Agrylin (anagrelide)

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.

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.

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.

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).

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.

Key recommendations included careful observation for asymptomatic patients with classical, low-risk, CALR-mutated essential thrombocythaemia without cardiovascular risk factors; caution in the use of antiplatelet therapy for symptomatic patients at low risk with platelet counts of 1000-1500 × 10 platelets per L, in such cases cytoreduction is an adequate option, especially if adquired Von Willebrand disease is present; cytoreduction is recommended for extreme thrombocytosis (platelet count >1500 × 10 platelets per L) with pegylated interferon alfa being the preferred option for younger patients; both hydroxycarbamide and anagrelide might be given to patients ineligible for pegylated interferon alfa; and treatment algorithms for patients with high-risk pregnancies should not be changed according to genotype. The European LeukemiaNet proposes to use these recommendations in the routine management of patients with CALR-mutated essential thrombocythaemia, and designing new clinical studies in this field might be useful.

Treatment included low-dose aspirin (LDA) in seven patients (50%), combination of LDA with hydroxyurea in three patients (21.4%), hydroxyurea in two patients (14.3%), combination of platelets apheresis with LDA and anagrelide in one patient each (7.1%). Children less than 1 year are at high risk for complications particularly during acute precipitating infectious episode. The potential complications and clinical course of pediatric ET are unpredictable.

- Treatment received: Hydrea + maintenance interferon (1/8), Anagrelide + antiplatelet (5/8), antiplatelet (ASA) (3/8), interferon due to pregnancy (1/8). - The most frequent side effects were: bleeding tendency, palpitations. The most serious side effect was pulmonary hypertension.

Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.

Management strategies included wait and watch [n = 22(12%)], Hydroxycarbamide [n = 111(61%)], Anagrelide[n = 5(3%)], Ruxolitinib [n = 8(4%)], Busulphan [n = 5(3%)], radiophosphorus [n = 1(1%)] and Venesection combined with hydroxycarbamide [n = 30(16%)]. Compliance was found to be poor in performing bone marrow biopsy as part of workup, discussing cases in MDT and documenting risk stratification and prognostic scoring. The recommendations are to update trust guidelines as per BSH recommendations, incorporate risk stratification/ prognostic scoring in treatment pathways for all MPN and conduct educational session to standardize practice across the trust

For treatment, almost all patients used hydroxyurea (97.8%); 68% used antiplatelet agents; 6.7% used anticoagulants and 13.3% of the patients were resistant to treatment with hydroxyurea, using anagrelide as a replacement agent. The studied group presented epidemiology consistent with the literature, but the female predominance was greater than expected. The rate of asymptomatic patients was also higher than that reported in the literature. The incidence of thromboembolic events after treatment was similar to that reported in the literature, despite the lack of rigor regarding the treatment protocol used.

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 likely be observed, as their bleeding risk from aspirin may outweigh any benefit in terms of thrombotic risk reduction.26 Evidence from phase 3, randomized controlled trials supports the use of either hydroxyurea (HU) or pegylated interferon alfa as frontline cytoreductive therapy27, 28; HU is, by far, the more commonly used drug...Although no benefits for ruxolitinib in any parameters other than symptoms were observed in the UK MAJIC-ET trial,33 in which ruxolitinib was compared with best available therapy (BAT) in HU-resistant/intolerant patients with ET, ruxolitinib continues to be developed for this indication (NCT03123588), based on long-term, phase 2 evidence of efficacy in terms of count and symptom control from other studies.34 Like ruxolitinib, ropeginterferon alfa-2b, a novel, monopegylated interferon formulation administered every 2 weeks, is also being compared against anagrelide for HU-resistant/intolerant ET (NCT04285086)...A clinical trial of bomedemstat, a small-molecule inhibitor of lysine-specific demethylase 1 (LSD1), has also been announced (NCT04254978)...If cytoreductive therapy is required, interferon alfa, usually pegylated interferon alfa, is the drug of choice. There is no experience with the use of ruxolitinib or other JAK inhibitors in pregnancy.

Prior to the pregnancies 50 women (83.3%) received cytoreductive therapy hydroksycarbamide (HU), Anagrelide (ANA) or interferon alfa (INF)...Anticoagulation therapy using LMWH was given during 19 pregnancies (18.3%), LMWH with aspirin (ASA) during 10 pregnancies (9.6%) and ASA alone during 24 pregnancies (24.2%)...A total of 92.3% of complications during the second trimester were observed in JAK2 positive women. The presence of the JAK-2 mutation did not affect the rate of complications in the first trimester but was the reason for doubling the rate of complications in the third trimester.

Initially, the patient was diagnosed with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and it was treated with aspirin and hydroxyurea. The platelet count decreased with the administration of anagrelide. In conclusion, comprehensive genetic profiling is very important, and it leads to accurate diagnosis and therapy.

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.

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.

While no curative treatment exists, cytoreductive treatment with hydroxyurea (HU) or ropeginterferon is approved in EU for first-line therapy, and ruxolitinib (RUX) is approved in EU and US for second-line therapy in patients with HU intolerance or resistance...Of the 50 patients, 28 patients with newly-diagnosed PV were randomized into the RUX arm and were analyzed (a maximum of 6 weeks of HU, anagrelide, or interferon therapy was allowed)... Treatment with ruxolitinib in first line PV is efficient regarding the above-mentioned endpoints. Recruitment of our trial will be ongoing. In order not to weaken the study´s statistical power, comparison of both arms was not performed.

Among patients with ET, aspirin was used most frequently (21 patients), followed by anagrelide (11 patients). To the best of our knowledge, this is the first nationally-representative survey to clarify the clinical aspects of pediatric patients with Ph-negative MPNs. Although the methodology was not standardized, the frequency of the JAK2V617F mutation appears to be lower than that previously reported for adult patients. Moreover, the incidence of adverse events, such as thrombosis, hemorrhage, leukemia development, and transformation to myelofibrosis, was much lower than that of adult patients.

Secondary: To evaluate parameters such as mutational status, platelet count, history of complications in previous Pcy, use of aspirin (ASA), low molecular weight heparin (LMWH) or interferon (IFN) and their relationship with obstetric outcomes...Before Pcy 17 cases received cytoreductive treatment: 2 with HU and 1 with anagrelide that were discontinued at the time Pcy was confirmed, 5 with peg IFN, and 9 conventional IFN... Pcy is a rare but high-risk event in MPN pts with 11/30 OC in this cohort. The live birth rate was high compared to the literature. The risk of MC was low, without thrombotic complications and 2/30 episodes of major postpartum bleeding.