Recurrent problems of patients with myelofibrosis (MF) are cytopenias, debiliating disease-related symptoms and splenomegaly. Whereas the latter are usually addressed by the JAK1/2 inhibitors ruxolitinib and fedratinib, cytopenias often remain critical. Momelotinib, a JAK1/2 inhibitor recently approved for the treatment of anemic MF patients, was shown to improve anemia via a direct inhibition of activin A receptor type I. In this German-wide, multicenter, retrospective analysis the safety and efficacy profile of momelotinib was evaluated in a real world setting within a cohort of 60 MF patients independent of pre-treatment. The median duration of treatment was 12 weeks. As a new, but manageable safety finding, creatinine increase (CTC°1-2) was detected in 10/60 patients (17%). Interestingly, not only hemoglobin levels increased in 84% of patients, but also platelet values (67%). In the cohort of transfusion-dependent individuals (n = 38), transfusion requirement improved in 15 patients (39%) with 8 reaching transfusion independency (21%). Transfusion independency was achieved within a median of 4 weeks (range 2-12). Spleen size decreased in 13/53 individuals (25%) with a median response time of 6 weeks. Thereof, 11 patients had been pre-treated with JAK inhibitor(s) (85%). Clinical improvement was detected in 24/51 symptomatic individuals (47%) with a median response time of 4 weeks. 5 patients stopped treatment due to side effects (8%), 6 patients due to a worsening of clinical symptoms (10%). Taken together, the MoReLife analysis identifies momelotinib as potent and safe therapeutic option also for heavily pre-treated cytopenic MF patients under real world conditions.

Despite advances in diagnosis of erythrocytosis and thrombocytosis due to driver mutation testing, many cases remain classified as "idiopathic". This can be explained by the absence of an evident secondary cause, inconclusive bone marrow biopsy or neglection of family history. Analysis of a broad panel of genes through next-generation sequencing (NGS) could improve diagnostic work-up identifying underlying genetic causes. We reviewed the results of NGS performed in our laboratory and its diagnostic impact on 117 patients with unexplained erythrocytosis and 58 with unexplained thrombocytosis; six patients (5.1%) were diagnosed with polycythaemia vera (PV) and 8 (6.8%) with familial erythrocytosis after NGS testing. Low EPO and a family history seemed to predict a positive result, respectively. However, a greater percentage of patients were ultimately diagnosed with secondary erythrocytosis (36%), remained as idiopathic (28.2%) or were self-limited (15%). The yield of NGS was shown to be slightly higher in patients with thrombocytosis, as 15 (25.9%) were diagnosed with essential thrombocythemia (ET) or familial thrombocytosis after variant detection; previous research has shown similar results, but most of them carried out NGS retrospectively, while the present study exhibits the performance of this test in a real-world setting. Overall, the low rate of variant detection and its poor impact on diagnostic work-up highlights the need for a thorough screening prior to NGS, in order to improve its yield.

Prefibrotic primary myelofibrosis (prefibrotic PMF) is a myeloproliferative neoplasm with distinct characteristics comprising histopathological and clinico-biological parameters. It is classified as a subtype of primary myelofibrosis. In clinical practice, it is essential to correctly distinguish prefibrotic PMF from essential thrombocythemia especially but also overt PMF besides other myeloid neoplasms. Risk stratification and survival outcomes for prefibrotic PMF are worse than that of ET but better than that of overt PMF. Rates of progression to overt PMF and blast phase disease are also higher for prefibrotic PMF than ET. In this review we first discuss the historical context to the evolution of prefibrotic PMF as an entity, its presenting features and diagnostic criteria. We emphasize the differences between prefibrotic PMF, ET, and overt PMF with regards to presenting features and disease outcomes including thrombohemorrhagic events and progression to fibrotic and blast phase disease. Next, we discuss the risk stratification models and contextualize these in the setting of clinical management. We share our view of personalizing treatment to address unique patient needs in the context of currently available management options. Lastly, we discuss areas of critical need in clinical research and speculate on the possibility of future disease course modifying therapies in prefibrotic PMF.

The present study aims to assess the mortality trends in myelodysplastic syndromes (MDS) in Spain from 1980 to 2021.

Deaths and mid-year population data were collected from the National Institute of Statistics. We estimated age-standardised mortality rates (ASMRs) per 100,000 person-years for all ages and ages 35-64. Joinpoint regression identified significant changes in mortality trends. The independent effects of age, period and birth cohort on MDS mortality were also examined.

MDS-related deaths gradually increased from 36 in 1980 to 1118 in 2021, with an overall increase of 6.6% in age-standardised mortality rates (ASMRs) for both men and women. Joinpoint analysis identified four periods for both men and women: 1980-1987 (stable rates), 1987-1990 (sharp increase), 1990-1999 (slower increase) and 1999-2021 (stable rates). ASMRs (35-64 years) increased by 2.5% over the study period, with a turning point identified in 1996 when rates decreased. Mortality from MDS increases with age and is higher in men. The cohort's relative risk increased until the mid-1950s and then stabilised, whilst the period relative risk increased between 1982 and 1996 and then stabilised.

The results of this study indicate a progressive increase in MDS-related deaths in Spain between 1980 and 2021. Notably, this increase was more pronounced in men than in women. Analysis of birth cohort trends revealed shifts in MDS risk, characterised by an increase until the mid-twentieth century, followed by a stabilisation. Using joinpoint analysis, four distinct periods were identified, shedding light on the changing patterns of mortality over time. These findings help to shape future research directions and inform public health strategies. They also provide optimism for advances in MDS treatment and potential reductions in mortality.

The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course.

An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL.

Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning.

This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Acquired myeloid malignancies are a spectrum of clonal disorders known to be caused by sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells, leading to their aberrant self-renewal and differentiation. The increasing use of induced pluripotent stem cell (iPSC) technology to study myeloid malignancies has helped usher a paradigm shift in approaches to disease modeling and drug discovery, especially when combined with gene-editing technology. The process of reprogramming allows for the capture of the diversity of genetic lesions and mutational burden found in primary patient samples into individual stable iPSC lines. Patient-derived iPSC lines, owing to their self-renewal and differentiation capacity, can thus be a homogenous source of disease relevant material that allow for the study of disease pathogenesis using various functional read-outs. Furthermore, genome editing technologies like CRISPR/Cas9 enable the study of the stepwise progression from normal to malignant hematopoiesis through the introduction of specific driver mutations, individually or in combination, to create isogenic lines for comparison. In this review, we survey the current use of iPSCs to model acquired myeloid malignancies including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia and MDS/MPN overlap syndromes. The use of iPSCs has enabled the interrogation of the underlying mechanism of initiation and progression driving these diseases. It has also made drug testing, repurposing, and the discovery of novel therapies for these diseases possible in a high throughput setting.

Background: Treatment of Philadelphia chromosome negative myeloproliferative neoplasms (Ph - MPNs) requires individualized approach depending on multiple factors. Novel pegylated Interferon (IFN) formulations have become an attractive therapeutic option in young Ph- MPN patients associated with better patient compliance. Methods: In this retrospective observational study a total of 16 high-risk Ph- MPN patients treated off-label with ropeginterferon alfa-2b given twice monthly, were included. Median follow-up was 24 months. High-risk patients were defined using the IPSET score. Response to treatment was evaluated using ELN, IWG-MET EUMNET standardized criteria and occurrence of side effects was documented. Results: 11 patients were female (68.8%) and 5 male (31.2%); average age at diagnosis was 36 years (17-51); 12 patients (75%) had ET, one (6.2%) PV and three (18.8%) hypercellular phase of PMF. JAK2V617F mutation was detected in 10 patients (62.5%), CALR in three (18.8%), and three (18.7%) were triple-negative cases. In 7 patients (43.7%), ropeginterferon alfa-2b was used in first-line, and 9 (56.3%) were previously treated with HU and/or standard IFN. Among initially ropeginterferon alfa-2b treated patients, complete haematological response was observed in 4/7 (57.1%), partial in 2/7 (28.6%) and suboptimal in one (14.3%). Complete haematological response was observed in 8/9 (88.9%) among previously treated patients. Average time to blood count normalization was 8 weeks, at a dose ranging between 100mcg and 300mcg. Side effects were observed in one patient (6.2%). Conclusion: Our experience is in support of previous studies regarding ropeginterferon alfa-2b efficacy and safety profile in the treatment of young patients with Ph- MPNs.

The liver has a central role in metabolism, therefore, it is susceptible to harmful effects of ingested medications (drugs, herbs, and nutritional supplements). Drug-induced liver injury (DILI) comprises a range of unexpected reactions that occur after exposure to various classes of medication. Even though most cases consist of mild, temporary elevations in liver enzyme markers, DILI can also manifest as acute liver failure in some patients and can be associated with mortality. Herein, we briefly review available data on DILI induced by targeted anticancer agents in managing classical myeloproliferative neoplasms: Chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and myelofibrosis.

Myeloproliferative neoplasm (MPN)-unclassifiable (MPN-U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence is difficult to define but likely represents close to 5% of all MPNs when strict World Health Organisation (WHO) criteria are applied. Dynamic review over time is required to assess if the disease can be re-classified into another MPN entity. A diagnosis of MPN-U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials. MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive. Moreover, despite the significant thrombotic risk, there is no agreement on systematic primary thromboprophylaxis. We hereby provide a contemporary overview of MPN-U in addition to four illustrative cases providing our collective suggested approaches to clinical challenges.