- Sustained Regression of Hydroxycarbamide Induced Actinic Keratoses after Switching to Anagrelide. [Journal Article]
- CRCase Rep Dermatol Med 2018; 2018:2874012
- Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatm...
Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatment with HC can result in the development of confluent actinic keratoses (AK) followed by invasive keratinocytic carcinomas ("squamous dysplasia"), preferentially on sun-exposed skin. Discontinuation or dose reduction of HC may result in partial improvement. A 59-year-old farmer after 14 years on HC (2 gr/d) and acetylsalicylic acid (100 mg/d) for ET, was referred for numerous, hyperkeratotic AK on face, scalp, and hands that could not be controlled with repeated (N = 15) cryosurgery sessions in the previous 3 years. Acitretin (0.32 mg/kg daily) and topical treatments (cryosurgery with ingenol mebutate) were initiated with only marginal improvement after 3 months. Acitretin dose was doubled and HC was switched to anagrelide (0.5 mg twice daily). Within a month the AK load regressed significantly and, at 3 months follow-up, complete clinical remission was achieved and acitretin was discontinued. Twenty months later the patient is clear from AK. In conclusion, the impressive and sustainable AK remission under anagrelide draws attention to a possible role of the phosphodiesterase 3 pathway, the major pharmacological target of anagrelide, as a potential therapeutic target for keratinocytic cancers.
- Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations. [Journal Article]
- BJBr J Haematol 2018 May 09
- Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently b...
Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5-base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR-Ins5 mutation and from a healthy individual (WT). Megakaryopoiesis was more prominent in Ins5-haematopoietic progenitor cells (Ins5-HPCs) than in WT-HPCs, implying that the system recapitulates megakaryocytosis observed in the bone marrow of CALR-mutant ET patients. Ins5-HPCs exhibited elevated expression levels of GATA1 and GATA2, suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3-hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an in vitro model system that recapitulates megakaryopoiesis caused by mutant CALR. This system can be used to validate therapeutic compounds for MPN patients harbouring CALR mutations and in detailed studies on mutant CALR in human haematological cell differentiation.
- Impact of white blood cells on thrombotic risk in patients with optimised platelet count in essential thrombocythemia. [Journal Article]
- EJEur J Haematol 2018 Mar 30
- CONCLUSIONS: This data suggests that additional correction of elevated WBC counts is mandatory in patients with optimally managed PLT counts in order to reduce thrombotic risk. The present study is the first investigation in a prospectively observed large patient cohort which was treated homogenously allowing for evaluation of single parameters for an effect on thrombophilia. This article is protected by copyright. All rights reserved.
- Ventricular tachyarrhythmia in a 78-year-old woman with essential thrombocythaemia. [Journal Article]
- BCBMJ Case Rep 2018 Feb 08; 2018
- Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and cardiomyopathy are rare but potentia...
Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and cardiomyopathy are rare but potentially fatal and should be made known to patients before starting the medication. It usually arises within the first 6 months after initiation of therapy and may be dose related. The elderly population are particularly susceptible. These cardiotoxicities result from an increase in cyclic AMP that induces positive inotropic and chronotropic effects and are often reversible with cessation of use. We report a case of a 78-year-old woman with essential thrombocythaemia and recently started on anagrelide who presented with syncope and multiple bruises and facial trauma and found to have developed ventricular tachyarrhythmia.
- Primary myelofibrosis and pregnancy outcomes after low molecular-weight heparin administration: A case report and literature review. [Case Reports]
- MMedicine (Baltimore) 2017; 96(46):e8735
- CONCLUSIONS: This case was rare and complex. Because it was related to pregnancy it required continuos collaboration and supervision between obstetrician and hematologist.
- Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the Evaluation of Anagrelide Efficacy and Long-term Safety study. [Journal Article]
- HHaematologica 2018; 103(1):51-60
- Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia pat...
Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.
- Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurposing AMPK activators? [Review]
- PRPharmacol Res 2018; 128:88-100
- Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascul...
Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
- Is anagrelide safe during pregnancy? [Letter]
- JGJ Gynecol Obstet Hum Reprod 2017; 46(9):697-699
- Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status. [Journal Article]
- LLeukemia 2018; 32(2):450-461
- The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown...
The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.
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- Efficacy and safety of anagrelide in childhood essential thrombocythemia. [Journal Article]
- PIPediatr Int 2017; 59(9):1017-1018