Agrylin (anagrelide) / Takeda - LARVOL DELTA

Identification and enrichment of a UV-induced degradant of Anagrelide drug substance. (PubMed, J Pharm Biomed Anal) - "Following isolation by prep-HPLC, 1D and 2D NMR studies and HRMS characterization assigned the products as a pair of 5-hydroxy-Anagrelide (5-OH-ANG) enantiomers. A plausible mechanism of formation is proposed."

Journal • Essential Thrombocythemia • Hematological Disorders • Myeloproliferative Neoplasm • Oncology • Thrombocytosis

A Phase 2 Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Essential Thrombocythemia (ET) (ASH 2021) - P2 | "Many patients with ET are resistant to or intolerant of current standards of care (SOC) - hydroxyurea (HU), interferon, anagrelide - underscoring the need for novel therapies with distinct modes of action that reduce the risk of thrombosis, improve the patient’s experience and favorably alter the natural history...Baseline median age was 68 (42-84) years with 33% males; 77% were resistant to or intolerant of HU, 10% to anagrelide, 7% to interferon, and 3% each to busulfan and ruxolitinib...The mutation burden remained stable despite high molecular risk mutations. Based on this promising data, a Phase 3 study of bomedemstat for the treatment of ET is being planned."

P2 data • Cardiovascular • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Myeloproliferative Neoplasm • Pulmonary Embolism • Respiratory Diseases • Thrombocytopenia • Thrombocytosis • ASXL1 • CALR • JAK2 • SF3B1 • TMB • TP53

[VIRTUAL] A PHASE 2 STUDY OF THE LSD1 INHIBITOR IMG-7289 (BOMEDEMSTAT) FOR THE TREATMENT OF ESSENTIAL THROMBOCYTHEMIA (ET) (EHA 2021) - P2 | "Background For patients with essential thrombocythaemia (ET) intolerant of or resistant to hydroxyurea (HU), interferon or anagrelide, there is a need for therapies with distinct MOAs that reduce thromboses, improve the patient experience and potentially offer distinct clinical benefits...60% were deemed resistant to or intolerant of HU (by ELN criteria), 20% to anagrelide and 10% to interferon or busulfan...Conclusion In this first clinical study of an LSD1 inhibitor in ET patients, IMG-7289 as monotherapy was generally well-tolerated, reduced platelets in all patients, moderated WBC counts, improved symptom scores and maintained haemoglobin levels without safety signals. The study is active and enrolling in the US, UK, EU, Australia and New Zealand."

P2 data • Cardiovascular • Myelofibrosis • Pain • Thrombocytosis • Thrombosis • TMB

[VIRTUAL] A Young Woman with Thrombocytosis (SOHO 2020) - P2, P3 | "Although not included yet in formal risk stratification models, a number of studies have shown leukocytosis to be a risk factor for thrombosis in ET.18, 19, 20, 21 Young patients with ET without high risk features for thrombosis or bleeding (e.g., platelets > 1.5×109/L) do not need cytoreductive therapy and should be managed with low-dose aspirin alone.22 Acquired von Willebrand's disease (AVWD) can occur, particularly at high platelet counts, and aspirin should be stopped and cytoreductive therapy started if AVWD is found.23 Twice daily aspirin has been proposed for low-risk patients with cardiovascular risk factors, as well as for intermediate-risk patients, as an alternative to cytoreductive therapy,17 but the evidence for this is limited.24, 25 Twice daily aspirin can be useful to control the microvascular/vasomotor symptoms not adequately addressed by once daily aspirin.23 Young patients with CALR-mutated ET and no history of thrombosis should..."

Clinical • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Solid Tumor • CALR • JAK2 • SF3B1 • SRSF2 • TP53 • U2AF1

MAJOR OR CLINICALLY RELEVANT NON-MAJOR HEMORRHAGIC EVENTS IN A LARGE POPULATION OF PATIENTS WITH POLYCYTHEMIA VERA OR ESSENTIAL THROMBOCYTHEMIA: LOCALIZATION, CONSEQUENCES AND DRUG USE (EHA 2019) - P=N/A; "Regarding cytoreduction: 37.9% received hydroxycarbamide, 13.6% anagrelide, 12.1% pipobroman, 7.6% interferon alpha, 3.8% ruxolitinib, 3.9% combinations of cytoreductive. Particular localizations seemed problematic such as gastro-intestinal (high transfusion rates) and CNS (high rate of death). Risk factors for bleeding events are under study and should help guiding antithrombotic management."

Clinical

Treatment of Ropeginterferon Alpha-2b Achieves Hematologic Remission and Molecular Response in Patients with Hydroxyurea- and/or Anagrelide-Resistant/Intolerant Myeloproliferative Neoplasms (ASH 2021) - "Patients who are HU/anagrelide resistant/intolerant have limited options, as ruxolitinib is not subsidized by the national health insurance in Taiwan for PV. Hematologic remission was observed in ET and PV patients, whereas molecular response was observed in only PV patients, possibly due to the small sample size of ET patients. Our experience with Ropeg suggests it to be a promising option for the treatment of MPNs with drug-resistance/intolerance."

Clinical • Acute Myelogenous Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Mental Retardation • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Psychiatry • Thrombocytosis • Thrombosis • JAK2

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 (ASH 2021) - P3 | "Low-dose aspirin with hydroxyurea (HU) is typically given as first-line therapy in high-risk patients. Forty-two subjects (76.4%) had a TSS < 20. The study is being overseen by a Data Safety Monitoring Board (DSMB)."

Clinical • P3 data • PK/PD data • Acute Myelogenous Leukemia • Cardiovascular • Chronic Eosinophilic Leukemia • CNS Disorders • Depression • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Psychiatry • Thrombocytosis • Thrombosis • CALR • JAK2

Disease and Clinical Characteristics of Patients with Myelofibrosis Enrolled in the MOST Study (ASH 2019) - P=N/A; "Low-risk patients received hydroxyurea (HU; 23/43 [54%]), ruxolitinib (15/43 [35%]), interferon (4/43 [9%]), or anagrelide (1/43 [2%]); INT-1 patients received ruxolitinib (30/68 [44%]), HU (28/68 [41%]), interferon (8/68 [12%]), or anagrelide (2/68 [3%]). These real-world data provide insight into the clinical characteristics, diagnosis, and treatment patterns of patients with low- or INT-1 risk (by age alone) MF in the United States. Data from this trial will help characterize the rate at which patients transition from low- or INT-1-risk disease to higher risk categories of disease and how management is affected by disease progression."

Clinical • JAK2

Expansion of Prior Existing TP53 Mutated Clones in Polycythemia Vera Patients Treated with Idasanutlin (ASH 2019) - P2; "A global, phase 2 trial is currently underway evaluating idasanutlin in hydroxyurea (HU) resistant/intolerant PV patients (NCT03287245)...There was no clear association of presence of TP53 mutations with prior HU, anagrelide or interferon exposure...We recommend that patients be screened for TP53 mutations prior to treatment with an MDM2 antagonist and that if present the TP53 mutant VAF be followed during their treatment course. Resistance to MDM2 inhibition is likely dependent on the TP53 mutant VAF and further studies will need to clarify the ideal dosing schedule of MDM2 antagonists and/or combinatorial therapy to prohibit TP53 mutant clonal expansion."

Clinical • CD34 • TP53

Overall Survival in Patients with Myelofibrosis Who Have Discontinued Ruxolitinib: A Literature Review (ASH 2019) - "Median OS in patients who received treatment with salvage therapy or conventional agents (e.g. hydroxyurea, danazol, anagrelide) was typically around 14 months (14, 14, and 15 months in Mehra et al...2018); median OS was 19.9 and 29.9 months for imetelstat 4.7 mg/kg and 9.4 mg/kg, respectively... This literature review revealed that patients with MF generally experience poor OS after discontinuing ruxolitinib, especially in patients who receive no further treatments. Line of therapy definitions were rarely reported across studies, which may contribute to variations across study findings. In addition, survival estimates after prior ruxolitinib therapy varied depending on the treatment received and the reason for discontinuation of ruxolitinib."

Clinical

TRIAL IN PROGRESS: A PHASE III STUDY OF ASCIMINIB VS AN INVESTIGATOR-SELECTED TKI IN PATIENTS WITH NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) (EHA 2022) - P3 | "Methods This is a multicenter, open-label, randomized, phase III study (NCT04971226) of asciminib 80 mg once daily (QD) compared with an approved, investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib) in the 1L (expected N=402)...Pts could have received hydroxyurea or anagrelide for urgent disease control...Secondary endpoints include MMR at week 96, safety, and DMR; exploratory endpoints include biomarker assessments. Conclusion This study will assess the efficacy of asciminib in adult pts with newly diagnosed CML-CP vs that of currently approved TKIs."

Clinical • P3 data • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1

Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden (Analysis of Data from the MOST Study) (ASH 2021) - P=N/A | " Eligible patients had high-risk (HR) (≥60 years of age and/or thromboembolic history) or low-risk (LR) ET (if receiving ET-directed therapy [not including aspirin only]); patients with MF (≥18 years of age) had LR MF or intermediate-1 (INT-1)–risk (INT-1R) MF by reason of age >65 years alone...Compared with ACs, a higher proportion of LR patients were receiving anagrelide and ruxolitinib, a higher proportion of INT-1R patients were receiving hydroxyurea, and a lower proportion of LR and INT-1R patients were receiving interferon in CCs... These real-world data from MOST demonstrate that care was generally similar between ACs and CCs. Although there were key statistical differences in demographics (eg, age, ethnicity, and education level), disease features, and treatment history, the clinical significance of these differences remains unclear. Some of these differences (eg, demographics), however, could be attributed to the geographic location of the enrollee."

Clinical • Cardiovascular • Hematological Disorders • Hematological Malignancies • Leukopenia • Lymphoma • Multiple Myeloma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytosis

Trial in Progress: A Multicenter, Open Label, Randomized, Phase III Study of Asciminib (80 mg Once Daily) Vs Investigator-Selected TKI in Newly Diagnosed Adult Patients with Chronic Myeloid Leukemia in Chronic Phase (ASH 2021) - P3 | "Background: Patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) may be treated with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for first-line (1L) use: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib...Pts who have previously received hydroxyurea or anagrelide may be included... This study will assess the efficacy of asciminib 80 mg QD in adult pts with newly diagnosed CML-CP vs currently approved TKIs in 1L. This study is sponsored by Novartis."

Clinical • P3 data • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • ABL2 • BCR

Increased Thrombotic Risk in Essential Thrombocythemia (Targeted Oncology) - "Srdan Verstovsek, MD, PhD, discusses the increased thrombotic risk and management for patients with essential thrombocythemia."

Video

Unmet needs and therapeutic strategies in essential thrombocythemia (YouTube) - "In this video, Srdan Verstovsek...discusses unmet needs and therapeutic strategies being investigated in essential thrombocythemia (ET). Dr Verstovsek first highlights the high risk of thrombosis in patients with ET and the importance of exploring novel agents to reduce this risk."

Interview • Video

"60s👱‍♂️, NSTE-ACS, on and off angina associated with EKG changes, rising trops —Hx of thrombocytosis (+JAK2 mutation, platelet count ~500K) recently started on Anagrelide. Diagnosis and management? @mmamas1973 @djc795 @ShariqShamimMD @agtruesdell @DLBHATTMD @AntoniousAttall" (@TTelila)

Cardiovascular • Hematological Disorders • Thrombocytosis • JAK2

Anagrelide for platelet-directed cytoreduction in polycythemia vera: Insights into utility and safety outcomes from a large multi-center database. (PubMed, Leuk Res) - "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. 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."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Hemophilia • Myeloproliferative Neoplasm • Pain • Polycythemia Vera • Thrombocytosis • Thrombosis

PROTEOMIC ANALYSIS ON PLATELETS OF ESSENTIAL THROMBOCYTHEMIA PATIENTS UNDERSCORES THE ROLE OF MITOCHONDRIA IN JAK2 V617F PLATELET REACTIVITY AND FUNCTION (EHA 2022) - "Most of the patients were treated with low dose aspirin (ASA), anagrelide (ANA) or hydrea (HU) or a combination of these. JAK2 V61F platelets are more activated than any other ET group according to their proteome profile, which is not fully reflected by the functional assays. Mitochondrial activity arises as an important factor in the control of platelet reactivity and it could be critical in disease management and treatment strategies, specifically for the JAK2 V617F patients."

Clinical • Cardiovascular • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis • Thrombosis • CALR • CD36 • JAK2

Expression of CD47 and CALR in myeloproliferative neoplasms: Potential new therapeutical targets. (ASCO 2022) - "Mononuclear cells were collected by Ficoll separation, from peripheral blood of 30 MPN (8 PV, 16 ET, 6 MF); 18 MPN patients received cyto-reductive therapies (Hydroxyurea, Anagrelide or Ruxolitinib); and 4 controls. CD47, but not CALR, is overexpressed on the membrane of patients with MPN, suggesting a role for CD47 as a strong antiphagocytic signal responsible for immune survival in MPN. We observed a significant difference in CD47 expression across different MPN subtypes with a significant increase in CD47 expression in PV and MF but not ET. The use of anti-CD47 antibodies could represent a new strategy to enhance the treatment response in particular in PV and MF."

Acute Myelogenous Leukemia • Hematological Disorders • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Solid Tumor • Thrombocytosis • CALR • CD47

Resurgence of myeloproliferative neoplasm in patients in remission from blast transformation after treatment with hypomethylating agents. (PubMed, Leuk Res) - "All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease."

Journal • Acute Myelogenous Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • JAK2 • TP53

Safety and efficacy of anagrelide in Japanese post-marketing surveillance, with subgroup analyses on the effect of previous cytoreductive therapies, age, and starting dose. (PubMed, Int J Hematol) - "This surveillance showed that anagrelide has a tolerable safety and efficacy profile."

Journal • P4 data • Hematological Disorders • Myeloproliferative Neoplasm • Pain • Thrombocytosis

"One Lot of Anagrelide Capsules - USP 0.5 mg by Teva: Recall - Due to Dissolution Test Failure https://t.co/tdqk685cYz" (@FDAMedWatch)

"بیماری های ریوی اینترستیشیال (مثل آلوئولیت آلرژیک، پنومونی ائوزینوفیلیک و پنومونیت اینترستیشیال) با مصرف Anagrelide گزارش شده است؛ بیشتر موارد همراه با دیس پنه پیش رونده و اینفیلتره های ریوی بوده اند توقف واردات دارو @merck #bleeding" (@sait11859965)

"نارسایی کبدی غلظت Anagrelide را افزایش می دهد و می تواند ریسک افزایش طول QTc را بالا ببرد؛ بیماران مبتلا به نارسایی کبدی را از نظر افزایش طول QTc و سایر واکنش های جانبی قلبی مانیتور کنید کویید ۱۹ @merck #cancer" (@joe56118162)

Oncology

Anagrelide-associated Cardiomyopathy and Heart Failure in a Patient with Essential Thrombocythemia: A Case Report and Literature Review. (PubMed, Intern Med) - "The cardiac function returned to normal after six months. This case suggests that anagrelide can cause cardiomyopathy and HF in ET patients, regardless of nationality, comorbid cardiovascular conditions, or therapy duration."

Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Myeloproliferative Neoplasm • Thrombocytosis