Treatment Of Essential Thrombocythemia Research Articles

Real-World Experience of Ropeginterferon-Alfa Treatment of PV and ET - Two Centers Experience

BACKGROUND AND AIM: Interferon alpha is an effective treatment for Polycythemia Vera (PV) and Essential Thrombocythemia (ET) and is the only treatment known to induce sustained molecular responses by decreasing JAK2 mutation allelic burden. Long-acting pegylated interferons are better tolerated. Ropeginterferon-alfa is a monopegylated interferon with a longer half-life and is the first interferon to be FDA-approved for the treatment of PV. It is not yet approved for ET, but clinical trials are ongoing. Given the similar disease biology between PV and ET and the efficacy of pegylated interferon-alfa in both PV and ET, this study aims to look at a real-world experience of treating PV and ET with ropeginterferon-alfa since its approval. METHODS: We conducted a retrospective chart review of all our PV and ET patients treated with ropeginterferon-alfa at Huntsman Cancer Institute, University of Utah (SLC cohort), and at the University of North Carolina at Chapel Hill (UNC cohort), since the drug's approval for PV from November 2021 through June 2023. The complete hematologic response (CHR) was defined as the normalization of blood counts within the reference range of the local lab standards. Prior to ropeginterferon-alfa, the participants were managed with therapeutic phlebotomies, or cytoreduced with either hydroxyurea, pegylated interferon-alpha 2a ( Pegasys), JAK2 inhibitors, or were newly diagnosed and previously untreated. RESULTS: A total of 120 patients (76 in SLC cohort and 44 in UNC cohort) were included in this study. Of those, 75 (62.5%) were diagnosed with PV, 37 (31%) with ET, and 1 with congenital polycythemia due to germline JAK2 mutation. Twenty-three (19%) patients had a prior history of thrombosis. JAK2 mutation was present in 100 (83%) patients, while 9 (7.5%) were CALR mutated, 1 with MPL mutation, and 1 with triple-negative ET. Extended myeloid gene panel sequencing was available in 64 (53.3%) patients and 35 of them (54.6%) patients had additional somatic mutations. Most common somatic mutations include TET2 (11 patients) and DNMT3A (8 patients) and CBL (3 patients), among others. Of the cohort, 15 (12%) patients discontinued ropeginterferon-alfa due to various adverse events, which included: fatigue, joint aches, skin rash, and increased anxiety and depression. Of the 105 patients who are on ropeginterferon-alfa, 9 patients were previously untreated patients while 96 (91.4%) were pretreated with other therapies and switched to ropeginterferon-alfa. In many patients, the switch to ropeginterferon-alfa was done because of the increased frequency and aggressivity of squamous cell skin cancers while on hydroxyurea treatment. All of them started ropeginterferon-alfa at a dose of either 50 mcg or 100 mcg every two weeks and were increased at an increment of 50 mcg to achieve a goal of CHR. As most of the patients were switching from prior therapies, 51 (49%) were already in CHR at the time of initiating ropeginterferon-alfa. The median ropeginterferon-alfa dose to maintain CHR was 50mcg in the SLC cohort and 100mcg in the UNC cohort. (See table for more details). We have 6 patients with DNMT3A mutation, 4 (66.6%) have achieved CHR at a median ropeginterferon-alfa dose of 100 mcg (range 50 mcg - 150 mcg), and 2 patients are undergoing dose titration. Of the 11 patients with TET2 mutation, 7 (63.3%) achieved CHR at a median ropeginterferon-alfa dose of 150 mcg (range 50 mcg - 500 mcg). The analysis of JAK2 V617F and CALR allelic burden, transcripts of inflammatory, prothrombotic, and hypoxia-regulated (HIFs) genes, and evaluation of females for reversal of clonal to polyclonal myelopoiesis is ongoing. CONCLUSION: Ropeginterferon-alfa is effective in PV and ET, however, the dose that achieves CHR is highly individualized, necessitating an incremental titration approach. The patients already in CHR from prior therapy needed relatively lower doses of ropeginterferon-alfa to maintain CHR. Clinical trials are ongoing with an alternate accelerated dosing scheme and results are awaited.

Low Thrombosis Risk CALR Mutations Confer Higher Risk of Essential Thrombocythemia Progression

Background: Patients (pts) with essential thrombocythemia (ET) face increased risk of thrombosis and the prospect of progression to myelofibrosis (MF) or acute leukemia. ET treatment recommendations from ELN 1 and NCCN 2 are largely governed by the revised IPSET-thrombosis score that identifies 4 risk categories from “very low” to “high” based on age, thrombosis history, and the presence of a JAK2 V617F mutation 3. Pts with CALR-mutated ET are known to have a lower risk of thrombosis than those with a JAK2 mutation, and for this reason, are often considered to have lower risk ET. Yet previous study of pts with clinically diagnosed ET found that CALR mutations may negatively impact progression risk 4. For this reason, we evaluated the impact of driver mutations on the risks of thromboembolic events, disease progression, and overall mortality for a cohort of pts with rigorously defined WHO ET treated at our institution. Methods: Medical records were queried for pts with the diagnosis (dx) of ET, as per ICD, code versions 9-10. The dx of ET and dx date were confirmed by manual review. All pts met the 2022 WHO criteria for ET, including a diagnostic marrow in all cases. Confounding diagnoses, including pre-fibrotic MF, polycythemia vera, or presumed ET in pts lacking a marrow biopsy, were strictly excluded by thorough review of the rich data available. Structured query language supplemented by manual review was used to extract clinical, laboratory, molecular, and marrow findings and treatment course. Overall (OS), MF-free (MFS), and thrombosis-free (TFS) survival were estimated using Kaplan-Meier methods. Univariable and multivariable analysis of post-ET MF (PETMF), thrombosis and mortality risk were performed using Cox proportional-hazards models using IPSET-survival 5 and revised IPSET-thrombosis variables as covariates. Results: The query returned 751 pts but only 338 met our strict criteria for ET with diagnostic marrows and had annotated driver mutations. Of these, 216 (64%) were positive for JAK2 V617F, 85 (25%) CALR, 19 (6%) MPL, and 18 (5%) triple negative (TN). We identified no significant differences among the driver mutation cohorts in dx age, sex, or median follow up duration. Semi-quantitative features of the diagnostic marrow biopsies, including age-adjusted cellularity and reticulin fibrosis score, were not significantly different among the groups. Red cell parameters at dx were mildly higher in the JAK2 pts (HCT, HGB, RBC all with p<0.001), WBC count was highest in TN pts ( p=0.012), and PLT count was not significantly different ( p=0.064). 20-year TFS for JAK2 was 71%, CALR 100%, MPL 90% and TN 83% ( p=0.0027, Figure 1); 20-year MFS for JAK2 was 87%, CALR 48%, MPL 65% and TN 94% ( p=0.00053, Figure 2); 20-year OS for JAK2 was 76%, CALR 86%, MPL 89% and TN 90% ( p=0.66). Multivariable analysis showed that CALR was associated with a significantly higher risk of PETMF as compared to JAK2 (HR 11.52, CI 1.88-70.51, p=0.008), independent of age, sex, WBC, and thrombosis history. Conversely, CALR was associated with a lower risk of thrombosis (HR 0.08, CI 0.01-0.58, p=0.013) when adjusting for sex and revised-IPSET thrombosis parameters. Discussion: We found that although pts with CALR-mutated ET have lower thrombosis risk, they experience higher risk of progression to MF. Current risk models for thrombosis yield treatment recommendations well suited to reducing thrombosis risk 3. With this success, pts are expected to live with ET for decades, thereby exposing them to other ET risks, most notably that of malignant disease progression. These risks are of particular concern for younger pts who suffer the greatest relative risk 6. It is important that thrombosis risk and fibrosis risk are not conflated as our data suggest that pts with low or very low risk CALR-mutated ET can be at higher risk of progression. Our findings reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression.

EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia.

TPS7088 Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by a high platelet count due to an overacting JAK-STAT pathway as a result of the most common mutations in JAK2, CALR and MPL genes. There is a high, unmet clinical need for safe and effective treatment options for patients with ET who require cytoreduction, both naïve and previously exposed to hydroxyurea (HU) or anagrelide (ANA). In addition to blood count control and thrombohemorrhagic risk reduction, treatment for ET should also halt/prevent disease progression to post-ET myelofibrosis. Reduction in variant allele frequency and changes in marrow morphology may lead to the elimination of the malignant clone, and treatment with an interferon may achieve this outcome. Interferons have been used in the treatment of MPNs for over 30 years with well-established improvements in hematological and molecular rates, but interferons are not approved by a regulatory agency for the treatment of ET. The objective of this study is to assess the efficacy of ropeginterferon alfa-2b-njft, a new generation interferon alfa, in adults with ET who live in the US or Canada. Methods: This single-arm, open-label study includes a 28-day screening period, a 12-month treatment phase, and a 28-day follow-up period, for a total trial duration of 14 months. An extension phase will supply ropeginterferon alfa-2b-njft to patients deriving benefit for a total of 3 years of treatment. Adults diagnosed with ET according to the WHO 2016 criteria with a platelet count at screening > 450 x 109/L, cytoreductive treatment naïve, or with prior use or currently on HU and/or ANA may participate. Prior treatment with an interferon is an exclusion factor. Patients with a history or presence of clinically relevant depression, risk of suicide, or autoimmune disease may not participate. Ropeginterferon alfa-2b-njft will be administered subcutaneously every 2 weeks at the starting dose of 250 mcg (Week 0), 350 mcg (Week 2), and target dose of 500 mcg (Week 4) and remain fixed for the 12-month treatment period. Subjects currently on HU or ANA will follow a pre-specified dose-tapering schedule. All subjects will receive low-dose aspirin unless contraindicated. The primary endpoint is a durable response defined as the proportion of subjects who achieve simultaneous peripheral blood count remission (platelets ≤400 x109/L and WBC < 10 x 109/L) for at least 80% of bi-weekly measurements consecutively between weeks 32-52, a durable resolution of disease-related symptoms according to the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and absence of bleeding or thrombotic events. This study is being sponsored by PharmaEssentia USA. Clinical trial information: NCT05482971 .

Values and Preferences Towards Antithrombotic Therapy in Patients with Myeloproliferative Neoplasms: A Qualitative Study

Background: Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET), confer a high risk for thrombotic events. The primary and secondary prevention of thrombotic events is managed with antithrombotic therapy, which is complicated by a high frequency of bleeding in Ph- MPN patients. When making shared decisions about antithrombotic therapy, physicians and patients must weigh thrombotic and bleeding risks and their consequences. However, little is known about the preferences and perceptions of patients with MPNs regarding antithrombotic therapy. The objectives of this study were therefore to identify: 1) patient-important factors and 2) barriers and facilitators to the use of antithrombotic therapy as thromboprophylaxis among patients with MPNs. Methods: In this qualitative study, semi-structured focus groups (FGs) were conducted with people diagnosed with PV and ET recruited via email from Canadian MPN Patient Support Groups. Focus groups were stratified based on previous history of a bleed requiring medical attention, previous history of thrombosis, or no history of bleeding or thrombosis. Open-ended questions and probes were used to guide FG discussions and FGs concluded with a polling exercise in which participants selected the most important facilitators and barriers to antithrombotic medication use. Data were analyzed using thematic analysis and the techniques of the Framework Method (Gale et al., 2013). Two team members independently reviewed and coded FG audio transcripts using NVivo to develop a coding framework. Coding comparison queries were run to assess agreement, discussion was used to resolve discrepancies, and the coding framework was iteratively refined. Data were reviewed by two members of the study team and preliminary themes were identified, guided by the research objectives. Results: We present preliminary results of our analysis. Four FGs were conducted with a total of 18 participants (range 3-6 participants). The average age of participants was 59 years, 13 (72%) were female and 10 (56%) had ET. Participants were taking aspirin (16/18, 89%), warfarin (1/18, 5%), and apixaban (1/18, 5%). Three participants (17%) had a prior thrombotic event, (ischemic stroke, myocardial infarction, and splanchnic vein thrombosis), and 3 (17%) had a prior bleeding event (epistaxis, gastrointestinal [GI] bleeding). The most important factors identified for taking antithrombotic therapy were preventing thrombotic events (94%) and a physician's recommendation (83%). Many participants perceived there was no choice when it came to the decision to use antithrombotic therapy; rather it was a physician-prescribed, necessary treatment to prevent thrombosis. Perceived downsides to antithrombotic therapy included the higher risk of bleeding, prolonged bleeding, and bruising, with specific concern about the visibility of bruises. Several participants also voiced concerns about the impact of long-term aspirin use on GI health and the potential for ulcer formation. A few participants reported lowering their dose of aspirin, as per physician recommendations or by self-adjusting the dose based on concerns about GI bleed risk. However, some participants did not perceive any downsides to using antithrombotic therapy or considered that the benefits outweighed the risks, while others were less certain. Additional analyses are underway. Conclusion: Patients with MPNs accept antithrombotic therapy use, motivated by trust in their physician's recommendations and the desire to prevent a stroke or myocardial infarction. While these values and preferences align with PV and ET treatment guidelines, it is important to recognize the influence that physician recommendations have on patients' perceptions towards antithrombotic therapy in the shared decision-making process.

Essential Thrombocythemia Associated with Plasma Cell Neoplasm

Abstract Introduction/Objective The co-occurrence of essential thrombocythemia (ET) and multiple myeloma (MM), two distinct entities with distinct cellular origin, is rare, with a limited number of cases reported. Methods/Case Report We report a case of a 63-year-old male who initially presented with thrombocytosis, splenomegaly and elevated LDH. A bone marrow examination showed hypercellularity (90%) with increased abnormal megakaryocytes, as well as a JAK2 V617F mutation, with overall features consistent with involvement by a myeloproliferative neoplasm (MPN), consistent with ET (versus early primary myelofibrosis (PMF)). Additionally, 6% kappa-restricted plasma cells were identified, consistent with involvement by a monoclonal gammopathy of undetermined significance (MGUS). The patient was subsequently treated with hydroxyurea. Four years later, he presented with evidence of paraproteinemia. IgG kappa monoclonal paraprotein was elevated at 3.4 g/dL. A repeat bone marrow examination showed hyper-cellularity (60%), including clusters of abnormal megakaryocytes and mild to moderate reticulin fibrosis. The previously identified kappa-restricted plasma cell population increased to approximately 40% of the total cellularity. Cytogenetic analysis showed a normal male karyotype (46,XY[20]), and a prognostic myeloma-FISH panel including 13q-/-13, 1q32/1q21, p53/NF1, CCND1/IgH t(11;14), FGFR3/IgH t(4;14), IgH/MAF t(14;16) and IgH/MAFB t(14;20) was negative for all tested abnormalities. The overall features were again consistent with involvement by an MPN and progression of the previously identified MGUS. Results (if a Case Study enter NA) NA. Conclusion Only a few cases of concurrent ET and MM have been previously reported in the literature, with most of these cases having a temporal association with alkylating agent therapy. However, MM development has also been reported in a patient with non-cytotoxic treatment of ET. In contrast, our patient was diagnosed with ET associated with MGUS at the initial diagnosis. Notably, the co-existence of early PMF with MM appears to be relatively more established. A large study showed that previous PMF was strongly associated with MM development (OR 24.3; 95% CI:2.9-201.5).

Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia.

Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET. International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.

PB2039: CLINICAL FEATURES AND NEXT-GENERATION SEQUENCING LANDSCAPE OF ESSENTIAL THROM-BOCYTHEMIA，PREFIBROTIC PRIMARY MYELOFIBROSIS, AND OVERT FIBROTIC PRIMARY MYELOFIBROSIS: A CHINESE RETROSPECTIVE STUDY

Background: Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate enti-ty in the 2016 revised classification of MPN differed from essential thrombocythemia (ET) or overt fibrotic primary myelofibrosis (overt PMF), it has been a subject of de-bate among experts due to its indefinite diagnosis. Aims: We conducted a retrospective study of patients with myeloproliferative neoplasms (MPNs) in China, including 56 ET pa-tients, 19 pre-PMF patients, and 43 overt PMF patients. Methods: We conducted a retrospective study of patients with BCR-ABL-negative MPN from October 2014 to May 2021 in the Fourth Affiliated Hospital of Zhejiang University School of Medicine. Patients who were diagnosed with ET, pre-PMF or overt PMF according to the 2016 WHO revised Classification of MPN were included. Patients with incomplete information from laboratory tests and medical records were excluded. This study was approved by the Ethics Committee of the Fourth Affiliated Hospital of Zhejiang University School of Medicine in line with the principles of the Declaration of Helsinki.Statistical analyses were performed using SPSS statistics 26.0 and GraphPad Prism 8.0 software. Results: Pre-PMF patients exhibited higher leukocyte counts[14.2(6.0-28.1)×109/L vs 9.6(4.0-55.0)×109/L, P=0.003], LDH values[307(233-479)U/L vs 241(129-1182)U/L, P<0.001], onset ages[67(32-76)years vs 50(16-79) years, P=0.006], a higher frequen-cy of splenomegaly(47.4% vs 16.7%, P=0.018) and hypertension(57.9% vs 23.2%, P=0.005) than ET patients. On the other hand, pre-PMF patients had higher platelet counts[960(500-2245)×109/L vs 633(102-1720)×109/L, P=0.017], haemoglobin levels[152(115-174)g/L vs 119(71-200)g/L, P=0.003], lower LDH val-ues[307(233-479)U/L vs 439(134-8100)U/L, P=0.007] and a lower frequency of splenomegaly(47.4% vs 75.6%, P=0.031) than overt PMF patients. Next-generation sequencing landscape was performed in 50 patients, revealed the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients (60% vs 10% vs 15.79%, P=0.033), and WT1 was more often overexpressed (WT1/ABL1 copies≥1.0%) in patients with overt PMF than in those with ET or pre-PMF(54.55% vs 16.67% vs 17.65%, P=0.009). In terms of outcome, male sex, along with symptoms including MPN10, anaemia (haemoglobin<120g/L), thrombocytopenia (platelet count<100×109/L), leucocytosis (leukocyte counts>13×109/L), high LDH value (>350U/L), splenomegaly, WT1 overexpres-sion(WT1/ABL1 copies≥1.0%), KMT2A, ASXL1 and TP53 mutations, indicated a poor prognosis for PMF patients. 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 2019–2024 Academician Workstation of the Fourth Affiliated Hospi-tal of the Zhejiang University School of Medicine; the 2019–2022 Key Medical Dis-cipline (Hematology) Fund of Jinhua, China. *Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. E-mail: [email protected] Image:Summary/Conclusion: In summary, the results of this study indicated that comprehensive evaluation of BM features, clinical phenotypes, haematologic parame-ters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients.

Clinical features and next-generation sequencing landscape of essential thrombocythemia, prefibrotic primary myelofibrosis, and overt fibrotic primary myelofibrosis: a Chinese monocentric retrospective study.

Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity in the 2016 revised classification of MPN differed from essential thrombocythemia (ET) or overt fibrotic primary myelofibrosis (overt PMF), it has been a subject of debate among experts due to its indefinite diagnosis. We retrospectively reviewed the clinical parameters, haematologic information, and genetic mutations of patients who were diagnosed withmyeloproliferative neoplasms (MPNs)according to the WHO 2016 criteria in China, including 56 ET patients, 19 pre-PMF patients, and 43 overt PMF patients. Pre-PMF patients exhibited higher leukocyte counts [14.2(6.0-28.1) × 109/L vs 9.6(4.0-55.0) × 109/L, P = 0.003], LDH values [307(233-479)U/L vs 241(129-1182)U/L, P < 0.001], onset ages [67(32-76) years vs 50(16-79) years, P = 0.006], a higher frequency of splenomegaly(47.4% vs 16.7%, P = 0.018) and hypertension (57.9 vs 23.2%, P = 0.005) than ET patients. On the other hand, pre-PMF patients had higher platelet counts [960(500-2245) × 109/L vs 633(102-1720) × 109/L, P = 0.017], haemoglobin levels [152(115-174)g/L vs 119(71-200)g/L, P = 0.003], lower LDH values [307(233-479)U/L vs 439(134-8100)U/L, P = 0.007] and a lower frequency of splenomegaly(47.4 vs 75.6%, P = 0.031) than overt PMF patients. Next-generation sequencing landscape was performed in 50 patients, revealed the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients (60 vs 10 vs 15.79%, P = 0.033), and WT1 was more often overexpressed (WT1/ABL1 copies ≥ 1.0%) in patients with overt PMF than in those with ET or pre-PMF(54.55 vs 16.67 vs 17.65%, P = 0.009). In terms of outcome, male sex, along with symptoms including MPN10, anaemia (haemoglobin < 120g/L), thrombocytopenia (platelet count < 100 × 109/L), leucocytosis (leukocyte counts > 13 × 109/L), high LDH value (> 350U/L), splenomegaly, WT1 overexpression(WT1/ABL1 copies ≥ 1.0%), KMT2A, ASXL1 and TP53 mutations, indicated a poor prognosis for PMF patients. The results of this study indicated that a comprehensive evaluation of BM features, clinical phenotypes, haematologic parameters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients.

Anagrelide-Induced Supraventricular Tachycardia: A Case Report

Anagrelide is an inhibitor of the phosphodiesterase-3 (PDE-3) enzyme that suppresses megakaryocytes; hence it is used in the treatment of essential thrombocythemia. Anagrelide can cause positive inotropic and chronotropic effects on the cardiovascular system. Its cardiovascular side effects are rare and include palpitations, tachyarrhythmias, cardiomyopathy, angina, and heart failure. We report the case of a 71-year-old female who presented with sudden onset chest pain. Her only outpatient medications included anagrelide and aspirin. She was found to have supraventricular tachycardia (SVT) with aberrancy that responded to beta-blockers. The chest X-ray, computed tomography angiogram (CTA), and echocardiogram were unremarkable. Her arrhythmia may be attributed to the anagrelide in the absence of any cardiovascular findings.

Low-risk polycythemia vera and essential thrombocythemia: management considerations and future directions.

Thrombotic events are a distinctive feature of the myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET). Patients with these MPNs may also experience a poor quality of life secondary to symptom burden, as well as progression of disease to acute leukemia or myelofibrosis. Over the years, various risk stratification methods have evolved in order to attempt to predict thrombotic risk, which is the largest contributor of morbidity and mortality in these patients. More than half of PV and ET patients are low- or intermediate-risk disease status at the time of diagnosis. While therapeutic development is presently focused on high-risk patients, there is a paucity of therapies, outside of aspirin and therapeutic phlebotomy, which can reduce the thrombotic risk or delay disease progression in low-risk patients. In this review, we first describe the various complications that patients with PV and ET experience, and then detail our evolving understanding of risk stratification in these diseases. We then highlight the available evidence on the management of low-risk PV and ET and include a description of novel therapies currently under investigation in this space. We conclude with recommendations for future directions to advance our understanding and improve the treatment of low-risk PV and ET.

Next-Generation Sequencing Mutational Landscape and Clinical Features of Chinese Adults with Myeloproliferative Neoplasms

▪Myeloproliferative neoplasms (MPNs) include three classical subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity in the 2016 revised classification of MPN, it has been a subject of debate among experts due to its indefinite diagnosis. However, pre-PMF usually has a distinct outcome compared with either ET or overt PMF. We conducted a retrospective study of MPN patients from October 2014 to June 2020 in the Fourth Affiliated Hospital of Zhejiang University. Patients who were diagnosed with ET, pre-PMF or overt-MF according to the 2016 WHO Classification were included. We reviewed the clinical parameters, haematologic information, and genetic mutations of patients using next-generation sequencing (NGS).Mutation screening was performed in 44 patients by next‐generation sequencing techniques, 84 genes and 258 mutations were detected. JAK2 was the most frequently mutated gene (25/44, 56.82%), followed by TET2 (14/44, 31.82%), KMT2C (13/44, 29.55%), and ASXL1 (10/44, 23.73%) in MPN (Figure 1-A). The VAFs of all studied genes with mutation frequencies >10% are shown in Figure 1-B. Of the 20 patients with ET, 9 (45%) were positive for the JAK2 mutation, 5 (25%) carried FAT1, 5 (25%) carried KMT2C, and 4 (20%) carried CALR. Of the 5 patients with pre-PMF, 4 (80%) carried JAK2, 3 (60%) carried EP300, and 2 (40%) carried TET2. Of the 19 patients with overt PMF, 12 (63%) carried JAK2, 10 (53%) carried TET2, 7 (37%) carried ASXL1, and 6 (32%) carried KMT2C, as reported in Figure 2. The median follow-up was 36 months for ET, 42 months for pre-PMF, and 53 months for overt PMF. Overall survival between pre-PMF, overt PMF, and ET was significantly different (P<0.001), as shown in Figure 3. During the follow-up time, only one death of ET was registered, so we analysed the impact of clinical parameters and mutational status at diagnosis on outcome in PMF, including pre-PMF and overt PMF. We performed Kaplan-Meier curves to examine the relationships between the clinical parameters and patient survival. We found that male sex (P=0.0107), MPN10 symptoms (P=0.0354), anaemia (haemoglobin<120g/L, P=0.0239), and thrombocytopenia (platelet count <100 ×10 9/L, P=0.0002) were significantly related to inferior OS (Figure 4). Pre-PMF patients exhibited higher leukocyte counts, higher LDH values, a higher frequency of splenomegaly, and a higher incidence of hypertension than ET patients. On the other hand, pre-PMF patients had higher platelet counts and haemoglobin levels than overt PMF patients. Molecular analysis revealed that the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients. In terms of outcome, male sex, along with symptoms including MPN10, anaemia, thrombocytopenia, and KMT2A and CUX1 mutations, indicated a poor prognosis for PMF patients.In conclusion, we identified differences in the clinical, haematologic, and molecular presentations of ET, pre-PMF, and overt PMF patients, indicating that comprehensive evaluation of not only BM features but also clinical, haematologic, and molecular profiles is needed for accurate diagnosis and treatment of these three disease entities. The molecular analysis revealed that pre-PMF might be relevant to EP300 mutation, demonstrating the value of molecular examination. The results of this study indicated that comprehensive evaluation of BM features, clinical phenotypes, haematologic parameters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients.Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Management Issues and Controversies in Low-Risk Patients with Essential Thrombocythemia and Polycythemia Vera.

Essential thrombocythemia (ET) and polycythemia vera (PV) are the most common myeloproliferative neoplasms (MPNs). Treatment of ET and PV is based on the risk for subsequent thrombosis. High-risk patients, defined as older than 60, JAK2 V617F-positive patients, or patients with a history of prior thrombosis, merit cytoreduction to control blood counts, whereas a watchful waiting paradigm is utilized in low-risk patients. However, low-risk patients have a host of other specific management issues that arise during their disease course. This review will discuss the most common management issues specific to the care of low-risk patients, including anti-platelet therapy dosing, pregnancy, and indications for early cytoreduction. Although low-dose aspirin is well established in PV, its indications and dosing regimens are less clear in ET. Recent evidence has supported twice daily low-dose aspirin in ET and observation alone in very low-risk ET patients. Pregnancy is not contraindicated in MPNs, and we recommend aspirin throughout pregnancy with consideration for prophylactic postpartum anticoagulation. High phlebotomy needs, symptom burden, and extreme thrombocytosis are common reasons for initiation of cytoreduction in low-risk patients, although we typically do not start cytoreduction for an isolated high platelet count alone. Recent data has also demonstrated a potential disease-modifying effect of interferons in MPNs, with some experts now advocating the early use of interferon in low-risk patients, although more mature data is needed before practice guidelines change. We evaluate the literature to inform clinical decision-making regarding these controversies, including most recent data that has challenged the "watchful waiting" paradigm. Our discussion provides guidance on common clinical scenarios seen in low-risk ET and PV patients, who face a myriad of complex management decisions in their care.

Identification of Potential Key Genes and Regulatory Markers in Essential Thrombocythemia Through Integrated Bioinformatics Analysis and Clinical Validation.

IntroductionEssential thrombocytosis (ET) is a group of myeloproliferative neoplasms characterized by abnormal proliferation of platelet and megakaryocytes. Research on potential key genes and novel regulatory markers in essential thrombocythemia (ET) is still limited.MethodsDownloading array profiles from the Gene Expression Omnibus database, we identified the differentially expressed genes (DEGs) through comprehensive bioinformatic analysis. GO, and REACTOME pathway enrichment analysis was used to predict the potential functions of DEGs. Besides, constructing a protein–protein interaction (PPI) network through the STRING database, we validated the expression level of hub genes in an independent cohort of ET, and the transcription factors (TFs) were detected in the regulatory networks of TFs and DEGs. And the candidate drugs that are targeting hub genes were identified using the DGIdb database.ResultsWe identified 63 overlap DEGs that included 21 common up-regulated and 42 common down-regulated genes from two datasets. Functional enrichment analysis shows that the DEGs are mainly enriched in the immune system and inflammatory processes. Through PPI network analysis, ACTB, PTPRC, ACTR2, FYB, STAT1, ETS1, IL7R, IKZF1, FGL2, and CTSS were selected as hub genes. Interestingly, we found that the dysregulated hub genes are also aberrantly expressed in a bone marrow cohort of ET. Moreover, we found that the expression of CTSS, FGL2, IKZF1, STAT1, FYB, ACTR2, PTPRC, and ACTB genes were significantly under-expressed in ET (P<0.05), which is consistent with our bioinformatics analysis. The ROC curve analysis also shows that these hub genes have good diagnostic value. Besides, we identified 4 TFs (SPI1, IRF4, SRF, and AR) as master transcriptional regulators that were associated with regulating the DEGs in ET. Cyclophosphamide, prednisone, fluorouracil, ruxolitinib, and lenalidomide were predicted as potential candidate drugs for the treatment of ET.DiscussionThese dysregulated genes and predicted key regulators had a significant relationship with the occurrence of ET with affecting the immune system and inflammation of the processes. Some of the immunomodulatory drugs have potential value by targeting ACTB, PTPRC, IL7R, and IKZF1 genes in the treatment of ET.

Real-World Patterns of First-Line Hydroxyurea Treatment Among Patients with Essential Thrombocythemia in US Community Oncology Practices

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by excessive clonal platelet production. Hydroxyurea (HU) is the recommended first-line cytoreductive treatment for ET. The objective of this study was to describe first-line HU treatment patterns and discontinuation among patients with ET in real-world US clinical practices.Methods: Data were extracted from medical charts of patients with an ET diagnosis who received cytoreductive therapy at community oncology/hematology clinics between June 1, 2011, and September 15, 2016 (study period). Demographics, clinical characteristics (ie, blood counts, symptoms, thrombotic events), and HU treatment patterns were evaluated. Data on HU treatment patterns included start date, signs/symptoms at treatment start, starting dose, dose change, most stable (longest duration) dose, and reasons for discontinuation. Kaplan-Meier estimates of HU discontinuation rates over time were reported.Results: 755 patients from 50 oncology/hematology practices who had HU as first-line cytoreductive therapy were included in this study. Most (65.4%) of the patients were diagnosed within the 3 years preceding the end of study period (ie, September 15, 2016). Mean (SD) age was 68.6 (11.5) years; 50.9% of patients were female. The median time from diagnosis to HU initiation was 0.3 months, and from HU initiation to the end-of-study follow-up (the most recent visit) was 20.2 months. The most frequent signs and symptoms at HU initiation were fatigue (48.6%), headache (16.0%), and splenomegaly (12.7%). The median duration of HU was 18.6 months, with 81.1% still on HU at the end of study period. The mean (SD) starting dose and stable dose were 1024.2 (522.3) mg/d and 1388.9 (726.5) mg/d, respectively. Only a small proportion (17.8%) of patients received HU doses >2000 mg/d. At the most recent visit, 27.6% of HU users had ≥1 ET symptom, with 20.3% reporting fatigue; 36.8% and 9.0% of patients had platelet counts ≥400 × 109/L and white blood cell (WBC) counts ≥10 × 109/L, respectively. 33 patients (4.4%) had died by the end of study period, with heart attack (n=10 [30.3%]) and hematologic malignancy (n=9 [27.3%]) being the most common causes of death.82 patients (10.9%) discontinued first-line HU treatment during the median follow-up of 20.2 months from HU initiation. Kaplan-Meier estimates of 1-, 3-, and 5-year discontinuation rates were 5.8%, 14.5%, and 20.7%, respectively. Among patients who discontinued, the median duration of HU treatment was 13.1 months. The most common physician-reported reasons for HU discontinuation were intolerance (35.4%), resistance (23.8%), progression to acute myeloid leukemia (9.8%), and progression to myelofibrosis (7.3%). At the most recent visit, 48.8% of patients who discontinued HU had ≥1 ET symptom; 51.9% and 33.8% had platelet counts ≥400 × 109/L and WBC counts ≥10 × 109/L, respectively; and 6.1% had ≥1 thrombotic event. In contrast, 25.0% of patients who continued HU had ≥1 ET symptom, with 18.7% reporting fatigue; 35.5% and 12.9% of patients had platelet counts ≥400 × 109/L and WBC counts ≥10 × 109/L, respectively. Upon HU discontinuation, 3.6% reinitiated HU at a later time, 36.6% used another cytoreductive therapy (anagrelide or ruxolitinib), and 59.8% did not receive any further treatment.Conclusions: The HU discontinuation rate among patients with ET increased over time, with a rate of 14.5% at 3 years. Intolerance or resistance were the primary reported reasons for discontinuation of HU. Almost two-thirds of patients with ET did not receive further treatment after HU discontinuation. A substantial proportion of patients who continued HU treatment still had elevated blood counts and symptoms. These patients may benefit from alternative management strategies. DisclosuresYu:Incyte Corporation: Employment, Equity Ownership. Colucci:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Sivaraman:Incyte Corporation: Employment, Equity Ownership. Atanasov:Incyte Corporation: Consultancy. Hanna:Incyte Corporation: Consultancy. Tang:Incyte Corporation: Consultancy. Parasuraman:Incyte Corporation: Employment, Equity Ownership.

The Impact of Hydroxyurea on Survival and Risk of Thrombosis Among Older Patients with Essential Thrombocythemia

Introduction: Patients with essential thrombocythemia (ET) are at greater than 20% risk for thrombotic complications. They are categorized into high- and low-risk groups based on the presence of advanced age (> 60 years) and / or thrombosis history. One of the main goals of ET treatment is thrombosis prevention. Use of hydroxyurea (HU) among high-risk ET patients improves rate of thrombosis and is the frontline guideline-recommended therapy for older patients. Little is known about HU impact on the survival and thrombosis in the real-world setting.Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified patients diagnosed with ET (International Classification of Diseases for Oncology, 3rd edition, code 9962) from 2007-2011. Patients were required to: 1) be aged 66-99 years; 2) have continuous enrollment in Medicare Parts A and B from one year before diagnosis to death or the end of study (12/31/2012); and 3) have continuous Part D six months before diagnosis to the end of follow-up to capture HU use. HU users were restricted to those who had more than two HU prescription claims. HU coverage was calculated as the percentage of days from diagnosis to the end of follow-up covered by HU prescriptions. Thrombotic events were defined as first occurrence of venous thrombosis, arterial thrombosis, or sudden death after diagnosis. Predictors of receiving HU were evaluated using multivariate logistic regression models. Multivariable Cox proportional hazard regression models were utilized to assess the impact of HU on survival and thrombotic events, controlling for patient age at diagnosis, sex, race, Part D low income subsidy (a proxy marker for lower socioeconomic status), influenza vaccination 12 months prior to diagnosis (an indicator for health care access), disability status (a claims-based proxy for poor performance status), modified Elixhauser comorbidity score (the original comorbidity score excluding cardiovascular conditions), and pre-existing cardiovascular conditions. HU was treated as a time-dependent variable in the Cox model.Results: A total of 654 high-risk ET patients with a mean age of 79.0 (standard deviation =7.4) years were included in the study, of which 67.9% were women and 85.5% were white. The median duration of follow-up was 2.5 years. In this large sample of older patients, only 59.2% of the patients received HU after ET diagnosis. Results of multivariate logistic regression models showed that patients with comorbidities (p<.01), with pre-existing cardiovascular conditions (p=.05), or disabled (p<.01) were less likely to receive HU. At the end of follow-up, 26.6% (n=103) HU users and 58.8% (n=157) non-users died. The median survival for HU non-users was 2.53 years, while it was not reached for HU users (log-rank test, p<.01, Figure 1). In the multivariate Cox model, HU usage after diagnosis was associated with a significantly lower risk of death (hazard ratio [HR]=0.42, 95% confidence interval [CI]: 0.32-0.54, p<.01). Every 10% increase of HU coverage was associated with a 16% decreased risk of death (HR=0.84, 95% CI: 0.81-0.88, p<.01). A total of 235 (35.9%) patients had thrombotic events after diagnosis, including 180 arterial thromboses, 54 venous thromboses and 1 sudden death. Thrombotic events occurred in 25.3% (n=85) HU users and nearly half of the HU non-users (47.2%, n=150). The median time to develop thrombosis was not reached for HU users and was significantly longer than for HU non-users (2.12 years, log-rank test, p<.01, Figure 2). In the multivariate model, compared with non-users, HU users had a significantly lower risk of thrombotic events (HR=0.51, 95% CI: 0.38-0.68, p<.01). Every 10% increase of HU coverage was associated with a 13% lower risk of thrombotic events (HR=0.87, 95% CI: 0.84-0.91, p<.01). Sensitivity analyses, which only included patients who survived more than 6 months, showed similar association between use of HU, improved survival and decreased incidence of thrombotic events.Conclusions: To our knowledge, this is the first study to evaluate association between HU and survival among high risk ET patients. Use of HU was associated not only with improved overall survival but also with reduced incidence of thrombotic events in older ET patients. HU was underutilized in the studied high risk ET population, including patients with pre-existing cardiovascular conditions who need the drug the most. [Display omitted] DisclosuresPodoltsev:Incyte: Consultancy; CTI biopharma/Baxalta: Consultancy; Alexion: Consultancy; Ariad: Consultancy. Zeidan:Otsuka: Consultancy; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau. Huntington:Celgene: Consultancy, Other: Travel; Janssen: Consultancy; Pharmacyclics: Honoraria. Ma:Incyte Corp.: Consultancy.

Essential Thrombocythemia in a 15-Year-Old Female: Presentation, Workup, and Treatment Considerations in the Pediatric Population.

Essential thrombocythemia (ET) is a diagnosis most often seen in adults but can also present in children in rare cases. This article reviews the presentation, diagnosis, and treatment of ET in a 15-year-old female followed by a review of the literature regarding special considerations in the workup, diagnosis, treatment, and follow-up of ET in the pediatric population.

What factors determine the pregnancy outcome in patients with essential thrombocythemia?

Objectives: Treatment of essential thrombocythemia (ET) is particularly challenging in pregnancy due to the increased risk of thromboembolic complications. Therefore, the use of antithrombotic regimens are recommended in pregnant women with ET. Methods: The study included 52 pregnancies in 27 patients diagnosed with ET, who were treated in Department of Haematology. The influence of anticoagulant, antiplatelet and cytoreductive therapy on the course and outcome of pregnancy was analysed. This study also examined if there was any correlation between molecular and clinical features such as mutational profile, blood count, presence of acquired von Willebrand syndrome (AvWS), the International Prognostic Score for Essential Thrombocythemia (IPSET) risk group and the IPSET-thrombosis risk group and pregnancy outcome. Results: Study participants who received antithrombotic therapy were significantly more likely to give birth to a healthy child. The best outcomes were observed in patients who received low dose acetylsalicylic acid (ASA) together with low-molecular-weight heparin (LMWH). There was a statistically significant correlation between classification to the high-risk group according to the IPSET-thrombosis score and incidence of miscarriage. Cytoreductive treatment with interferon-α2, as well as the presence of AvWS did not increase the likelihood of pregnancy loss. Blood counts and presence of specific gene mutations profile were also not found to be significant determinants of pregnancy outcome. Conclusion: To our best knowledge, this is the first clinical study investigating the correlation between risk group (according to IPSET and IPSET-thrombosis) and pregnancy outcome in women with ET.

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study.

Lack of demonstrable mutations affecting JAK2, CALR, or MPL driver genes within the spectrum of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5–10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the TET2 gene (55.0%), followed by KIT (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.

Treatment of Essential Thrombocythemia with Anagrelide Is Associated with an Increased Risk of Worsened Kidney Function

Background and Purpose: When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. Experimental Approach: The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. Key Results: A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m² [interquartile range (IQR) (−4)–(+7)] in the HU group vss. median −13 mL/min/1.73 m² [IQR (−18)–(−6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17–15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m² occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21–3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). Conclusions and Implications: The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.

State-of-the-art management for essential thrombocythemia and polycythemia vera

Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN), wherein JAK2 V617F mutation exists as a common driver mutation, and the JAK-STAT pathway is constitutively activated. The treatment goal for ET and PV is the prevention of thrombosis and bleeding. The treatment strategy for ET is careful observation or antiplatelet therapy with or without cytoreductive therapy based on the thrombotic risk. The treatment strategy for all PV patients is phlebotomy with a target hematocrit of <45% in addition to antiplatelet therapy. Moreover, for patients at a high risk of thrombosis, additional cytoreductive therapy is considered beneficial. In this session, we discuss important points for ET diagnosis, thrombotic risk stratification, and the details of treatment strategy and current practice with evidence from clinical trials in ET. Furthermore, current topics in the treatment of ET and PV will be introduced with a focus on clinical data about interferon-α, which is reported to induce not only hematologic response but also molecular and histopathologic response in MPN.