloproliferative neoplasms (MPNs) are clonal stem cell-derived diseases. This chapter focuses on the subcategory of Philadelphia (Ph) chromosome-negative classical MPNs, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF). These MPNs are associated with both microvascular and macrovascular thrombosis, which may occur in the venous and arterial circulation. Erythrocytosis, leukocytosis, and increased JAK2V617F allele burden are known to be risk factors. In this chapter, we review the thrombotic and hemostatic manifestations of the Philadelphia (Ph) chromosome-negative classical MPNs, including the clinical manifestations, the pathophysiology, as well as management.

Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

Do All Patients With Polycythemia Vera or Essential Thrombocythemia Need Cytoreduction?

Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs), characterized by expansion of normal blood counts, bleeding, thrombosis, and the potential for transformation to myelofibrosis (MF) or acute myeloid leukemia (AML). The primary goals of treatment for MPNs are to reduce the risk of thrombosis, alleviate systemic symptom burden (eg, fatigue, pruritus, microvascular symptoms, and symptomatic splenomegaly), and to prevent transformation to MF/AML. Preventing transformation is clearly important, but not expected with current therapies. Currently, cytoreduction is advised based on vascular risk assessments, which include age and thrombosis history, as well as molecular profile in ET. Traditionally, cytoreduction has been advised only in patients with high vascular risk. Recently, a large prospective study evaluated the safety and efficacy of cytoreduction in patients with ET with less-than-high-risk vascular profiles. A larger question in the MPN field is whether cytoreduction is advisable for all patients with ET and PV, regardless of risk. This article reviews existing data on cytoreduction, evaluating hydroxyurea, interferons, and ruxolitinib in ET and PV. This review evaluates whether evidence supports a more liberal strategy of cytoreduction for all patients with ET and PV.

Clinical and Disease Characteristics From REVEAL at Time of Enrollment (Baseline): Prospective Observational Study of Patients With Polycythemia Vera in the United States.

BACKGROUND: Polycythemia vera (PV) has a prevalence of 44 to 57 per 100,000 people in the United States. Prospective data concerning the demographics, clinical characteristics, and treatment patterns of patients with PV in the United States are lacking. PATIENTS AND METHODS: The ongoing, prospective, observational REVEAL study evaluates demographics, disease burden, clinical management, patient-reported outcomes, and health care resource utilization of adult patients with PV in the United States. This report summarizes the demographics and clinical characteristics of patients at enrollment (baseline). RESULTS: Patients (n = 2510) were a median age of 67.0 years, 54.2% were male, and 89.1% were white. The median time from PV diagnosis to study enrollment was 4.0 (range, 0-56.3) years. Most patients (89.7%) were diagnosed after an abnormal blood test. Less than half (49.2%) underwent JAK2 mutation analysis, of whom 95.8% were JAK2 V617F mutation positive; < 1% were positive for JAK2 exon 12 mutations. At enrollment, 47.7% of patients had elevated hematocrit (> 45%), 35.8% had elevated platelets (> 400 × 109/L), and 37.0% had elevated leukocytes (> 10 × 109/L). Most patients (94.5%) were receiving active PV treatment, predominantly therapeutic phlebotomy alone (33.6%), hydroxyurea monotherapy (29.0%), or hydroxyurea plus phlebotomy (23.7%). Thrombotic events occurred in 11.9% of patients before PV diagnosis (venous, 6.7%; arterial, 5.7%), and 8.3% between diagnosis and enrollment. Hypertension (70.6%) was the most common previous medical condition. CONCLUSION: REVEAL enrollment data inform our understanding of the baseline demographics, diagnostic approach, disease characteristics, and treatment patterns of patients with PV in the United States. Longitudinal real-world data collected in this study will complement information collected during randomized controlled clinical trials.

Patient-Reported Outcomes Data From REVEAL at the Time of Enrollment (Baseline): A Prospective Observational Study of Patients With Polycythemia Vera in the United States.

BACKGROUND: Patients with polycythemia vera (PV) often experience symptoms that adversely affect their quality of life (QoL). The ongoing, prospective, observational REVEAL (Prospective Observational Study of Patients With Polycythemia Vera in US Clinical Practices) study was designed to collect contemporary data regarding burden of disease, clinical management, patient-reported outcomes (PROs), and health care resource utilization from adult patients with PV in the United States. PATIENTS AND METHODS: Data on PROs were collected at enrollment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; range, 0-100); the European Organization for Research and Treatment of Cancer-Core Quality of Life Questionnaire, version 3.0 (EORTC QLQ-C30; range, 0-100); and the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP; range, 0%-100%). RESULTS: Among 2309 patients, mean (SD) disease duration was 5.8 (6.1) years and Charlson Comorbidity Index was 3.4 (0.8); 54.0% (1247/2309) were male. Mean (SD) MPN-SAF TSS was 18.8 (15.5). The most common symptoms were fatigue (80.1% [1844/2302]), early satiety (60.9% [1402/2302]), and inactivity (57.6% [1324/2302]). The most common severe symptoms were fatigue (16.8% [387/2302]), itching (13.4% [308/2302]), and inactivity (11.8% [271/2302]). The mean (SD) EORTC QLQ-C30 global health status/QoL score was 73.1 (23.2): mean functional subscale scores ranged from 80.5 (23.9) for cognitive functioning to 85.7 (24.6) for social functioning. The mean WPAI-SHP activity impairment score was 19.7% (n = 2300). Employed patients had mean WPAI-SHP scores for absenteeism, presenteeism, and overall work impairment of 3.2% (n = 810), 12.1% (n = 807), and 13.4% (n = 802), respectively. CONCLUSION: These data confirm that many patients with PV experience symptoms, QoL impairments, and work productivity impairments that negatively affect their lives. Longitudinal data from REVEAL will be important for evaluating how PROs change over time in these patients.

NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018.

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis.

While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

Prognostication and Initiation of Therapy in Polycythemia Vera: Do We Have it Right?

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