This UK-based retrospective analysis describes real-world treatment patterns and outcomes in 175 patients with accelerated (AP, n = 69) or blast-phase (BP, n = 106) 'Philadelphia-negative' myeloproliferative neoplasms (MPN-AP/BP) diagnosed between 2013 and 2025. Median age at transformation was 71 years. With a median follow-up of 45.2 months, median overall survival (OS) was 14.9 months, significantly worse for MPN-BP (6.7 months) versus MPN-AP (25.3 months). Treatment selection was heterogeneous across centres. Intensive chemotherapy (IC) improved outcomes only when followed by allogeneic haematopoietic stem cell transplant (allo-HSCT) (median OS 24.7 months). Ruxolitinib-based regimens, particularly combined with azacitidine, showed acceptable activity in AP (median OS 27.2 months). Venetoclax-based regimens achieved a median OS of 14.9 months across the cohort. Multivariable analysis identified IC and venetoclax-based therapy as independently associated with better outcomes, reflecting patient selection, while TP53 mutations predicted inferior survival. IC carried high rates of febrile neutropenia and sepsis; venetoclax was associated with prolonged cytopenias. This study confirms the poor prognosis of MPN-AP/BP, the absence of a unified UK consensus approach and the need for improved therapies and prospective studies to determine optimal treatment approaches for this challenging cohort.

Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti-apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B-cell lymphoma (BCL)-XL/BCL-2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi-naïve patients with myelofibrosis. JAKi-naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate-2 and high-risk myelofibrosis, and ECOG 0-2) and platelet count > 100 × 109/L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 109/L or > 150 × 109/L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR35) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS50) at week 24, change in grade of BMF, anemia response, and safety. Thirty-two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow-up was 44 months (5-58). 63% (20/32) of patients achieved SVR35 at week 24; median (range) time to first SVR35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS50 at week 24; median (range) time to first TSS50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion-independent and 100% (2/2) for transfusion-dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi-naïve patients with myelofibrosis. TRIAL REGISTRATION: NCT03222609.

Acute myeloid leukaemia (AML) is a clonal disorder of the bone marrow, attributable to genetic alterations leading to clonal stem cell overproduction. Tazi et al., have developed a unified molecular and risk stratification tool for AML, based on the correlation between clinical presentation, cytogenetics and a 32-gene variant signature. This classification proposes an integrated risk score based on 16 molecular classes defined by favourable, intermediate and adverse risks groups. The aim of this retrospective study was to investigate the utility of the AML online calculator to stratify real-world data relating to 159 patients diagnosed with AML in Northern Ireland (NI) between 2017 and 2023 into the appropriate classification and risk group in comparison to their classification under European LeukaemiaNet 2017 guidelines. 15% of patients were reclassified, showing the benefit of incorporating clinical and molecular data into classification and risk stratification models.

Background: In myelofibrosis (MF), JAK2 inhibitors alone are not curative. Fedratinib is a selective JAK2 inhibitor. Ropeginterferon Alfa-2b (ropeg), a next generation pegylated IFN, has been shown to induce significant responses in myeloproliferative neoplasms. Combining JAK2 inhibition with interferon may be more effective in the treatment of MF, as haematopoietic cells are activated from quiescence which may render them more sensitive to inhibition. FEDORA is a UK-based phase II trial designed to test the safety, tolerability and efficacy of a combination of fedratinib and ropeg in treatment naïve, JAK2 V617F mutated myelofibrosis. Methods: In this prospective, multicentre, open label, Bayesian, phase II clinical trial patients with JAK2V617F positive primary or secondary MF with an indication for treatment were recruited (ISRCTN:88102629). Each patient was commenced on fedratinib 400mg, as tolerated and when on a stable dose for 28 days, ropeg was introduced at a starting dose of 100micrograms (mcg) subcutaneously every 2 weeks. The dose of ropeg was increased by 50mcg each cycle to the maximum tolerated level or 250mcg. Combination treatment then continues for up to 2 years (until progression, patient choice or unacceptable side effects). Primary outcome was tolerability of the combination. Secondary endpoints included dynamic assessments of JAK2 allele burden and quality of life evaluation. Results: 34 patients from 12 UK sites were recruited. Median age was 68.8 yrs (range (r),32.8-82.9). 47% were female, 74% were White/White European and 12% Asian/Asian British. Median follow-up to date is 12.9 months. Four patients were replaced (3 did not start combination treatment, 1 withdrew within 4 months of starting combination treatment due to scheduled transplant). A total of 31 patients commenced combination treatment, with the majority doing so after receiving 1 cycle of fedratinib monotherapy. The trial met its primary outcome, defined as at least 23 of 30 patients tolerating combination treatment for at least 4 months. At the time of the data snapshot (29th May 2025), 11 patients had discontinued combination treatment. Reasons included: treatment related toxicity (n=6, 3 of which were after the 4-month primary outcome timeframe), proceeding to transplant (n=4) and both treatment-related toxicity (after 4 months) and disease progression (n=1). Symptom scores, as assessed by MPN-SAF, after 3 months of combination treatment had improved from baseline, with the average change across the 15 patients with available baseline and 3-month data showing a decrease for all symptoms. The greatest changes were observed for night sweats (mean change: -1.6 points (range: -7, 1)), abdominal discomfort (mean: -2 (range: -9, 3)), pain under the ribs (mean: -2.3 (range: -8, 1)) and satiety (mean: -2.1 (range: -9, 2)). In total,10 patients (50%) had a palpable spleen at the end of Cycle 4, compared to 25 (89%) at baseline. Across all doses, 32 patients (94%) had an adverse event (AE) related to at least 1 trial treatment, with 18 (53%) patients having a grade 3 or above related AE. The most common related grade ³3 events were anemia and uveitis (affecting 8 and 3 patients respectively). There were 18 serious AEs affecting 12 patients. This includes 9 SUSARs (Suspected Unexpected Serious Adverse Reactions) and 1 expected SAR (Serious Adverse Reaction). Of the samples that have been analysed to-date, paired data are available for 15 patients at baseline and 12 months. Seven patients achieved a relative reduction in JAK2 VAF from baseline of at least 20%, with 4 achieving at least a 50% relative reduction. Comparison of baseline to the last time point was available for 26 patients. The median relative reduction was –14.1% (range: -98.7%, 155.7%). 11 of these patients had achieved at least a 20% relative reduction, including 7 who had a 50% relative reduction or more. Conclusion: The combination of the JAK2 inhibitor fedratinib and ropeg interferon alfa-2b appears tolerable and safe. Symptom score responses and spleen reductions were observed and encouraging reductions in JAK2 allele burden seen in a proportion.

Essential thrombocythemia (ET) and polycythemia vera (PV) are rare in adolescent and young adult (AYA). These conditions, similar to those in older patients, are linked with thrombotic complications and the potential progression to secondary myelofibrosis (sMF). This retrospective study of ET and PV patients diagnosed before age 25 evaluated complication rates and impact of cytoreductive drugs on outcomes. Among 348 patients (278 ET, 70 PV) with a median age of 20 years, the of thrombotic events was 1.9 per 100 patient-years. Risk factors for thrombosis included elevated white blood cell count (>11 × 109/L) (HR: 2.7, p = 0.012) and absence of splenomegaly at diagnosis (HR: 5.7, p = 0.026), while cytoreductive drugs did not reduce this risk. The incidence of sMF was 0.7 per 100 patient-years. CALR mutation (HR: 6.0, p < 0.001) and a history of thrombosis (HR: 3.8, p = 0.015) were associated with sMF risk. Interferon as a first-line treatment significantly improved myelofibrosis-free survival compared to other treatments or the absence of cytoreduction (p = 0.046). Although cytoreduction did not affect thrombotic event, early interferon use reduced sMF risk. These findings support interferon use to mitigate sMF risk in AYA ET and PV patients.

Abstract Background Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial. Methods FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable. Discussion FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based. Trial registration EudraCT number: 2021–004056-42. ISRCTN: 88,102,629.

Treatment with pegylated interferon α resulted in a molecular response in 91% of patients with an average decrease in JAK2V61F VAF of 48.5% from baseline. In patients that discontinued treatment, the JAK2V617F VAF at the time of treatment discontinuation was the best indicator of durable remission over the 6-month follow-up period. Created with SMART Servier Medical Art (https://smart.servier.com/).

Objectives:Activation of IL-6 facilitates CD45 expression in myeloma cells, but little has been reported for myeloid malignancies. This study aimed to investigate whether IL-6 enhances CD45 expression on myeloid malignancies and whether myeloid cells are dependent on IL-6 activation to express CD45 on their cell membrane. Methods:This study was conducted from January to March 2022 at the Queen's University Belfast, UK. Myeloid cell lines such as HEL and OCI-AML3 which expressed higher levels of CD45, and UT-7 and the pro-B NALM-6 cell lines that had lower CD45 levels as well as primary cells were used. The correlation between CD45 expression and IL-6 activation in myeloid cells was studied in terms of survival and response to chemotherapy such as cytarabine. Results:It was found that IL-6 enhances cellular survival in myeloid leukaemia cells. Expression of CD45 could be correlated with IL-6 activation in myeloid leukaemia cells. Quantification of IL-6 confirms the significant effect on cellular proliferation. More importantly, IL-6 significantly alters CD45 expressed myeloid leukaemia cellular response to chemotherapy such as cytarabine. Conclusion:IL-6 significantly induced alteration to cytarabine cellular response in those cells of higher CD45 expression, while its effect on cells of lower CD45 expression was minimal. This suggests the importance of CD45 in the activation of IL-6 pathway and initiation of cellular proliferation events with its consequences of cytarabine chemo resistance and enhancement of leukaemia cells survival and proliferation by inhibiting the apoptotic activities of cytarabine.

Polycythemia vera (PV) was first described by Vaquez in 1892. This is a chronic hematological malignancy which affects both older and young patients. Perhaps due to lack of a curative treatment and the perceived toxicities of prior therapies our focus in the past was to intensify treatment only for patients at higher risk of thrombosis. Recent triggers to challenge this approach include: a recognition that low-risk PV is not "no-risk", our ability to better recognize patients who would benefit from more intensive therapy from the perspective of thrombosis, and data showing that some treatments may reduce risk of transformation to myelofibrosis. Furthermore, there is emergent evidence that molecular monitoring may identify an improvement in disease state translating to improved overall survival. Here we describe clinical situations that would trigger the use of cytoreductive treatment for low-risk PV patients as well as our approach to choosing a specific cytoreductive agent and how to effectively monitor treatment.

Approximately 1140 people are diagnosed with polycythaemia vera (PV) annually in the United Kingdom (UK). Adherence to the British Society of Haematology (BSH) guidelines for PV diagnosis and management is not well understood. To explore UK's PV diagnosis, management practices and unmet needs. A structured survey, co-developed with a UK haematology consultant, an advanced nurse practitioner and a pharmacist, was completed by 57/332 invited healthcare practitioners from July to October 2023 through 1:1 interviews conducted by Novartis Medical Science Liaisons. Results were analysed descriptively. Most respondents (68%) follow the BSH 2018 guidelines for diagnosing PV. Treatment goals are to reduce thromboembolic event risk and control haematocrit and symptoms. Most patients (68%) were receiving cytoreductive therapy (typically first-line hydroxycarbamide); 28% received antiplatelet medication and/or venesection alone. Stable patients are usually monitored every 3 months through telephone (68%), increasing to monthly when uncontrolled, mainly in-person (54%). General practitioners (56%) manage cardiovascular risks, but there is doubt over referral response. All respondents monitor symptoms, with only 19% regularly using MPN10. The greatest educational need was identifying hydroxycarbamide resistance and intolerance (58%). This survey offers insights into therapeutic approaches and areas for improvement in the UK's PV clinical practice.

BACKGROUND:In patients with acute myeloid leukaemia treated with curative intent, the detection of measurable residual disease (MRD) generally confers a poor prognosis. This study aimed to identify whether altering treatment based on MRD results can improve survival. METHODS:In the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials, performed in the UK, Denmark, and New Zealand, we screened patients aged 16-60 years with newly diagnosed acute myeloid leukaemia for molecular markers suitable for disease monitoring, including NPM1 mutations and fusion genes. Patients with a marker were randomly assigned (2:1) to either sequential molecular MRD monitoring during treatment and for 3 years after, or standard clinical care only with no molecular monitoring. In the monitoring group, treating physicians decided whether and how to incorporate the MRD results into the patient's therapy, including in cases of MRD relapse. The primary endpoint was overall survival. Prespecified subgroup analysis of the primary outcome included analysis by molecular group (NPM1mut with FLT3-ITD, NPM1mut without FLT3-ITD, and fusion gene transcripts). Both trials were registered with ISRCTN, ISRCTN55675535 and ISRCTN78449203, and are completed. FINDINGS:In the AML17 trial, 1836 patients were enrolled between June 1, 2012 and Dec 31, 2014. In the AML19 trial, 965 patients were enrolled between Nov 9, 2015, and Jan 23, 2018. 637 patients were randomly assigned across both trials (289 to MRD monitoring and 144 to no monitoring in AML17 and 136 to MRD monitoring and 68 to no monitoring in AML19). With a median follow-up time of 4·9 years (IQR 3·6-5·9), overall survival at 3 years was 70% (95% CI 66-75) in patients in the monitoring group and 73% (68-80) in patients in the no-monitoring group. Meta analysis of the two studies showed no difference in overall survival (hazard ratio [HR] 1·11, 95% CI 0·83-1·49; p=0·25). In the pre-specified subgroup analysis of the primary endpoint, overall survival at 3 years in patients with both NPM1 and FLT3 internal tandem duplication (ITD) mutations was 69% (95% CI 60-79) in the monitoring group and 58% (45-74) in the no-monitoring group (HR 0·53, 95% CI 0·31-0·91; p=0·021). However there was no difference in survival by randomisation in patients with NPM1 mutations without FLT3-ITD (overall survial 69% [95% CI 62-77] in the monitoring group and 78% [70-87] in the no monitoring group; HR 1·56, 95% CI 0·96-2·52) or those with fusion gene transcripts (overall survial 72% [95% CI 65-79] in the monitoring group and 77% [68-87] in the no monitoring group; HR 1·28, 95% CI 0·80-2·18). INTERPRETATION:Sequential molecular MRD monitoring, coupled with MRD-guided treatment, did not improve overall survival in the entire study population; however, in the subgroup of patients with baseline NPM1 and FLT3 ITD mutations, we observed a survival benefit for MRD monitoring. FUNDING:National Institute for Health Research, Blood Cancer UK, and Cancer Research UK.

BACKGROUND:Early cancer recognition is key to improving patient outcomes. Diagnosis is often delayed in patients with myeloproliferative neoplasms (MPNs), putting them at risk of thromboembolic events and other complications pre-diagnosis. A clear understanding of the barriers to presentation and diagnosis is required. AIM:To explore barriers and factors influencing delayed presentation and diagnosis of MPNs. DESIGN & SETTING:A cross-sectional study of patients with MPN within the UK and the Republic of Ireland. METHOD:An online cross-sectional survey of patients with MPN was undertaken. Symptoms and factors influencing patient and GP delay were examined. Adjusted odds ratios (aORs) were calculated to explore the relationship between these factors and patient and GP delay. RESULTS:Most (80.2%) of the 620 patients completing the survey reported symptomatic presentation. The most common symptoms associated with patient delay were pruritus (aOR 1.89, 95% confidence interval [CI] = 1.19 to 3.01), headaches (aOR 1.86, 95% CI = 1.13 to 2.82), and concentration difficulties (aOR 1.75, 95% CI = 1.12 to 2.76). Attributing symptoms to ageing (aOR 1.92, 95% CI = 1.19 to 3.11) and not wanting to burden the GP (2.04, 95% CI = 1.24 to 3.39) were significantly associated with patient delay. Those reporting >3 blood cancer warning signs were more likely to experience GP delay than those experiencing fewer (aOR 3.26, 95% CI = 1.75 to 6.29), and lack of relational continuity of GP care was significantly associated with GP delay (aOR 3.41, 95% CI = 1.65 to 7.28). CONCLUSION:Debunking misconceptions around ageing, encouraging timely communication with GPs, and improving relational continuity of GP care could assist in reducing diagnostic delays, prevent potentially fatal disease complications, and ultimately improve outcomes for patients with MPN.

Myelofibrosis (MF) a myeloproliferative neoplasm is characterised by progressive splenomegaly, cytopenia, debilitating symptoms, and leukemic progression. MF patients (pts) classified as Dynamic International Prognostic Scoring System (DIPSS) High or Intermediate-2 (Int-2) risk have median overall survival of 2-4 years (yrs). Ruxolitinib (rux) is approved for MF and effectively controls disease-related symptoms and splenomegaly in some pts; however, disease control is often inadequate and the disease eventually progresses, thus a major unmet medical need remains. In MF mouse models, the effects of rux are complemented by targeting BET (bromodomain and extra-terminal) proteins. BET and JAK inhibitor combinations have also demonstrated clinical activity in pts with MF, with reduction in spleen size, increase in hemoglobin levels, and alleviation of symptoms reported. The Phase 1, multicentre, dose-finding PROMise trial (EudraCT 2019-000916-27) was designed to evaluate whether the BETi OPN-2853 could be safely combined with rux and restore or increase disease control in MF pts with inadequate response to single-agent rux. Eligible pts are ≥16 yrs, have primary or secondary DIPSS Int-2 or High MF, received ≥24 weeks (wks) of rux (stable dose prior 4 wks), and residual splenomegaly >5cm below costal margin. Two OPN-2853 doses (40 and 80mg QD) are evaluated with 2 rux dose groups (Low [5-20mg daily] and Mid/High [≥25mg daily]) in 21-day cycles. Spleen is assessed by ultrasound at Screening (SCR) and end Cycles 5 & 8, and by palpation at SCR, Day 1 every cycle, and end Cycle 8. Primary outcome measures are dose-limiting toxicities (DLTs) and >50% reduction in palpable spleen from SCR to end Cycle 8. Other key outcomes include adverse events (AEs), symptoms (MFSAF at SCR, Cycles 5 & 8), and molecular response. Recruitment closed in June 2025. As of 05-March-2025, 24 pts have been treated (14 at 40 mg and 10 at 80 mg OPN-2853 QD, respectively; the majority [18/24] in Mid/High category for rux dosing). Median age was 70 yrs (range: 44 to 81) and 13/24 male. 54% of pts had primary MF, 46% secondary MF, 85% and 15% were Int-2 and high-risk respectively. The median baseline spleen length by ultrasound was 20.2 cm (IQR: 16.3 to 23). The median baseline spleen length by palpation was 9 cm (IQR: 6 to 15.3). At the time of analysis 16 pts had completed 8 cycles; with 11 of these continuing beyond that point. Two DLTs (thrombocytopenia and elevated ALT) have been reported; both were at 40 mg QD OPN-2853. AEs ≥ grade 3 include: platelet count decreased (6/24, 25%); anemia (2/24, 8.3%). The median (IQR) spleen size by palpation, calculated as the change from baseline to minimum post-baseline spleen size, reduced by 5.0 (4.8, 6.2) cm in 20 evaluable patients. Of the 9 evaluable pts with non-missing baseline and post baseline values, mean change from baseline to cycle 8 in Brief Fatigue Inventory score improved by 0.9 (95% CI: 0, 1.77). Encouraging levels of spleen reduction and a manageable safety profile have been observed with combination OPN-2853 & rux treatment. Clinical activity observed is supported by symptom assessment and molecular data, and no patients experienced leukemic progression.

Abstract INTRODUCTION The myeloproliferative neoplasms (MPNs) are clonal haematological disorders that display significant clinical heterogeneity. A significant challenge remains identifying patients at increased risk of death, life-altering vascular events or disease transformation (secondary myelofibrosis or blast phase disease/AML). Conventional risk predictors incorporate patient age, blood parameters, molecular profiling and previous thrombosis. However, these risk predictors are restricted to specific clinical events, incompletely capture the dynamic nature of MPN and have limited scope to detect therapy-driven disease modification. Improved dynamic personalised risk prediction that captures fundamental aspects of bone marrow (BM) health in MPN have potential to complement and enhance existing risk models and support the evaluation of new treatments. Here, we propose a novel multi-endpoint AI morphological model (MEAM) that derives risk scores from Essential Thrombocythemia (ET) and Polycythemia Vera (PV) BM trephine (BMT) samples. The adverse events captured include vascular events (thrombosis and haemorrhage), fibrotic (MF) transformation, blast phase / AML transformation and overall survival (OS). METHODS Our training data consists of 949 patients drawn from independent MPN cohorts [PT1 (n=545), MAJIC (n=216), and supplementary internal sources (n=188)], including 643 ET, 145 PV, 39 MF, 102 normal, and 20 AML cases. A total of 1661 H&E WSIs were used. Using a Cox proportional hazards (CPH) framework, we trained a vision transformer to predict multi-dimensional log hazard ratios for four survival endpoints, with built-in attention heatmaps for interpretability. Patch-level features were extracted at 20x magnification using the CTransPath foundation model. The algorithm was developed using 5-fold cross-validation, achieving an average C-index of 0.77 ± 0.017. Predictions on the screening samples from the validation folds were used to illustrate the tool’s clinical utility. RESULTS In ET patients, MEAM matched or exceeded established clinical models in C-index: OS prediction (0.66 vs IPSET = 0.63) and vascular events (0.60 vs revised IPSET thrombosis R-IPSET-T = 0.64). Although no validated risk models currently exist to predict transformation in chronic MPN, we also compared our model's performance against IPSET. MEAM outperformed secondary MF prediction (0.68 vs IPSET =0.57) and AML transformation (0.76 vs IPSET =0.52). Combining MEAM with conventional risk scores markedly improved the prediction across all endpoints: OS [MEAM+IPSET=0.71 (+13%)], vascular events [MEAM+R-IPSET-T=0.68 (+5.9%)], MF transformation [MEAM+IPSET=0.68 (+19%)] and AML transformation [MEAM+IPSET=0.75 (+44%)]. In PV patients, MEAM improved risk prediction over conventional models that incorporates age and previous thrombosis: C-index in progression to secondary MF [MEAM=0.67, conventional=0.50, combined=0.66 (+31%)] and AML progression [MEAM=0.69, conventional=0.56, combined=0.70 (+24%)]. MEAM brought an uplift of 0.02% and 4.1% to vascular and death risk predictions, respectively to the conventional C-index (0.53 and 0.62) when used in conjunction. With an optimised threshold for time-dependent AUROC, ET patients were binarized into low/high risk groups. MEAM stratified all four endpoints significantly (log-rank p < 0.01). Within 5 years of biopsy 80 ET patients experienced a vascular event, with R-IPSET-T failing to flag 25 as being high risk. Notably, MEAM flagged 10 of these cases correctly as high risk. Of 35 patients younger than 60 at diagnosis in whom there was a subsequent vascular event, R-IPSET-T misclassified 77% (27/35) as (very) low/intermediate risk. MEAM correctly identified 10/27 (37%) of these as high risk. Among 34 deaths in this younger age group, IPSET labelled all as low/intermediate risk. By contrast, MEAM identified 13/34 (38%) as high risk. CONCLUSIONS We present an AI-based morphological model that enhances risk stratification in ET and PV. Our morphology predictor offers prediction power comparable or superior to established clinical risk predictors for vascular events, disease progression and OS. Using MEAM to augment existing and newly emerging prognostic tools, we envision an interpretable and dynamic morphological risk score that is ideally suited to routine clinical application and can support the development of novel therapies that aim to induce meaningful disease modification in MPN.

An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non-hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non-hematological reasons for the elevated hemoglobin.

We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.