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The article discusses the treatment of polycythaemia vera (PV) with ropeginterferon alfa-2b, focusing on molecular remission and complete haematological response. The study conducted in China showed that a higher initiating dose of ropeg led to a significant anti-neoplastic effect, with patients achieving complete molecular remission and a decrease in JAK2V617F allele burden over time. The treatment was well-tolerated, with a high rate of complete haematological response and a favorable safety profile observed over 24 months. The findings suggest that this treatment regimen may offer robust clinical benefits for patients with PV. [Extracted from the article]

The article discusses the use of ruxolitinib after fedratinib failure in patients with myelofibrosis. It presents a case series of 14 patients who received ruxolitinib after fedratinib therapy, detailing their clinical outcomes and responses. The study highlights the potential clinical benefit of second-line ruxolitinib, achieving spleen and symptoms response in a subset of patients. The findings suggest that sequential use of ruxolitinib after fedratinib may be beneficial for selected patients, with no observed excess toxicity in the second-line setting. [Extracted from the article]

Summary Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF)‐related splenomegaly or symptoms. The recommended starting dose depends on platelet count, regardless of haemoglobin level at baseline. In the recent years, an overall survival (OS) advantage was reported in patients treated with ruxolitinib compared with best available therapy. We analysed a large Italian cohort of 3494 patients identified by Agenzia Italiana del Farmaco (AIFA) monitoring registries. Of them, 2337 (66.9%) started at reduced dose: these patients were older (median age 70 vs. 67), with increased incidence of large splenomegaly (longitudinal diameter 20 vs. 19.1 cm, median volume 1064 cm3 vs. 1016 cm3), with higher IPSS risk (30.9% vs. 26.1%), and worse ECOG score (more than 1 in 14.3% vs. 9.8%). After balancing for baseline characteristics, Kaplan–Meier analysis showed a median OS of 78.2 months (95% CI 65.9–89) for patients who started at full dose and 52.6 (95% CI 49–56.6) months for patients who started with reduced dose (p < 0.001). Group analysis also showed a substantial difference in patients with intermediate‐2 and high IPSS risk. The majority of MF patients in real‐world analysis started with a reduced dose of ruxolitinib, which is associated with less favourable outcomes. [ABSTRACT FROM AUTHOR]

Summary: We describe the clinical phenotype, management strategies and outcomes of 22 patients with autoimmune myelofibrosis (AIMF); median age: 45 years; 77% females; 83% with autoimmune disease, pancytopenia in 32% and transfusion‐requiring anaemia in 59%. All informative cases were negative for JAK2 (n = 18) and CALR/MPL mutations (n = 12). Fourteen of nineteen (74%) evaluable patients achieved complete response (CR) based on the resolution of cytopenias. First‐line treatments included steroids +/− immunosuppressive agents, cyclosporin and mycophenolate with CR in 7 of 13 (54%), 1 of 2 (50%) and 1 of 2 (50%) respectively. Rituximab salvage therapy yielded CR in 4 of 5 (80%) cases. The current study provides information on steroid‐sparing treatments for AIMF. [ABSTRACT FROM AUTHOR]

The article discusses the presence and characteristics of NFE2 mutations in myeloid neoplasms, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML). The study found that NFE2 mutations were most common in MPN and MDS, and were associated with elevated NFE2 mRNA expression levels in MPN. The mutations may also play a role in the development of bone marrow fibrosis in MPN and MDS. Further research is needed to fully understand the impact of NFE2 mutations on disease progression and transformation to leukemia. [Extracted from the article]

Summary: This study examines spermatogonial numbers in testicular samples from 43 prepubertal patients undergoing haematopoietic stem cell transplantation (HSCT). High‐dose chemotherapy and/or radiation during HSCT can impact spermatogenesis requiring fertility preservation. Results show that 49% of patients have decreased and 19% severely depleted spermatogonial pool prior to HSCT. Patients with Fanconi anaemia exhibit significantly reduced spermatogonial numbers. Patients with immunodeficiency or aplastic anaemia generally present within the normal range, while results in patients with myelodysplastic syndrome or myeloproliferative neoplasm vary. The study emphasizes the importance of assessing spermatogonial numbers in patients with severe haematological diseases for informed fertility preservation decisions. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR‐ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well‐tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts. [ABSTRACT FROM AUTHOR]

Summary: Juvenile myelomonocytic leukaemia (JMML) is a rare myeloproliferative neoplasm requiring haematopoietic stem cell transplantation (HSCT) for potential cure. Relapse poses a significant obstacle to JMML HSCT treatment, as the lack of effective minimal residual disease (MRD)‐monitoring methods leads to delayed interventions. This retrospective study utilized the droplet digital PCR (ddPCR) technique, a highly sensitive nucleic acid detection and quantification technique, to monitor MRD in 32 JMML patients. The results demonstrated that ddPCR detected relapse manifestations earlier than traditional methods and uncovered molecular insights into JMML MRD dynamics. The findings emphasized a critical 1‐ to 3‐month window post‐HSCT for detecting molecular relapse, with 66.7% (8/12) of relapses occurring within this period. Slow MRD clearance post‐HSCT was observed, as 65% (13/20) of non‐relapse patients took over 6 months to achieve ddPCR‐MRD negativity. Furthermore, bone marrow ddPCR‐MRD levels at 1‐month post‐HSCT proved to be prognostically significant. Relapsed patients exhibited significantly elevated ddPCR‐MRD levels at this time point (p = 0.026), with a cut‐off of 0.465% effectively stratifying overall survival (p = 0.007), event‐free survival (p = 0.035) and cumulative incidence of relapse (p = 0.035). In conclusion, this study underscored ddPCR's superiority in JMML MRD monitoring post‐HSCT. It provided valuable insights into JMML MRD dynamics, offering guidance for the effective management of JMML. [ABSTRACT FROM AUTHOR]

Summary: Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET‐thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti‐platelet treatments differ depending on the molecular genotype. While anti‐platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence‐based management according to revised IPSET‐thrombosis stratification, we also provide specific observations for those patients with CALR‐, MPL‐mutated and triple‐negative ET, as well as cases with high‐risk mutations. [ABSTRACT FROM AUTHOR]

This article examines the occurrence of liver complications in patients with myelofibrosis who undergo allogeneic hematopoietic stem cell transplantation (HSCT). The study found that liver adverse events (AEs) were more common than expected, with 64% of patients experiencing liver AEs within the first 100 days after HSCT. The most common liver AEs were caused by the conditioning regimen. Risk factors for liver toxicity included worse performance status, higher comorbidity index, and higher prognostic scoring system score. The study also found that hyperbilirubinemia and hepatic graft-versus-host disease were associated with increased mortality. The text emphasizes the importance of monitoring liver complications in HSCT patients and suggests using imaging and biopsies to determine the cause and guide treatment. The study included various factors in the analysis and was approved by the appropriate ethics committee. [Extracted from the article]

This document is an update of the British Society for Haematology guideline on the management of myelofibrosis. It provides healthcare professionals with clear guidance on the stratified management of primary myelofibrosis, as well as post-polycythemia myelofibrosis and post-essential thrombocythemia myelofibrosis. The guidelines discuss various treatment options, including medications like ruxolitinib, fedratinib, momelotinib, and pacritinib, as well as other therapies such as hydroxycarbamide, pegylated interferons, and anti-platelet agents. The document also covers the management of MF-associated anemia, the use of erythropoiesis-stimulating agents, danazol, immunomodulating drugs, and iron chelation therapy. It provides recommendations for special situations and emphasizes the importance of individualized treatment approaches and patient support. Additionally, the document provides recommendations for pretransplant workup, donor choice, conditioning choice, and post allo-HSCT monitoring for patients considering allogeneic stem cell transplantation. [Extracted from the article]

This document is an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF), providing healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of different types of MF. It emphasizes the importance of bone marrow biopsy and molecular testing for diagnosis, as well as the use of various prognostic models to inform clinical decisions and guide therapy. The document also discusses risk stratification and prognostication for MF patients, including the use of validated risk scores. Additionally, it provides information on the diagnosis and prognostication of prefibrotic MF, highlighting the importance of diagnostic criteria and mutational profiles. [Extracted from the article]

A total of 14 consecutive I IDH1/2 i -mutated patients with MPN-BP (median age 76 years) received ivosidenib ( I n i = 5) or enasidenib ( I n i = 9), either in the up-front ( I n i = 8) or relapsed ( I n i = 6) setting; one patient harboured both I IDH1 i and I IDH2 i mutations and received ivosidenib as front-line therapy followed by enasidenib at the time of relapse. Anaemia response was documented in five of 13 (38%) evaluable patients, which included two of four (50%) with CR/CRi; none of the patients with palpable splenomegaly displayed spleen response. Outcome of patients with IDH1/2-mutated post-myeloproliferative neoplasm AML in the era of IDH inhibitors. Figure 1A provides a timeline of treatment history, maximal response and duration of response for patients who achieved CR/CRi/PR. [Extracted from the article]

Summary: Donor‐derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor‐derived T‐cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B; the latter targetable with the clinically available drugs, venetoclax and ruxolitinib. [ABSTRACT FROM AUTHOR]

In Europe, ruxolitinib and fedratinib are the only JAK2 inhibitors available in local pharmacies. According to trial data, myelofibrosis patients should mostly receive ruxolitinib as first‐line treatment and fedratinib in case of failure or intolerance (depending on their profile). Is it possible to reverse the choice of these drugs? Commentary on: Palandri et al. Ruxolitinib after Fedratinib failure in patients with myelofibrosis: a real‐world case series. Br J Haematol 2024; 205:1605‐1609. [ABSTRACT FROM AUTHOR]

Evidence‐based guidelines for rare diseases, such as myelofibrosis (MF), continue to prove challenging to develop, and decision‐making for MF is complex. The British Society for Haematology (BSH) has created a pragmatic symptom‐guided risk‐adapted framework on all aspects of management of MF and shared best practices on the use of JAK inhibitors, transplantation and other conventional therapies in the management of myelofibrosis. Commentary on: McLornan et al. The management of myelofibrosis: A British Society for Haematology Guideline. Br J Haematol 2024;204:136–150. [ABSTRACT FROM AUTHOR]

ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high‐risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia‐related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co‐mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild‐type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative neoplasms in blastic phase (MPN‐BP) have a dreadful prognosis. We report the characteristics and outcomes of five MPN‐BP patients treated with a never‐before‐described combination of azacytidine and venetoclax (to control BP transformation), added to ruxolitinib (needed to control constitutional symptoms). Median age was 76 years (range 72–84), and worst performance status was 2. The overall response rate was 80%, and the complete remission rate was 40%. With median follow‐up of 10.0 months (range 4.2–13.4), median overall survival was 13.4 months (95% CI 4.2–13.4). We did not detect any unexpected treatment‐related toxicity, and quality of life was improved. [ABSTRACT FROM AUTHOR]

Classical myeloproliferative neoplasms (MPNs) are characterized by distinct clinical phenotypes. The discovery of driver mutations in JAK2, CALR and MPL genes provided new insights into their pathogenesis. Next‐generation sequencing (NGS) identified additional somatic mutations, most frequently in epigenetic modulator genes. In this study, a cohort of 95 MPN patients was genetically characterized using targeted NGS. Clonal hierarchies of detected mutations were subsequently analysed using colony forming progenitor assays derived from single cells to study mutation acquisition. Further, the hierarchy of mutations within distinct cell lineages was evaluated. NGS revealed mutations in three epigenetic modulator genes (TET2, DNMT3A, ASXL1) as most common co‐mutations to the classical driver mutations. JAK2V617F as well as DNMT3A and TET2 mutations were detected as primary events in disease formation and most cases presented with a linear mutation pattern. Mutations appear mostly in the myeloid lineages but can also appear in lymphoid subpopulations. In one case with a double mutant MPL gene, mutations exclusively appeared in the monocyte lineage. Overall, this study confirms the mutational heterogeneity of classical MPNs and highlights the role of JAK2V617F and epigenetic modifier genes as early events in hematologic disease formation. [ABSTRACT FROM AUTHOR]

Summary: JAK2V617F is the most frequent mutation in BCR‐ABL‐negative myeloproliferative neoplasms (MPNs). It is an important but not the only determinant of MPN phenotype. We performed high‐throughput sequencing on JAK2V617F+ essential thrombocythaemia (ET) and polycythaemia vera (PV) patient samples to unveil factors involved in phenotypic heterogeneity and to identify novel therapeutic targets for MPN. Two concurrent mutations that may affect phenotype were identified, including mutations in SH2B3, which is primarily prevalent in PV, and SF3B1, which is more commonly mutated in ET. Next, we conducted transcriptomic analysis at the haematopoietic stem cell (HSC) and megakaryocyte (MK)‐erythroid progenitor (MEP) levels. Inflammatory signalling pathways were elevated in both ET HSCs and MEPs, unlike in PV HSCs and MEPs. Notably, Wnt/β‐catenin signalling was uniquely upregulated during ET haematopoietic differentiation from HSC to MEP, and inhibiting Wnt/β‐catenin signalling blocked MK differentiation in vitro. Consistently, Wnt/β‐catenin inhibitor administration decreased platelet counts in JAK2V617F+ MPN mice by blocking MEPs and MK progenitors and by inhibiting maturation of MKs, while in wild‐type mice, Wnt/β‐catenin inhibitor did not significantly reduce platelet counts. In conclusion, our findings provide new insights into the mechanisms underlying phenotypic differentiation of JAK2V617F+ PV and ET and indicate Wnt/β‐catenin signalling as a potential therapeutic target for MPN. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%). [ABSTRACT FROM AUTHOR]

Of the 26 patients with NPM1 + FLT3+ AML, 12 patients (48%) expressed HLA-DR and seven patients (27%) expressed CD34. Three patients (8%) developed primary graft failure, nine patients (24%) developed acute graft versus host disease (GVHD), 13 (35%) developed chronic GVHD, CMV reactivation was detected in 28 patients (75%).Two patients developed metastatic squamous cell carcinoma, both died 5.5 and 12 years post-alloHSCT, both had cGVHD of the mouth and none has received irradiation. Thirteen patients (20.3%) had VTE events at diagnosis of which 10 patients had DVT, and three patients had PE. Further filtering of these patients and those from MDT provided a list of recruited patients ( I n i = 10, at time of writing); this comprises seven patients from the Royal London Hospital, two patients from St Bartholomew's Hospital and one patient from Hammersmith Hospital. BSH23-EP13 UK healthcare professional experiences with intensive chemotherapies for AML: Survey of toler... Dr Priyanka Mehta 1, Dr Joe Cross 1, Ms Hayley Kuter 2, Dr Mariette Odabashian 2, Mr Emil... 1 University Hospitals of Bristol and Weston NHS Trust, Bristol, UK, 2 Jazz Pharmaceuticals,... B Background: b Patients with AML treated with intensive chemotherapy (IC) may experience a high symptom burden/prolonged hospitalisation; however, relative IC toxicities are difficult to gauge from patient experience as patients typically receive only one regimen. [Extracted from the article]

Of the PNH positive patients, 8 patients were known to have a PNH clone with aplastic anaemia; one patient had a hypoplastic bone marrow and a known PNH clone whilst only one patient with cytopenia had a new positivity for PNH. Seven patients with progressive clinical features had ASCT consolidation (median age 59 years [range 43-68]): three patients had additional parenchymal intracranial disease on MRI and two patients also had peripheral nerve involvement, including one patient with suspicion of high-grade transformation (HGT) on CSF. Out of the 206 patients that received 1st line treatment, 92 (44%) patients proceeded to 2nd line treatment, 31 (15%) patients proceeded to 3rd line treatment and 21 (10%) of patients required treatment beyond 3rd line Within the poor risk category, 173 patients were identified with 38 had TP53 deletion or mutation and 135 patients had other poor risk mutations such as NOTCH1, SF3B1, ATM. Patients were risk stratified into good, poor or not poor risk categories as per Rodríguez-Vicente et al. SP 2 sp B Statistical Analysis and Results: b For 349 patients analysed, 143 (41%) patients were under active surveillance, and 206 (59%) patients received 1st line treatment. B Methodology: b Using a mixed methods approach we evaluated the app via: usage data from Google's Firebase platform (https://firebase.google.com/) healthcare professional benchmarking, using the Mobile App Rating Scale (MARS) questionnaire patient questionnaires, using the mHealth App Usability Questionnaire (MAUQ) patient focus groups one-to-one patient interviews Patient recruitment was undertaken via CML online support groups. [Extracted from the article]

Entospletinib is also able to induce cell death I in vitro i in ETV6:RUNX1-derived cell lines, and is again stronger in this respect than fostamatinib.[14] Together, the data strongly support that the I ETV6:SYK i tyrosine kinase gene fusion is the driver underlying this clinicobiological entity. Spleen tyrosine kinase (SYK), a 72 kDa cytoplasmic non-receptor protein tyrosine kinase, is expressed primarily in haematopoietic cells like B-cells, monocytes, macrophages, mast cells, and neutrophils. [Extracted from the article]

Summary: Nestin is an intermediate filament protein, which was originally detected in neuroepithelial stem cells. Besides its use as a phenotypic marker of mesenchymal stem cells in the hematopoeitic stem cell niche, the functional interpretation of nestin+ cells remains elusive. We investigated the cellular expression of nestin in bone marrow trephine biopsies of MPN patients, following myeloablation at a stage of hypocellularity during early regeneration. Here, nestin is highly expressed in mature osteocytes, arteriolar endothelial and perivascular cells and small capillaries within the bone marrow space, but not in sinusoid lining cells. This is in stark contrast to nestin expression pattern in myeloproliferative neoplasms that show hypercellularity due to oncogenic driver mutations. Here, nestin is expressed exclusively in endothelial cells of arterioles, but not in osteocytes or small capillaries. Thus, the pattern of nestin expression following myeloablation inversely correlates with cellularity in the bone marrow. This nestin expression pattern is mimicking early postnatal transcriptional programming during bone marrow development. We show that nestin expression in osteocytes occurs across different species following transplant and also in bone marrow metastasis. [ABSTRACT FROM AUTHOR]

Summary: We evaluated CD34+ cells in a single‐centre series of 49 consecutive patients with myelofibrosis (MF) at baseline and during ruxolitinib therapy and examined any association with spleen response. The median (range) absolute number of circulating CD34+ cells was 0.0835 (0.001–1.528) × 109/L at diagnosis, and 0.123 (0.002–1.528) × 109/L at ruxolitinib start. With the exception of a transient increase after 3 months of ruxolitinib therapy, a progressive reduction in CD34+ cells count was documented, down to a minimum of 0.063 × 109/L after 36 months. We then assessed the association between spleen diameter expressed as the distance from the left costal margin (outcome) and log(CD34+) cells count using random‐intercept and random slope multivariable regression models to take into account within subject correlation: after adjusting for time and ruxolitinib dosage, we estimated a 0.7 cm increase (95% confidence interval 0.2–1.2, p = 0.003) in spleen length for each unit increase in log(CD34+) cells count (× 109/L). Although our study has some limitations, mainly related to its retrospective design, our approach may introduce a reproducible and simple tool that could facilitate the assessment of spleen response more objectively in patients with MF treated with ruxolitinib. [ABSTRACT FROM AUTHOR]

Summary: Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient‐years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient‐years. Prior history of thrombosis, the JAK2 mutation, and the intermediate‐2/high‐risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk‐modifying effect of anti‐thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti‐thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient‐years. Patients in the intermediate‐2/high‐risk IPSS categories treated with anti‐coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision‐making in clinical practice. [ABSTRACT FROM AUTHOR]

Summary: Myeloproliferative neoplasms can be associated with bleeding manifestations which can cause significant morbidities. Although haematologists are aware of the likelihood of this complication in the setting of myeloproliferative neoplasms, it may often be overlooked especially in patients with no extreme elevation of blood counts and those with myelofibrosis. Acquired von Willebrand syndrome and platelet dysfunction are the two common diagnoses to be considered in this regard. In this review article, we discuss the mechanisms for the development of these rare bleeding disorders, their diagnosis and practical management. [ABSTRACT FROM AUTHOR]

Keywords: myelofibrosis; prognostic factors; quality of life; survival EN myelofibrosis prognostic factors quality of life survival 1065 1068 4 09/13/22 20220915 NES 220915 Patient-reported outcomes (PROs) have considerable value for survival prediction, and generally include both quality of life (QOL) and symptom measures. The COMFORT-I study enrolled 309 patients (155 ruxolitinib, 154 placebo); 111 (72%) placebo patients ultimately crossed over to ruxolitinib.4 Baseline GHS/QOL was available in 296 patients and did not differ by treatment arm (Table S1). Quality of life independently predicts overall survival in myelofibrosis: Key insights from the COntrolled MyeloFibrosis Study with ORal Janus kinase inhibitor Treatment (COMFORT)-I study. [Extracted from the article]

IFN has the advantage of a disease modifying capacity, i.e., reduction of the malignant clone that in many patients leads to long therapy free intervals after obtaining a deep molecular response.26 The PROUD-PV trial and its continuation study compared a novel mono-pegylated IFN -2b (ropeg) with HU/best available therapy. Prior to transplant, if the patient has resources available, either insurance and/or ability to pay out-of-pocket, we will consider starting the patient on ruxolitinib as bridging therapy with the objective of improving the patient's performance status and reducing splenomegaly prior to transplant. As haematologists, we always seek to follow standardised guidelines for practice and apply the best treatment for our patients with blood diseases within our means. Question 2 (Q2): Assuming that a diagnosis of PV is reached, please relate your preferred first-line therapy and how to and where the patients should be followed Question 3 (Q3): At 26 months after diagnosis at a scheduled control visit you find that first-line therapy has had limited effects. [Extracted from the article]

Limited activity of fedratinib in myelofibrosis patients relapsed/refractory to ruxolitinib 20 mg twice daily or higher: A real-world experience Keywords: fedratinib; myelofibrosis; ruxolitinib EN fedratinib myelofibrosis ruxolitinib e54 e58 5 08/10/22 20220815 NES 220815 To the editor, Fedratinib, an oral JAK2/FLT3 inhibitor is FDA-approved for myelofibrosis (MF), including primary MF (PMF), post-essential thrombocythaemia (post-ET MF) and post-polycythaemia vera (post-PV MF), for treatment-naïve and relapsed/refractory patients following ruxolitinib failure.1 The high ruxolitinib discontinuation rate of 50 and 75% at 3 and 5 years, respectively,2,3 poses a therapeutic dilemma with fedratinib as the only FDA approved salvage therapy.1,4 In the Phase 3 JAKARTA study with fedratinib in JAK inhibitor naïve patients with MF, spleen and symptom response rates were 47 and 40%, respectively.5 Similarly, in the JAKARTA-2 study which included MF patients with ruxolitinib failure, corresponding rates for spleen and symptom response were 31 and 27%.6 Historically, clinical development of fedratinib was halted in 2013 due to concern for Wernicke's encephalopathy, and after subsequent safety analysis, FDA approval was obtained in August 2019. On the other hand, only one of 14 (7%) transfusion-dependent patients achieved anaemia response by IWG-MRT response criteria; moreover, resolution of leukocytosis was noted in two of 14 (14%) patients with leukocytosis >11 x 109/l at the time of treatment initiation. [Extracted from the article]

Summary: Fedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109/l, based on outcomes from the phase 3, placebo‐controlled JAKARTA trial in JAK‐inhibitor‐naïve MF, and the phase 2, single‐arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109/l ("Low‐Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low‐Platelets cohort and patients with baseline platelet counts ≥100 × 109/l ("High‐Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low‐ and High‐Platelets cohorts. Fedratinib was generally well‐tolerated in both platelet‐count cohorts. New or worsening thrombocytopaenia was more frequent in the Low‐Platelets (44%) versus the High‐Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low‐Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients. [ABSTRACT FROM AUTHOR]

Summary: Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched‐control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD‐TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non‐fatal outcomes, and provide preliminary suggestions for parameters to evaluate further. [ABSTRACT FROM AUTHOR]

REFERENCES 1 Zhang Y. Can circulating CD34+ cell count be used for the prognosis of myelofibrosis? Consequently, it would be important to evaluate the feasibility of including a CD34+ cells count in other standard prognostic stratification models as well (e.g., IPSS/DIPSS/DIPSS-plus for PMF and MYSEC-PM for SMF). Reply to: Can circulating CD34+ cells count be used for the prognosis of myelofibrosis?. [Extracted from the article]

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. Short Summary: Myeloproliferative neoplasm (MPN)‐unclassifiable or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. In this review we provide a practical and clinically‐orientated approach to challenging situations and suggest how these patients should best be managed through expert opinion and review of the literature. [ABSTRACT FROM AUTHOR]

(A) Hepcidin levels (ng/ml) in normal (N = 9) and MF patients (N = 99). p < 0.0001 by Mann-Whitney U test. (B) Hepcidin levels (ng/ml) in patients with primary MF (N = 49) and secondary MF (N = 50). p = 0.38 by Mann-Whitney U test. (C) Hepcidin levels (ng/ml) in normal (N = 9) and MF patients treated with (N = 21) and without ruxolitinib (N = 78). p < 0.0001 by Mann-Whitney U test gl Erythroferrone (ng/ml) concentrations were quantified using a sandwich ELISA protocol.7 Initially, 96-well plates were coated with a monoclonal capture antibody, washed and blocked. Hepcidin levels (ng/ml) were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) assay from Intrinsic Lifesciences, La Jolla, CA, USA (Intrinsic Hepcidin IDx™ ELISA) in 99 MF patient plasma samples and nine normal controls. We observed that I JAK i 2-mutated and I CALR i -mutated patients had a significantly higher hepcidin level than patients who were triple-negative, although it is difficult to draw conclusions based on the small sample size of I CALR i -mutated ( I N i = 11) and particularly triple-negative patients ( I N i = 4) and warrants further investigation in larger cohorts. [Extracted from the article]

Summary: Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX‐IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX–DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1–71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX‐ or DFX‐related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion‐independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX–DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation. [ABSTRACT FROM AUTHOR]

In G1, all patients, allogeneic recipients and autologous recipients had significantly lower antibody levels than HC, whereas no differences were found in G2. Among the patients vaccinated >5 years after HSCT, allogeneic recipients had antibody titres comparable to HC; in contrast, autologous recipients had significantly lower titres than HC. Keywords: stem cell transplantation; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination; seroconversion EN stem cell transplantation severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination seroconversion 928 931 4 02/14/22 20220215 NES 220215 Adult patients with haematological malignancies (HM) and coronavirus disease 2019 (COVID-19) have a higher mortality than healthy subjects.1-3 In particular, haematopoietic stem-cell transplantation (HSCT) recipients have a poor prognosis,4,5 strongly supporting the role of vaccination. Serological response following BNT162b2 anti-SARS-CoV-2 mRNA vaccination in haematopoietic stem cell transplantation patients. [Extracted from the article]

I TableGeometric mean concentrations of anti-SARS-CoV-2 IgG and response rates according to seven different cohorts of haematological malignancy patients compared to a control cohort at 5 and 12 weeks after BNT162b2 vaccination. Keywords: severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); BNT162b2; haematological cancers EN severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) BNT162b2 haematological cancers 362 367 6 01/17/22 20220115 NES 220115 To date, studies on anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine efficacy in blood cancers show that different responses may be observed according to the haematological malignancy diagnosis, stage of disease and ongoing treatment. Single dose of BNT162b2 mRNA vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces neutralising antibody and polyfunctional T-cell responses in patients with chronic myeloid leukaemia. Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. [Extracted from the article]

Summary: Myelofibrosis (MF) is a clonal stem cell neoplasm with heterogeneous clinical phenotypes and well‐established molecular drivers. Allogeneic haematopoietic stem cell transplantation (HSCT) offers an important curative treatment option for primary MF and post‐essential thrombocythaemia/polycythaemia vera MF or secondary MF. With a disease course that varies from indolent to highly progressive, we are now able to stratify risk of mortality through various tools including patient‐related clinical characteristics as well as molecular genetic profile. Owing to the high risk of mortality and morbidity associated with HSCT for patients with myelofibrosis, it is important to improve patient selection for transplant. Our primary goal is to comprehensively define our understanding of current practices including the role of Janus Kinase (JAK) inhibitors, to present the data behind transplantation before and after leukaemic transformation, and to introduce novel personalization of MF treatment with a proposed clinical‐molecular prognostic model to help elucidate a timepoint optimal for consideration of HSCT. [ABSTRACT FROM AUTHOR]

Mutations are less frequent (<20%) in patients with indolent SM (ISM).101,102 In advanced SM, mutations in I SRSF2 i , I ASXL1 i , I RUNX1 i , I EZH2 i and I NRAS i have been associated with an adverse prognosis and thus molecular profiling is useful to guide transplant decisions.98,102-104 In ISM, high VAF (>=30%) mutations in I ASXL1 i , I RUNX1 i and/or I DNMT3A i have been associated with an adverse prognosis102 but the value of routine molecular profiling in this subtype remains to be established. Keywords: myeloproliferative neoplasms; myelodysplastic/myeloproliferative neoplasms; mastocytosis; eosinophilia; chronic myelomonocytic leukaemia EN myeloproliferative neoplasms myelodysplastic/myeloproliferative neoplasms mastocytosis eosinophilia chronic myelomonocytic leukaemia 338 351 14 11/01/21 20211101 NES 211101 Methodology This Good-Practice Paper was compiled according to the BSH process at https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. For older patients without thrombosis, testing may be considered but results must be interpreted with caution in view of the possibility of incidental CH. Testing is not indicated in patients with normal or reactive bone marrow histology. More than half of patients with "triple-negative" PMF do harbour additional mutations when screened with comprehensive genomic assays31 and approximately a third have an abnormal karyotype.51 In patients with bone marrow histology and clinical features consistent with PMF, myeloid gene panel testing in combination with conventional karyotyping (or SNP array) is recommended. [Extracted from the article]

Summary: Fedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis. [ABSTRACT FROM AUTHOR]

Analysis restricted to first trimester fetal losses confirmed the significant/near-significant influence of prior thrombosis history (60% vs. 11%; I P i = 0-03), pre-PMF phenotype (31% vs. 0%; I P i = 0-09) and aspirin use during pregnancy (8% vs. 36% I P i = 0-07). Keywords: polycythaemia; thrombocythaemia; JAK2; CALR; thrombosis EN polycythaemia thrombocythaemia JAK2 CALR thrombosis 133 137 5 09/30/21 20211001 NES 211001 Among young patients with myeloproliferative neoplasms (MPN), women constitute the majority in essential thrombocythaemia (ET; ˜69% and 64% for ages <=40 and 41-60 years respectively), whereas the corresponding percentages were lower in polycythaemia vera (PV; 46% and 48%) and primary myelofibrosis (PMF; 41% and 41%).1,2 Accordingly, current literature on pregnancies in MPN is heavily skewed towards ET; in a recent review,3 close to 500 pregnancies in ET were pooled from four independent series with ˜100 or more pregnancies reported in each study, whereas the largest reported experience in PV included 48 women with 121 pregnancies.4 Current literature regarding pregnancy outcome in patients with MF is scant with <20 reported cases.2,5-7 In the present study, we describe the experience from two centres of excellence in MPN regarding outcome of pregnancy in MF, including PMF, post-ET MF and pre-fibrotic PMF (pre-PMF). Study patients fulfilled the 2016 World Health Organization (WHO) and the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria for the diagnosis of PMF, secondary MF (post-ET/post-PV MF) or pre-PMF respectively.8,9 The 2016 WHO classification emphasises the prognostic relevance of differentiation between ET and pre-PMF and distinguishes pre-PMF from overt PMF, based on the absence of Grade >=2 bone marrow reticulin fibrosis. [Extracted from the article]

The COVID-19 pandemic has had a severe impact on people with blood cancers. (A) Percentage of patients with a chronic myeloid malignancy (n = 59) versus healthcare worker (HCW) controls (n = 232) of a similar age (>60 years), with positive anti-spike (anti-S) serology and no evidence of past COVID-19 infection [224/232 (97%) HCW vs 34/59 (58%) patients; P < 0-0001]. Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines. medRxiv. While it is expected that a higher proportion of patients will respond following booster vaccine doses, the suboptimal responses observed here to the first vaccine dose highlight an unexpected and potentially important immunocompromise in this patient group, which will be informative for planning our ongoing response to this evolving pandemic. [Extracted from the article]

Mutation analysis of peripheral blood revealed a I CALR i type 1 mutation and a I JAK2 i V617F mutation with allele frequencies of 36% and 15%, respectively. These results suggested that additional I JAK2 i V617F mutations occurred in HSC populations and that myeloid and erythroid progenitors with I JAK2 i / I CALR i double mutations might have a growth advantage over the I CALR i single-mutated populations. Keywords: genetic analysis; myelofibrosis; myeloproliferative disease EN genetic analysis myelofibrosis myeloproliferative disease e89 e92 4 09/02/21 20210901 NES 210901 Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share three common driver mutations in the Janus kinase I 2 i ( I JAK2 i ), calreticulin ( I CALR i ) and myeloproliferative leukaemia oncogene ( I MPL i ) genes.1 Although these driver mutations are thought to be mutually exclusive, rare cases of MPN with two or more co-existing driver mutations have been reported: I JAK2 i V617F/ I JAK2 i exon 12,2 I JAK2 i V617F/ I CALR i ,2-8 I JAK2 i V617F/ I MPL i ,2,4,7,9-11 I CALR i / I MPL i 2,12,13 and I JAK2 i V617F/ I CALR i / I MPL i .14 Clonogenic evaluation studies indicated these mutations mostly co-existed in separate clones. [Extracted from the article]

Summary: There is limited understanding of the impact of frailty on clinical outcomes in patients with myelofibrosis (MF). In this retrospective cohort study on 439 chronic phase MF patients [mean age: 68·7 ± 12 years; median follow‐up: 3·4 years (IQR 0·4–8·6)] from 2004 till 2018, we used a 35‐variable frailty index (FI) to categorise patient's frailty status as fit (FI < 0·2, reference), prefrail (FI 0·2–0·29) or frail (FI ≥ 0·3). The association of frailty with overall survival (OS) and cumulative JAK inhibitor (JAKi) therapy failure was measured using hazard ratio (HR, 95% CI). In multivariable analysis, prefrail (HR 1·7, 1·1–2·5) and frail patients (HR 2·9, 1·6–5·5), those with higher DIPSS score (HR 2·5, 1·6–3·9) and transfusion dependency (HR 1·9, 1·3–2·9) had shorter OS. In a subset analysis of patients on JAKi treatment (n = 222), frail patients (HR 2·5, 1·1–5·7), patients with higher DIPSS score (HR 1·7, 1·0–3·1) and transfusion dependence (HR 1·7, 1·1–2·7) had higher cumulative incidence of JAKi failure. Age, comorbidities, ECOG performance status, and MPN driver mutations did not impact outcomes. Thus, higher frailty scores are associated with worse OS and increased JAKi failure in MF, and is a superior indicator of fitness in comparison to age, comorbidities, and performance status. [ABSTRACT FROM AUTHOR]

Summary: We report on 45 patients with myeloid neoplasms and concurrent Janus kinase 2 (JAK2) V617F and KIT proto‐oncogene, receptor tyrosine kinase (KIT) D816V (JAK2pos./KITpos.) mutations, which are individually identified in >60% of patients with classical myeloproliferative neoplasms (MPN) and >90% of patients with systemic mastocytosis (SM) respectively. In SM, the concurrent presence of a clonal non‐mast cell neoplasm [SM with associated haematological neoplasm (SM‐AHN)] usually constitutes a distinct subtype associated with poor survival. All 45 patients presented with a heterogeneous combination of clinical/morphological features typical of the individual disorders (e.g. leuco‐/erythro‐/thrombocytosis and elevated lactate dehydrogenase for MPN; elevated serum tryptase and alkaline phosphatase for SM). Overlapping features identified in 70% of patients included splenomegaly, cytopenia(s), bone marrow fibrosis and additional somatic mutations. Molecular dissection revealed discordant development of variant allele frequency for both mutations and absence of concurrently positive single‐cell derived colonies, indicating disease evolution in two independent clones rather than monoclonal disease in >60% of patients examined. Overall survival of JAK2pos./KITpos. patients without additional somatic high‐risk mutations [HRM, e.g. in serine and arginine‐rich splicing factor 2 (SRSF2), additional sex combs like‐1 (ASXL1) or Runt‐related transcription factor 1 (RUNX1)] at 5 years was 77%, indicating that the mutual impact of JAK2 V617F and KIT D816V on prognosis is fundamentally different from the adverse impact of additional HRM in the individual disorders. [ABSTRACT FROM AUTHOR]

Evidence of robust memory T-cell responses in patients with chronic myeloproliferative neoplasms following infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Keywords: COVID-19; immunity; T cell; myeloproliferative neoplasm; CML EN COVID-19 immunity T cell myeloproliferative neoplasm CML 692 696 5 05/17/21 20210515 NES 210515 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, has led to very significant global healthcare challenges. Patients with chronic MPN without detectable antibodies had a T-cell response that was broadly equivalent in many areas to that seen in those with detectable anti-SARS-CoV-2 antibodies. For the first time, we have demonstrated that patients with chronic MPN can mount functional memory T-cell responses following natural SARS-CoV-2 exposure. [Extracted from the article]

Summary: Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non‐melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real‐world context. Median follow‐up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22–4·60, P = 0·01] and thrombocytosis> 400 × 109/l at RUX start (HR:1·98, 95%CI: 1·10–4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24–7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17–8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39–6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11–5·25, P = 0·03), platelet > 400 × 109/l (HR: 3·30, 95%CI: 1·67–6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48–8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males. [ABSTRACT FROM AUTHOR]