High-risk Essential Thrombocythemia Research Articles

Treatment comparison of hydroxyurea versus ruxolitinib in essential thrombocythaemia: A matched-cohort analysis.

Hydroxyurea is the preferred first-line cytoreductive treatment for high-risk essential thrombocythaemia (ET), but many patients are intolerant or refractory to hydroxyurea. Ruxolitinib has been shown to improve symptoms in patients with ET. This post hoc analysis compared the clinical outcomes of patients with ET who received hydroxyurea only with those who switched from hydroxyurea to ruxolitinib due to intolerance/resistance to hydroxyurea. Patients with ET refractory/intolerant to hydroxyurea treated with ruxolitinib in a completed phase 2 study (HU-RUX) were propensity score matched with patients who received hydroxyurea only in an observational study (HU). Changes in leukocyte and platelet counts were reported at 6-month intervals during the 48-month follow-up. Following propensity score matching, 37 patients were included for analysis in each cohort. Mean (standard deviation [SD]) leukocyte and platelet counts at index were higher for HU-RUX versus HU (leukocyte: 9.3 [5.1] vs. 6.8 [3.1]×109/L; platelet: 1027.4 [497.8] vs. 513.9 [154.7]×109/L), both of which decreased significantly from index to 6 months through to 48 months in HU-RUX (mean [SD] change from index at 6 months-leukocyte: -1.8 [4.6]×109/L; platelet: -391.7 [472.9]×109/L; at 48 months-leukocyte: -3.8 [5.3]×109/L; platelet: -539.0 [521.8]×109/L), but remained relatively stable in HU (mean [SD] change from index at 6 months-leukocyte: 0 [1.8]×109/L; platelet: -5.7 [175.3]×109/L; at 48 months-leukocyte: -0.1 [2.7]×109/L; platelet: -6.9 [105.1]×109/L). In conclusion, these results demonstrate that switching from hydroxyurea to ruxolitinib in patients with ET who are intolerant or refractory to hydroxyurea could improve abnormal haematologic values similar to those who receive first-line hydroxyurea.

Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: Preliminary results from MANIFEST study.

7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 109/L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), WBC count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]

A multicenter, open-label study for efficacy and safety evaluation of anagrelide in patients with treatment-naïve, high-risk essential thrombocythemia as a primary treatment.

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg - 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.

Patient-reported outcomes of patients with myelofibrosis or essential thrombocythemia enrolled in the MOST study

The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) is an ongoing, noninterventional study assessing clinical characteristics and patient-reported outcomes (PROs) of patients with myelofibrosis (MF) or essential thrombocythemia (ET). This analysis assessed PROs at enrollment; symptom burden and quality of life (QoL), work productivity, and activity were assessed using validated questionnaires in patients with low- or intermediate-1-risk (age-alone) MF, or high- or low-risk ET (receiving ET-directed therapy) at enrollment. In MF and ET cohorts, fatigue had highest mean symptom score. Women had higher mean total symptom scores (TSS), mean symptom scores, and reduced QoL versus men. In patients with MF, mean TSS and symptom scores were similar between risk groups. Patients with low-risk ET had higher mean TSS and symptom scores than patients with high-risk ET. In conclusion, patients with lower risk MF and low- or high-risk ET experience significant symptom burden affecting QoL and ability to work.

Anagrelide in essential thrombocythemia: Efficacy and long-term consequences in young patient population

According to the current treatment recommendations, anagrelide, an oral antiplatelet agent, is recommended as a second-line therapy for patients with high-risk essential thrombocythemia experiencing intolerance or refractoriness to first-line approach, such as hydroxyurea or pegylated interferon alpha-2a. If there is a need for introduction of cytoreductive treatment in young patients with a perspective of lifelong exposure, both the efficacy and long-term outcomes should be known. We present the analysis of 48 young patients, diagnosed with essential thrombocythemia below the age of 60, who were exposed to anagrelide treatment for over 10 years. Our observations show that the highest proportion of complete remissions without adverse events and disease progression is seen in the JAK2-mutated patients. By evaluating the changes in hemoglobin concentration and serum erythropoietin throughout the study, we were able to reveal the development of progressive anemia, resulting from diminished susceptibility to erythropoietin and unrelated to bone marrow fibrosis, in patients harboring CALR mutation. Additionally, occurrence of new bone marrow fibrosis was confirmed in seven JAK2-unmutated patients at the end of the study. In summary, in young patient population, we recommend limiting the use of anagrelide to JAK2-mutated subgroup, reducing exposure time and underline the importance of periodic monitoring for the presence of bone marrow fibrosis.

SURPASS-ET: phase III study of ropeginterferon alfa-2b versus anagrelide as second-line therapy in essential thrombocythemia.

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerabilityand pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.

Anagrelide for platelet-directed cytoreduction in polycythemia vera: Insights into utility and safety outcomes from a large multi-center database

Anagrelide (ANA) is a platelet-specific cytoreductive agent utilized in the guideline-directed management of high-risk essential thrombocythemia. In the context of polycythemia vera (PV), ANA is occasionally employed in clinical practice, although data has not consistently demonstrated a benefit to targeting a platelet goal as a therapeutic endpoint. The aim of the current study was to delineate the patterns of ANA use in PV, and to describe outcomes and toxicities. Within a multi-center cohort of 527 patients with PV, 48 received ANA (9 excluded for absent data). 27 (69.2%) had high-risk PV, 10 (25.6%) had prior thrombosis, and none had extreme thrombocytosis, acquired von Willebrand disease, and/or documented resistance to hydroxyurea. While ANA effectively lowered median platelet count, 43.5% of patients had an unresolved thrombocytosis at time of ANA discontinuation. Treatment-emergent adverse events—including headaches, cardiac palpitations and arrhythmias, nausea, vomiting and/or diarrhea—led to ANA discontinuation in 76.9% of patients. Further, three patients experienced arterial thromboses during a median duration of 27.5 months of ANA therapy. In conclusion, this study highlights ANA’s restrictive tolerability profile which, compounded by the absence of clear advantage to strict platelet control in PV, suggests the use of ANA should be limited in this setting.

What's new in myeloproliferative neoplasia?

Treatment of myeloproliferative neoplasia (MPN) is based on patients' individual risk-stratification and includes cytoreductive agents for high-risk essential thrombocythemia (ET), polycythemia vera (PV) and Myelofibrosis (MF). Classical cytoreductive drugs largely fail to modify the basic clonal composition of the disease. In contrast, in PV for example treatment with Ropeg-Interferon not only results in higher hematological response rates compared to hydroxyurea but in addition significantly reduces JAK2 allele-burden in high-risk PV patients as well as it depletes concurrent cytogenetic and molecular abnormalities. Treatment with Ropeg-Interferon so far is only approved for high-risk PV. A very recent trial however also demonstrated this disease-modifying effect also in low-risk PV patients in addition to an increased rate of transfusion independence. Thus, Ropeg-Interferon is the current standard for first line treatment of high-risk PV and we assume that the data in low-risk PV will lead also to a broader clinical use of Ropeg-Interferon this particular patient group, as it may decrease transformation to MF or even MPN-blast crisis.Myelofibrosis management has been extended by novel JAKi. Fedratinib is the first second generation JAK-inhibitor approved for Ruxolitinib-intolerant or refractory patients. Fedratinib reduces both spleen volume as well as symptom burden. Two other second generation JAK-inhibitors are in clinical development for MPN treatment. Pacritinib has demonstrated efficacy in reducing both spleen volume and symptom score in MF including a cohort of Ruxolitinib-pretreated patients and Momelotinib is the only JAK-inhibitor which has been shown to alleviate anemia in addition to its effect on improving spleen volume and symptom. So far, neither Pacritinib nor Momelotinib are currently EMA-approved for MPN treatment.Finally, it has recently been acknowledged that inflammation is a key driver of MPN pathogenesis. Both, mutated as well as non-clonal inflammatory and other stromal cells produce significant amounts of local cytokines. Also the initiation of the neoplastic process itself seems to depend on inflammatory cytokines. Recent scRNASeq data revealed components of the alarmin complex (S100A8 und S100A9) drive this local sterile inflammation process, which also represents a potential therapeutic target, as the S100A8 and A9 inhibitor Tasquinimod reduced fibrosis in a pre-clinical animal model.

Thrombotic events and mortality risk in patients with newly diagnosed polycythemia vera or essential thrombocythemia

Patients with polycythemia vera (PV) and essential thrombocythemia (ET) have increased thrombotic risk. This retrospective, real-world analysis of Medicare patients (age ≥ 65 years) newly diagnosed with high-risk PV or intermediate-/high-risk ET compared mortality risk among those with versus without thrombotic events during the study period. Patients diagnosed with PV or ET with ≥ 1 inpatient or ≥ 2 outpatient claims (January 1, 2010–December 31, 2017; index was date of first qualifying claim) were included. The study included 50,405 Medicare beneficiaries with PV and 124,569 with ET. During follow-up (median [range]: PV, 34.5 [0–97.3] months; ET, 25.5 [0–97.4] months), 14,334 patients (28.4%) with PV and 30,478 (24.5%) with ET experienced thrombotic events (most commonly ischemic stroke [PV, 46.0%; ET, 42.5%]. Mortality risk was increased for patients with versus without post-index thrombosis for both PV (adjusted hazard ratio [aHR; 95% CI], 18.6 [16.1–21.6]; P < 0.001) and ET (aHR [95% CI], 25.2 [23.1–27.5]; P < 0.001). Median survival was shorter for patients who experienced a thrombotic event ≤ 1 year post-index versus those who did not (PV, 5.1 years vs not reached; ET, 3.7 vs 6.7 years; both P < 0.001). These findings highlight the importance of thrombosis risk mitigation in PV and ET management.

Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials

Patients with essential thrombocythaemia or polycythaemia vera have several symptoms that can worsen their quality of life. We aimed to assess how symptom burden changes over time with cytoreductive therapy. We performed a post-hoc analysis of data from MPN-RC 111-a single-arm, open-label, phase 2, multicentre trial at 17 hospitals and cancer centres in Italy and the USA, evaluating the clinical-haematological response to pegylated interferon alfa-2a in patients who were resistant or intolerant to hydroxyurea (NCT01259817)-and MPN-RC 112-a randomised, open-label, phase 3, multicentre trial at 25 hospitals and cancer centres in France, Germany, Israel, Italy, the UK, and the USA, comparing the clinical-haematological response to pegylated interferon alfa-2a versus hydroxyurea in therapy-naive patients with either high-risk essential thrombocythaemia or polycythaemia vera (NCT01258856). Patients completed the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire through 12 months after initiation of treatment as secondary endpoints. In this post-hoc analysis, we examined the association of symptom burden with the clinical-haematological response at 12 months and the effect of baseline symptom burden (ie, high burden [total symptom score ≥20] vs low burden [total symptom score <20]) on subsequent changes in symptoms, estimated via mixed models. A clinically significant improvement in symptom burden was defined as 50% or greater improvement in the MPN-SAF total symptom score from baseline to 12 months in patients with a total symptom score greater than zero at baseline. 135 patients were enrolled in MPN-RC 111 between Feb 15, 2012, and Dec 23, 2015, and 168 were enrolled in MPN-RC 112 between Sept 24, 2011, and June 30, 2016. For this analysis, we included data from 114 patients from MPN-RC 111 (64 [56%] with essential thrombocythaemia and 50 [44%] with polycythaemia vera; 56 [49%] were female, and 100 [91%] of 110 were white) and 166 patients from MPN-RC 112 (79 [48%] with essential thrombocythaemia and 87 [52%] with polycythaemia vera; 68 [41%] were female, and 145 [93%] of 156 were white). At 12 months, a clinically significant improvement in symptom burden was reported by 12 (32%) of 38 complete responders and seven (20%) of 35 partial responders treated with pegylated interferon alfa-2a in MPN-RC 111; five (19%) of 27 complete responders and six (18%) of 34 partial responders treated with pegylated interferon alfa-2a in MPN-112; and eight (27%) of 30 complete responders and six (22%) of 27 partial responders treated with hydroxyurea in MPN-112. More complete and partial responders reported a clinically significant improvement than did non-responders (44 [22%] of 191 complete and partial responders vs four [5%] of 76 non-responders; Fisher's exact p=0·0003). Symptom burden improved between 3 and 12 months in patients with high baseline symptom burden, both those treated with pegylated interferon alfa-2a (mean total symptom score change -10·2, 95% CI -13·2 to -7·2) and those treated with hydroxyurea (-6·8, -11·2 to -2·4). However, symptom burden worsened between 3 and 12 months in patients with low baseline symptom burden (patients treated with pegylated interferon alfa-2a: mean total symptom score change 3·2, 95% CI 0·9 to 5·4; patients treated with hydroxyurea: 3·4, 0·6 to 6·2). Results can inform treatment decisions, including treatment timing and goals in managing essential thrombocythaemia and polycythaemia vera, because measuring symptom burden from the patient perspective is crucial to understanding treatment efficacy and tolerability. US National Cancer Institute of the National Institutes of Health, and Roche Genentech.

Surpass-ET Trial: A Phase 3, Open-Label, Multicenter, Randomized, Active-Controlled Study to Assess Pharmacokinetics and Compare the Efficacy, Safety, and Tolerability of P1101 Vs Anagrelide As Second Line Therapy for Essential Thrombocythemia

▪Background: Essential thrombocythemia (ET) is a subtype of chronic myeloproliferative neoplasms (MPN) characterized by thrombocytosis and disease-related symptoms, which may be difficult to manage. Patients with ET are also at higher risk of thrombosis and hemorrhage. Ideal therapeutic approaches should achieve adequate cytoreduction, reduce the risk of thrombo-hemorrhagic complications, and prevent progression to post-ET myelofibrosis (PET-MF) or secondary acute myeloid leukemia (AML). Low-dose aspirin with hydroxyurea (HU) is typically given as first-line therapy in high-risk patients. However, approximately 20-40% of ET patients become HU-intolerant or -resistant. In ET, resistance and/or intolerance portend an increased risk of thrombosis, hemorrhage, disease transformation and death. There is a paucity of prospective clinical trial data to guide management of ET patients who are HU resistant or intolerant. P1101 is a next generation monopegylated interferon (IFN) alfa-2b, developed specifically to treat MPNs, including ET.Study Design and Methods: The SURPASS-ET trial (NCT04285086) is a Phase 3, open-label, multicenter, randomized, active-controlled study to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of P1101 after 12 months of treatment compared with anagrelide as second line therapy for subjects with ET who have shown resistance or intolerance to HU. The primary endpoint is durable modified ELN composite response at 9 and 12 months from dosing. Cochran-Mantel-Haenszel test will be used for comparing the primary endpoint in the two treatment arms. The PK parameters of P1101, including (but not limited to) C min, T max, C max, and area-under-curve (AUC) will be derived using PPK analysis and the relationship between exposure and efficacy and safety endpoints will be examined using E-R analysis. Evaluation of efficacy will include clinical laboratory assessments, allelic burden measurements of CALR, JAK2, and MPL, spleen size measurements, bone marrow sampling (optional), EQ-5D-3L, and MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) assessments.A total of 130 randomized subjects is planned to detect a difference of 40% (P1101) versus 15% (anagrelide) in durable ELN response rate with 90% power at alpha level = 0.05 using the chi-square test. To account for possible non-evaluability (e.g., no follow-up data), approximately 160 subjects will be randomized in this study to get 130 completed patients. Because of uncertainty in the assumptions on which the calculation of the sample size is based, an interim analysis for sample size adjustment will be implemented.Major inclusion criteria include subjects diagnosed with high-risk ET (either older than 60 years and JAK2V617F-positive at screening or having disease-related thrombosis or hemorrhage in the past), diagnosed according to the World Health Organization (WHO) 2016 criteria, documented resistance/intolerance to HU and IFN naïve or anti-P1101 binding antibody negative. Key exclusion criteria include pregnant females, significant cardiovascular disease, documented autoimmune disease and a history or presence of clinically significant depression or neurological disease.The study involves approximately 65 sites across the US, Taiwan, Japan, China, Hong Kong, Singapore, S. Korea, Canada, and Europe. To-date 55 patients (54 Asians, 1 Caucasian) have been randomized. The mean and median age at recruitment was 58.9 years (SD: 14.34) and 63 years (range 21 to 80 years) respectively. Twenty-seven men (49.1%) and twenty-eight women (50.9%) were recruited. Forty-two subjects (76.4%) had a TSS < 20. The study is being overseen by a Data Safety Monitoring Board (DSMB). [Display omitted] DisclosuresMesa: Gilead: Research Funding; Promedior: Research Funding; AOP: Consultancy; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; La Jolla Pharma: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy, Research Funding; Samus: Research Funding; Pharma: Consultancy; CTI: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; CTI: Research Funding. Komatsu: Fujifilm Wako Pure Chemical Corporation: Research Funding; Fuso Pharmaceutical Industries, Ltd.: Research Funding; Japan Tobacco Inc.: Consultancy; Otsuka Pharmaceutical Co. Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma KK: Consultancy, Research Funding, Speakers Bureau; Shire Japan KK: Consultancy, Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Consultancy, Current Employment, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Sato: PharmaEssentia Japan KK: Current Employment. Qin: PharmaEssentia Corp.: Current Employment. Urbanski: PharmaEssentia Corporation: Current Employment. Shih: PharmaEssentia Corporation: Consultancy. Zagrijtschuk: PharmaEssentia U.S.A. Corp.: Current Employment. Zimmerman: PharmaEssentia Corporation: Current Employment. Verstovsek: Gilead: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Ital Pharma: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

The Approach to Thrombosis Prevention across the Spectrum of Philadelphia-Negative Classic Myeloproliferative Neoplasms

Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of hematopoietic insufficiency, and disturbing symptoms such as pruritus, night sweats, and bone pain. In patients with essential thrombocythemia (ET) or polycythemia vera (PV), current guidelines recommend both primary and secondary measures to prevent thrombosis. These include acetylsalicylic acid (ASA) for patients with intermediate- or high-risk ET and all patients with PV, unless they have contraindications for ASA use, and phlebotomy for all PV patients. A target hematocrit level below 45% is demonstrated to be associated with decreased cardiovascular events in PV. In addition, cytoreductive therapy is shown to reduce the rate of thrombotic complications in high-risk ET and high-risk PV patients. In patients with prefibrotic primary myelofibrosis (pre-PMF), similar measures are recommended as in those with ET. Patients with overt PMF may be at increased risk of bleeding and thus require a more individualized approach to thrombosis prevention. This review summarizes the thrombotic risk factors and primary and secondary preventive measures against thrombosis in MPN.

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.

Single-Arm Phase II Trial of Pegylated Interferon Alpha 2a in Patients with High-Risk Essential Thrombocythemia or Polycythemia Vera Resistant or Intolerant to Hydroxyurea: MPN Symptom Impact & Quality of Life Results of the Myeloproliferative Disorders-Research Consortium (MPD-RC) Protocol 111 Global Phase II Trial

Abstract Background: Resistance or intolerance to hydroxyurea (HU) in highrisk essential thrombocythemia (ET) or polycythemia vera (PV) leaves clinicians with few treatment options other than anagrelide (ET) or ruxolitinib (PV). Historical data on pegylated interferon alpha 2a (PEG) has been favorable in ET and PV, but reports of its use in HU-resistant and -intolerant patients have been anecdotal. We initiated a large phase II trial to better characterize the impact of second-line PEG therapy in these patients and focus on impact on symptom burden and quality of life (QOL). Methods: MPD-RC 111 trial (NCT01259817) enrolled HU-resistant or -intolerant (modified European LeukemiaNet [ELN] criteria) patients with high-risk ET or PV to receive response-adjusted PEG. Patients were assessed for MPN symptoms, treatment toxicities, and QOL using the MPN-SAF, EORTC QLQ-C30, and 5 exploratory PEG-related side effect questions at baseline and 3, 6, 9, and 12 months. Within-group change and between-group differences over time were based on mixed models adjusting for age. T-tests compared baseline scores among groups. ANCOVA adjusting for baseline scores compared 12-month scores between patients with complete hematologic response (CR) by ELN criteria versus those with partial/no response. Results: Patients: MPD-RC 111 enrolled 115 patients from 02/2012 to 12/2015. 114 (ET 64, 56%; PV 50, 44%), 104, 92, 81, and 74 patients completed surveys at baseline and 3, 6, 9, and 12 months. Survey completion rates did not differ between ET and PV. Among 114 patients with baseline surveys, median age was 64 years (range 20-85) with 56 (49%) females; 8 (7%) had prior splenectomy; and 40 (35%) had splenomegaly. Among 107 with known mutation status, 68 (64%) had JAK2 mutations and 23 (21%) had CALR mutations. Baseline Symptom Burden/QOL: Mean MPN-SAF Total Symptom Score (TSS, scale 0 [absent]-100 [worst imaginable]) was 19.5 (SD 18.4; range 0-95) with means of 19.0 (SD 18.1) / 20.1 (SD 19.0) for ET / PV (p=0.76) which were similar to reported means of a previous cohort receiving any line of treatment (ET mean 18.7, SD 15.3; PV mean 21.8, SD 16.3; Emanuel RM, JCO 2012). Symptoms (scale 0 [absent]-10 [worst imaginable]) with the highest prevalence (score >0) included fatigue (106/114, 93%) and insomnia (74/114, 65%). The symptom with the lowest prevalence was fever (15/114, 13%). Mean QLQ-C30 global health status/QOL (GHS/QOL, scale 0 [very poor]-100 [excellent]) was 71.6 (SD 20.1) which is comparable to a general healthy population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). Baseline TSS and GHS/QOL did not significantly differ between ET and PV, nor between patients by mutational status (TSS 19.5 (17.0) JAK2 vs 14.9 (13.5) CALR, p=0.25; QOL 72.7 (20.0) JAK2 vs 68.1 (22.8) CALR, p=0.36). Impact of Therapy on Symptom Burden/QOL: Patients experienced statistically significant improvements from baseline in MPN-related symptoms including TSS, fatigue, dizziness, numbness/tingling, and weight loss (all p Conclusions: Second-line PEG in patients with high-risk ET or PV appears to improve certain MPN-related symptoms but does come with several relevant low-grade toxicities. Despite the mixed symptom picture PEG appears to not decrease QOL for those patients who are able to tolerate treatment. Extended PEG appears to be challenging for some patients given the observed high rate of treatment discontinuation due to adverse events and patient refusal. Further research is needed to better select patients who are likely to tolerate treatment. Download : Download high-res image (259KB) Download : Download full-size image Disclosures Mascarenhas: Novartis: Other: DSMB member , Research Funding; Janssen: Research Funding; Merck: Research Funding; CTI Biopharma: Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding; Promedior: Research Funding. Yacoub: Seattle Genetics: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Speakers Bureau; CTI: Consultancy; Sandoz: Consultancy; Incyte: Consultancy, Speakers Bureau. Berenzon: Incyte Corporation: Research Funding. Ritchie: Pfizer: Consultancy, Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; NS Pharma: Other: Research funding to my institution; Astellas Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau. Rambaldi: Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses; Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy. Vannucchi: Shire: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: Incyte Corporation: Research Funding; Ariad: Consultancy; Galena Biopharma, Inc.: Consultancy; Promedico: Research Funding; Celgene Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Gilead Sciences, Inc.: Research Funding; CTI BioPharma Corp.: Research Funding.

Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Essential Thrombocythemia Enrolled in the MOST Study

Few data exist regarding the disease and clinical characteristics of patients with essential thrombocythemia (ET) in the United States. The ongoing, multicenter, noninterventional, prospective, Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) was designed to collect data pertaining to the demographics, clinical management, and patient-reported outcomes in patients with myelofibrosis or ET in the United States (NCT02953704). This analysis examines the clinical characteristics of patients with clinical diagnoses of high-risk or low-risk ET receiving ET-directed therapy at enrollment. At data cutoff (June 17, 2019), 1207 of 1234 enrolled patients were eligible for this analysis (median age, 70 years; 65% female; 88% white); 917 patients (76%) had mutation testing results available. The median time from ET diagnosis to study enrollment was 4.2 years. The majority of patients (87%) had high-risk ET. Of 333 patients with a history of thrombotic events, 247 had at least 1 event classified as arterial and/or venous. Platelet count was above normal range in 54% of patients. Hypertension (56%) was the most common comorbidity. At enrollment, the majority of patients (low-risk ET, 94%; high-risk ET, 79%) were receiving ET-directed monotherapy. Additional prospective analyses from MOST will help to identify areas of unmet need.

Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations.

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Thrombotic Events and Mortality Risk in Patients Newly Diagnosed with Intermediate- to High-Risk Essential Thrombocythemia in the United States

Background Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) associated with an increased risk of thrombotic events (TEs), which represent a substantial cause of mortality in this population. There is limited contemporary, real-world evidence exploring the effect of TEs on mortality in patients with ET. The aim of this analysis was to compare risk of mortality among patients newly diagnosed with intermediate- or high-risk ET who experienced a TE vs those who did not experience a TE. Study Design and Methods All data from the Medicare Fee-for-Service (FFS) claims database (Parts A/B/D) from January 2010-December 2017 were used to identify patients with an ET diagnosis (all intermediate or high risk based on cohort age ≥65 years) with ≥1 inpatient or ≥2 outpatient claims. The index date was the date of the first qualifying ET claim. Patients with an ET diagnosis, use of hydroxyurea, or use of ruxolitinib within 12 months before the index date and patients with a myelofibrosis diagnosis during the study period were excluded. A minimum of 12 months of continuous medical and pharmacy enrollment pre-index was required. The study sample was categorized into TE and non-TE groups based on the occurrence of any of the following events during follow-up: deep vein thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, transient ischemic attack, peripheral arterial thrombosis, or superficial thrombophlebitis. TEs were evaluated from the index date to the end of follow-up. Cox regression analyses with time-varying effects were used to assess mortality risk among patients with ET with post-index TE as a time-dependent variable, stratified by pre-index TE, and adjusting for patient demographic characteristics and comorbid conditions. Results A total of 143,588 Medicare FFS beneficiaries with a diagnosis of ET met the study inclusion criteria; median age was 76.0 years, 68.1% were female, and 84.2% were white. Pre-index TE was reported in 37,284 patients (26.0%). In the follow-up period, 49,497 patients (34.5%) had a TE and 94,091 patients (65.5%) did not have a TE. In the comparison between the TE vs non-TE groups, the median (range) age (77 [65-107] vs 75 [65-110] years, respectively), mean (SD) Charlson comorbidity index score (4.8 [3.5] vs 3.8 [3.5]), and percentage of patients with a history of bleeding (27.0% vs 22.2%), anemia (64.7% vs 55.9%), or a cardiovascular event (45.8% vs 33.5%) were higher (Table 1). The median time from ET diagnosis to first TE in the follow-up period was 2.8 months for all patients, 0.5 months for patients with pre-index TE, and 8.0 months for those without pre-index TE. The most common types of first TE in the follow-up period were ischemic stroke (37.3%), acute myocardial infarction (23.2%), and transient ischemic attack (22.6%). The risk of mortality was increased for patients who experienced a TE compared with those who did not (hazard ratio [HR; 95% CI], 11.2 [10.6-11.8]; P&amp;lt;0.001), including for both those with pre-index TE (HR [95% CI], 9.3 [8.6-10.1]; P&amp;lt;0.001) and those without pre-index TE (HR [95% CI], 15.4 [14.2-16.8]; P&amp;lt;0.001). Conclusions In this contemporary, real-world analysis, approximately one-third of patients with newly diagnosed intermediate- to high-risk ET experienced a TE. Elderly patients with ET who experienced a TE had an approximately 11-fold increased risk of mortality vs those who did not experience a TE, highlighting a continued unmet need in this population. Further efforts are needed to better define and mitigate TE risk in patients with ET, particularly in those with prior TE. Disclosures Pemmaraju: Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Plexxikon: Research Funding; Blueprint Medicines: Honoraria; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Roche Diagnostics: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; MustangBio: Honoraria; Celgene: Honoraria; DAVA Oncology: Honoraria; SagerStrong Foundation: Other: Grant Support. Gerds:Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; AstraZeneca/MedImmune: Consultancy; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding. Yu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Xi:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Kumar:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding.

Interferon alpha for essential thrombocythemia during 34 high-risk pregnancies: outcome and safety.

Pregnancies in women with essential thrombocythemia (ET) are at a higher risk for obstetrical complications. Acetylsalicylic acid (ASA) and low-molecular weight heparin (LMWH) are common options to prevent miscarriages and maternal complications, whereas interferon alpha (IFN) seems to be the cytoreductive therapy of choice. This retrospective study analyzes the largest number of IFN pregnancies to date in terms of outcome and safety. Data of 34 high-risk pregnancies in 23 women presenting at the University hospitals of Minden and Jena from 01-Jun-2007 to 01-Jun-2020 were collected. Reasons defining high-risk ET pregnancy in all 23 patients were: Thrombosis (n = 9) or severe hemorrhage (n = 2) in history, platelet count ≥ 1500 × 103/µl (n = 8) or severe microcirculatory disturbances not completely responding to ASA (n = 4). Without the use of IFN, live birth rate was 60% (6/10), however, after the use of IFN live birth rate increased to 73.5% (25/34 pregnancies). Nine pregnancies ended in miscarriages (9/34; 26.5%); all of them spontaneous abortions. Live birth rate significantly improved with ASA (90% versus 50%, p = 0.0168), however, if ASA and LMWH was added (n = 14), live birth rate was 100%. IFN compound (PEGylated versus standard IFN) and JAK2-driver mutation had no impact on pregnancy outcome. One major maternal complication occurred as a major peripartal bleeding after abortion curettage. IFN was associated with an encouraging live birth rate of 73.5% with no fatal maternal events and manageable side effects.