Essential thrombocythemia (ET) is a myeloproliferative neoplasm in which JAK2, CALR, and MPL mutations are associated with distinct clinical phenotypes. Here, we analyzed the platelet proteome of ET patients by MS, combined with functional assays, to investigate platelet activation. Compared with healthy controls, ET platelets showed altered abundance of mitochondrial and metabolic proteins, including reduced levels of tricarboxylic acid cycle enzymes and a relative enrichment of glycolytic signatures. Acetylsalicylic acid decreased the abundance of metabolic proteins in CALR Type1 platelets, whereas JAK2 V617F platelets showed only minor, heterogeneous increases restricted to a subset of proteins and samples. In functional assays, JAK2 V617F platelets showed aggregation responses similar to or lower than those of healthy controls, whereas untreated CALR Type2 platelets showed higher CD62P expression, indicating a more activated phenotype than the other ET groups. These findings indicate that ET platelets display mutation-associated proteomic and functional differences and suggest that an altered metabolic state may contribute to platelet reactivity.

Data on real-world survival and treatment patterns in large, unselected myelofibrosis (MF) cohorts remain limited. We analysed 1649 patients with MF diagnosed from 2010 onwards and included in the Spanish Myelofibrosis Registry across 64 centres. Janus kinase (JAK) inhibitors were administered to approximately half of the patients. Among those aged ≤70 years with intermediate-2/high-risk International Prognostic Scoring System (IPSS), only 25% ultimately underwent transplantation. Median survival was 6.6 years, with no significant differences between primary and secondary MF; acute leukaemia was the most frequent cause of death, accounting for 20% of cases. Compared with a matched general population, relative survival at 5 and 10 years was 68% and 44% respectively. The reduction in relative survival was more pronounced in patients aged >65 years and in male patients, two subgroups that also exhibited a higher burden of comorbidities and a greater frequency of high molecular risk mutations. Remarkably, patients in the high-risk IPSS category had a 10-year relative survival of only 12%; however, survival reduction was not confined to high-risk disease, with divergence from expected survival emerging early among lower-risk categories. These findings highlight the persistent impact of MF on life expectancy in the contemporary JAK inhibitor era and the need for improvement in its overall management.

Abstract Response to cytoreductive therapy according to CALR mutation type, CALR variant allele frequency (VAF), and additional mutations has not been previously studied in essential thrombocythemia (ET). The impact of the molecular profile on treatment response and the main clinical outcomes was analyzed in 557 CALR ET patients (CALR Type 1, n = 339, median VAF 36%; and CALR Type 2, n = 218, median VAF 35%). NGS data on additional mutations were available for 257 patients. CALR Type 2 showed a significantly higher rate of complete hematological response (CHR) to first‐line cytoreduction. However, in the multivariate analysis, the effect of CALR mutation type in response rates was no longer significant once CALR VAF was considered, whereas high VAF remained independently associated with a lower likelihood of achieving CHR (hazard ratio [HR] = 0.482, 95% confidence interval (CI): 0.297–0.781; P = 0.003). Moreover, high VAF was also associated with an increased risk of arterial thrombosis (HR = 4.135, 95% CI: 1.093–15.645; P = 0.037), and progression to MF (HR = 2.631, 95% CI: 1.004–6.890; P = 0.049). Although allele burden affects overall survival (OS) in the entire population, its impact was surpassed by the presence of high molecular risk (HMR) mutations (HR = 2.114, 95% CI: 1.070–4.176; P = 0.031). Furthermore, the HMR profile was also associated with a higher risk of progression to acute leukemia, while it did not influence the probability of CHR or progression to MF. In conclusion, CALR VAF and HMR profile appear to be more important than CALR mutation type regarding treatment response and major clinical outcomes in ET.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Following its initial commercial availability in the USA on 14 December 2012, safety concerns, notably vascular occlusive events, led to the implementation of post-approval risk-management measures (RMMs). This retrospective study assessed the impact of these measures on adverse event (AE) reporting rates for ponatinib’s important identified risks (IIRs). AEs related to ponatinib’s IIRs were identified from the Incyte Global Safety Database for the period 14 December 2012 to 13 December 2022, using a Medical Dictionary for Regulatory Activities–based search of postmarketing reports. Reporting rates were calculated as the ratio of reported AEs to estimated postmarketing exposure. During the first year of commercialization, the most frequently reported AEs for ponatinib pertained to the IIRs of myelosuppression, skin reactions, infections, and arterial occlusive events, with reporting rates of 0.505, 0.362, 0.330, and 0.291, respectively. Following implementation of post-approval RMMs in December 2013, reporting rates of these IIRs decreased considerably during the first 2 years of commercialization. By the end of year 10, reporting rates of these IIRs further decreased to 0.043, 0.030, 0.045, and 0.038, respectively. Notably, reporting rates for each IIR across the 10-year period were considerably lower than the reporting rates observed during the first year of ponatinib commercialization. This study shows declining AE reporting rates for ponatinib’s IIRs since it first became commercially available, potentially because of the implementation of RMMs and increased clinicians’ awareness.

PURPOSE:Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in Janus kinase inhibitor-naïve MF. METHODS:In this double-blind, phase III trial, patients were randomly assigned (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Coprimary end points were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. RESULTS:A total of 353 patients were randomly assigned. At week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58 [95% CI, 1.60 to 4.17]; P < .0001). Differences were evident by week 12 and through week 36. The AbsTSS coprimary end point was not met; however, symptom scores improved from baseline in both groups (-9.9 selinexor plus ruxolitinib, -10.9 placebo plus ruxolitinib), with no significant between-group difference. At a median follow-up of approximately 12 months, the overall survival (OS) hazard ratio was 0.43 ([95% CI, 0.19 to 1.00]; nominal P = .022). Grade ≥3 adverse events (AEs) occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early. CONCLUSION:In patients with JAK inhibitor-naïve MF, selinexor plus ruxolitinib met its coprimary end point of improved SVR35 but did not meet the AbsTSS coprimary end point, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known AE profiles of the individual agents.

Triple-negative essential thrombocythemia (TN-ET) represents a diagnostic and therapeutic challenge. The aim of the present study was to identify prognostic factors useful for tailoring treatment. 241 TN-ET patients with myeloid panel sequencing and confirmatory bone marrow biopsy were selected. Pathogenic/likely pathogenic variants were identified in 19.5% of patients. Mutation carriers were older (median age 66 years vs. 53, p < 0.001) and had a higher frequency of prior thrombosis (19.6% vs. 6.5%, p = 0.013). Presence of pathogenic/likely pathogenic variants was associated with leukemic progression (HR 12.608; 95% CI: 2.616-60.775, p = 0.002) and lower overall survival (HR 3.008; 95% CI: 1.43-6.327, p = 0.004). ASXL1 (p = 0.004), CBL (p < 0.001), EZH2 (p < 0.001), and ZRSR2 (p < 0.001) mutations were associated with inferior leukemia-free survival. Age over 60 years, previous thrombosis, and cardiovascular risk factors were associated with higher thrombotic risk. Revised IPSET-thrombosis was useful for risk stratification (10-year probability of overall thrombosis: 30%, 15%, and 6% for high-, intermediate-, and very-low risk patients, respectively, p < 0.001). ARTS score refined arterial thrombosis stratification (10 years probability: 25% and 6% for high- and low-risk, respectively, p < 0.001). Progression to myelofibrosis was a rare event in this cohort (2.5%). These results highlight the biological and prognostic relevance of molecular profile in TN-ET.

Tyrosine kinase inhibitors (TKIs) discontinuation is the standard option for patients with chronic myeloid leukaemia (CML) in deep molecular response (MR) with imatinib. This study aimed to evaluate the efficacy and safety of one year consolidation with ponatinib on treatment-free remission (TFR) rate. This was a multicenter open-label, single-arm, phase II, exploratory clinical trial including patients with CML treated ≥4 years with imatinib therapy, and MR4.0 ≥12 months. Patients entered the TFR phase after receiving ponatinib at 15 mg/day for one year. Twenty three patients received ponatinib and 19 completed consolidation. Among the patients with detectable BCR::ABL1, 70

Myelofibrosis (MF) is a rare myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, splenomegaly, and debilitating symptoms. Anemia, present in approximately 35

Introduction Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts, risk of vascular events and disease progression to myelofibrosis or acute leukemia. Most available therapies primarily focus on reducing platelet counts without any demonstrated impact on disease progression. Moreover, these treatments are often limited by intolerance, resistance or contraindications, leaving a substantial proportion of patients without satisfactory therapeutic options. Ropeginterferon alfa-2b (BESREMi®), a mono-pegylated, next-generation interferon alfa, approved globally for polycythemia vera with the potential to modify disease course, is being studied to address this unmet need. Methods This fully recruited, ongoing, phase 3, prospective, multicenter, single-arm study (ROP-ET; NCT06514807) enrolled adults with ET according to WHO 2016 criteria requiring cytoreduction, who were intolerant or resistant and/or ineligible for all locally approved cytoreductive therapies including hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman (PB). A single-arm design was selected due to lack of an ethically acceptable comparator. Ropeginterferon alfa-2b is administered subcutaneously every two weeks starting at 125μg, with dose escalation to 250μg and 500μg if needed to achieve hematologic response. The primary endpoint is a composite durable hematologic and clinical response after 12 months based on modified European LeukemiaNet (ELN) criteria, including peripheral blood count remission, absence of thrombotic/hemorrhagic events and disease progression, and symptom improvement measured by the MPN-SAF Total Symptom Score (MPN-SAF TSS). The sample size was determined to ensure at least 93 evaluable patients for 12-month primary analysis (10% precision), with target enrollment of at least 117 to account for 20% dropout. The observed 12-month response rate will be statistically compared to a historical efficacy of 40%. Secondary endpoints include molecular response, quality of life, safety, and long-term outcomes. The total study duration is three years. Results A total of 132 ET patients received ropeginterferon alfa-2b. The study population had a median age of 56.5 years (range 22-87), included 58.3% females, and the median time from diagnosis was 3.3 years (range 0-25). Baseline median platelet count was 579 ×109/L (range 201-1958) and median white blood cell count was 7.3 ×109/L (range 3.2-20.5). At baseline, splenomegaly was present in 25.8% of patients and median MPN-SAF TSS was 8.0 (range 0-66). Driver mutations were distributed as follows: JAK2 (59.8%), CALR (27.9%), and MPL (1.6%). Risk stratification per revised IPSET-thrombosis criteria identified 43.8% patients as high, 13.8% as intermediate, 22.3% as low and 20% as very low risk. Of 132 patients 110 (83.3%) had prior cytoreductive therapy with either HU (32.6%), ANA (13.6%), HU and ANA (36.4%), or HU and PB (0.8%) but none received BUS. Among pre-treated patients, 107 (97.3%) patients were cytoreductive treatment resistant and/or intolerant with intolerance being most prominent (77.2% and 78.8% among HU and ANA pre-treated patients, respectively). All patients were interferon-naïve per inclusion criteria; 22 (16.7%) patients had not received any other cytoreductive therapy and were ineligible for all locally approved cytoreductive agents for ET. As of data cut-off (median exposure 301 days) treatment-emergent adverse events led to discontinuation in only 4 (3%) patients. The last patient 12-month visit will occur in Q3 2025 and primary endpoint results will be presented at the meeting. Conclusions Our study highlights the unmet need among ET patients of all risk levels for additional therapeutic options, since all patients enrolled required cytoreduction but were unable to receive locally approved agents. Aside reduction of thrombotic risk, ET patients, in particular younger individuals, have a significant lifetime risk of disease progression, requiring a disease modifying therapy. In this last-line population, treatment with ropeginterferon alfa-2b was well tolerated, with few discontinuations due to adverse events. The planned primary endpoint analysis will provide data on the efficacy of ropeginterferon alfa-2b in this underserved population.

LBA3 Background: PV is characterized by red blood cell overproduction. Rusfertide is a subcutaneous (SC), self-injected, first-in-class peptide hepcidin mimetic that decreases erythrocytosis. VERIFY (NCT05210790) is a global, ongoing phase 3 study designed to assess rusfertide vs PBO in phlebotomy (PHL)-dependent patients (pts) with PV receiving standard of care (SOC) therapy. Methods: In VERIFY Part 1a (Weeks [Wks] 0-32), pts requiring frequent PHL with or without stable cytoreductive therapy (CRT) to control hematocrit (Hct) were randomized (1:1) to receive once-weekly rusfertide or PBO. Pts were stratified by concurrent PV therapy. All pts completing Part 1a were eligible for open-label rusfertide in Part 1b (Wks 32-52). Pts who completed Part 1b were eligible to continue receiving rusfertide. The primary efficacy endpoint was the proportion of pts achieving a clinical response (ie, absence of PHL eligibility and no PHLs from Wks 20-32, and Part 1a completion). Key secondary endpoints (Wks 0-32) included mean number of PHLs, proportion of pts with Hct <45%, and mean change from baseline at end of Part 1a (Wk 32) in the (1) PROMIS Fatigue Short Form 8a (SF-8a) total T-score and (2) MFSAF v4.0 Total Symptom Score (TSS). Results: A total of 293 pts (male, 73.0%; median age, 57 [27-86] years) were randomized to receive rusfertide (n=147) or PBO (n=146). In the rusfertide and PBO groups, 56.5% (n=83) and 55.5% (n=81) of pts, respectively, received concurrent CRT. During Wks 20-32, significantly more pts in the rusfertide group (76.9%) achieved a clinical response vs PBO (32.9%) (p<0.0001). The mean (SE) number of PHLs (Wks 0-32) was 0.5 (0.2) with rusfertide vs 1.8 (0.2) with PBO (p<0.0001). More pts treated with rusfertide maintained Hct <45% from Wks 0-32 vs PBO (rusfertide, 62.6%; PBO, 14.4%; p<0.0001). For patient-reported outcomes (PROs), pts treated with rusfertide demonstrated a statistically significant improvement in the PROMIS Fatigue SF-8a total T-score and MFSAF TSS (p<0.03). During Part 1a, the most common treatment-emergent adverse events (AEs) in the rusfertide and PBO groups, respectively, were injection site reactions (55.9% and 32.9%), anemia (15.9% and 4.1%), and fatigue (15.2% and 15.8%). Serious AEs occurred in 3.4% (rusfertide) and 4.8% (PBO) of pts; none were considered related to rusfertide. During Part 1a, new malignancies were reported in 1 (rusfertide) and 7 (PBO) pts. Conclusions: In pts with PV receiving SOC, rusfertide resulted in a statistically significant reduction in the mean number of PHLs and improved Hct control. Rusfertide is the first investigational agent to target the hepcidin pathway to control Hct and the first agent to prospectively demonstrate a statistically significant improvement in the PROMIS Fatigue SF-8a and MFSAF PROs in pts with PV. Rusfertide had a safety and tolerability profile consistent with rusfertide in prior studies. Clinical trial information: NCT05210790 .

In patients with myelofibrosis (MF), driver mutation status, presence of additional mutations (especially of high-molecular risk, HMR) and adverse karyotype all have prognostic value and, as a result, have been incorporated into recent prognostic models. Published data from several real-world studies on momelotinib-treated (MMB) MF patients confirm its efficacy—particularly in improving anemia and reducing transfusion dependence. The MOMGEMFIN study included 154 MF patients treated with MMB, 76.6% of which had prior JAK inhibitor exposure. At baseline, 70.1% were transfusion-dependent (TD). MMB led to a sustained improvement in anemia, with achievement of transfusion independence (TI) in 48.4% of TD patients at 3 months. However, there is still limited data regarding predictors of response based on patients' mutational profiles. In this context, we present the results of the molecular sub-analysis from the MOMGEMFIN project, which studied the impact of genetic profile on response to (MMB). The main variables analyzed were driver gene mutations and presence of additional mutations, evaluated with next-generation sequencing (NGS) using a myeloid gene panel. HMR were defined as presence of pathogenic/probable pathogenic mutation in ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 genes. NGS data was available in 108 patients prior to MMB start. Sixty-two percent were male, with a median follow-up of 4.95 months. The most frequent driver mutation genotype was JAK2 (63%), followed by CALR (22.7%), triple negative (TN) (6.5%), MPL (5.8%), and unknown (1.9%). Among patients with NGS data, 63.9% harbored additional mutations, the most common being ASXL1 (34.3%), TET2 (14.8%), U2AF1 (11.1%), SRSF2 (8.3%), EZH2 (8.3%), SF3B1 (8.3%), RAS (7.4%), and IDH1/2 (3.7%). Among 122 patients with baseline anemia, no association was observed between anemia response (according to 2024 IWG-ELN criteria) and driver mutations. However, patients with additional mutations showed a trend toward poorer anemia response (>1 g/dL, p=0.013; >1.5 g/dL, p=0.002; Pearson), particularly those with a HMR. Statistical significance was not reached for individual genes, likely due to the small sample size, with the exception of U2AF1. Driver mutations had no significant impact on transfusion independence (TI, according to 2024 IWG-ELN criteria). However, only a third of patients with additional mutations achieved transfusion independence (15/45, 33.3%), compared to 55.6% of patients without an additional mutation (p=0.103). This decreased further to just 16.7% of patients with more than one HRM mutation (p=0.023). The presence of a U2AF1 mutation was significantly associated with not reaching TI (p=0.022). For the group of patients previously treated with JAK inhibitors (n=118), JAK2 mutation was associated with TI (p=0.008), whereas TN and MPL were negative predictors (p=0.067 and p=0.155). This trend was not observed for the JAK inhibitor-naïve group (p=0.053), likely due to the small sample size. Overall survival from the initiation of MMB differed significantly according to driver mutation status (p = 0.023; Log-rank test). Longer survival was observed in patients with JAK2 (mean: 11.7 months) and CALRmutations (mean: 13.7 months), whereas patients with MPL mutations or TN had shorter survival (mean: 7.0 and 7.1 months, respectively). Presence of additional mutation was not significant, but a negative trend was observed with U2AF1 and HMR. JAK2mut patients who had received prior JAK inhibitor treatment also showed superior OS compared to other driver mutations (p=0.042). The positive impact of JAK2mut on OS (p=0.034 Log-rank, JAK2mut vs. JAK2WT) was completely negated if patients also harbored a U2AF1 mutation (n=12 JAK2/U2AF1 co-mutated), with survival significantly reduced from MMB initiation (p=0.037) and from the time of diagnosis (p<0.001). Importantly, TI was associated with improved overall survival, both from diagnosis (p=0.012) and from MMB start (p=0.007). These data show that U2AF1mut correlates with a lower probability of TI in MMB treated patients. The JAK2 driver mutation was associated with a better response to MMB with the exception of those with a U2AF1 co-mutation. Transfusion dependence negatively impacted overall survival, consistent with published data.

Abstract Background: Patients with polycythemia vera (PV) are at increased risk of developing other non-PV malignancies, including skin cancers (Landtblom AR, et al. Leukemia. 2018;32:2203-10; Loscocco GG, et al. Blood. 2024;144(Supplement 1):4552). Given the propensity of patients with PV to develop cutaneous malignancies, we performed dermatologic screening examinations prior to patient randomization and at Week 32 as part of the primary efficacy and safety analysis in the phase 3 VERIFY study (NCT05210790) to ensure patients received appropriate care and treatment. The primary objective of this abstract is to report results from dermatologic screening examinations that were conducted prior to randomization in the rusfertide and placebo groups and in the placebo group at the end of VERIFY Part 1a (Week 32, ie, prior to when patients cross over to rusfertide at the beginning of Part 1b). Methods: The ongoing phase 3 VERIFY study enrolled patients with PV who required frequent phlebotomies (defined as ≥3 phlebotomies in 28 weeks or ≥5 phlebotomies in 52 weeks prior to randomization) to control and maintain hematocrit <45%. Patients were randomized (1:1) to either rusfertide or placebo in addition to current standard-of-care (SOC) therapy for PV. After patients provided informed consent, they underwent mandatory dermatologic examinations during a 4-week screening period, at Week 32 following completion of Part 1a, and at other periods throughout the study. Examinations by dermatologists were preferred but not required. If a dermatologist was not available, a trained investigator or medical professional performed the skin examination. If a patient had in situ or stage 1 squamous cell carcinoma (SCC) of the skin, in situ or stage 1 basal cell carcinoma (BCC) of the skin, or in situ melanoma of the skin identified during the dermatologic examination at screening, the patient was not eligible to participate in VERIFY unless the cancer was adequately treated (ie, curative treatment such as Mohs surgery). Patients diagnosed with skin cancer at Week 32 received appropriate therapy and were allowed to proceed onto Part 1b, the open-label portion of the study (Weeks 32-52). Results: We screened 399 patients for study eligibility; of these patients, 106 failed screening, and 293 patients were randomized to rusfertide (n=147) or placebo (n=146). Of the 293 patients who were randomized in VERIFY, 47 (16.0%) had medical history of other non-PV cancers, and 40 (13.7%) had history of skin cancer. During screening, skin malignancies were identified in 11 patients, including 7 who had BCC, 1 who had malignant melanoma, 1 who had melanoma in situ, and 1 who had scrotal SCC in situ. Of the 11 patients who had skin malignancies identified during screening, 2 patients failed screening, and 9 patients were randomized to the rusfertide (n=4) or placebo (n=5) groups. Of these 11 patients, 9 (81.8%) received hydroxyurea (HU), 2 (18.2%) received interferon, and 1 (9.1%) received ruxolitinib prior to being screened for their potential participation in VERIFY (3/11 patients received more than one prior cytoreductive therapy [CRT]). During screening, 2 patients were found to have non-malignant dysplastic nevi, and an additional patient had non-malignant atypical nevus. In addition, 1 patient had two separate actinic keratosis lesions and a dermatofibroma lesion that was identified during screening. Another patient received treatment with liquid nitrogen for a suspicious lesion of uncertain behavior with a differential diagnosis of actinic keratosis vs SCC. After randomization to the placebo group, 6 patients (4.1%) were diagnosed with new skin cancers, including 3 BCCs (2.1%), 2 SCCs (1.4%), and 1 malignant melanoma (0.7%). Four of these 6 patients (66.7%) also received CRT prior to study entry (HU, n=3; ruxolitinib, n=2; 1 patient received both HU and ruxolitinib). Conclusions: To our knowledge, this is the first phase 3 study in the setting of PV to prospectively screen patients for skin cancers prior to being exposed to the investigational agent under study. Identification of non-malignant and malignant skin lesions in VERIFY prior to rusfertide exposure illustrates the importance of screening patients with PV for these lesions. Routine dermatologic screening deserves further investigation in other clinical studies and as a potential SOC for optimal treatment and management of patients with PV.Supported by: Protagonist Therapeutics, Inc.

[This corrects the article DOI: 10.3389/fimmu.2025.1571680.].

ABSTRACT:The efficacy of and disease control afforded by tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia in chronic phase (CML-CP) have led to increased longevity and thus the continued pursuit of alternative therapies that are efficacious and maximize tolerability. The 24- and 96-week analyses from ASCEMBL demonstrated superior efficacy, safety, and tolerability of asciminib when compared with bosutinib in later-line therapy, thereby meeting the primary and key secondary objectives. With nearly 4 years of follow-up, data from ASCEMBL continued to demonstrate the superior efficacy, safety, and tolerability of asciminib over bosutinib. At week 156, the major molecular response (MMR) rates remained higher with asciminib (33.8%) than with bosutinib (10.5%); the difference in MMR rates between arms, after adjusting for baseline major cytogenetic response, was 23.2% (95% confidence interval, 13.14-33.18; 2-sided P < .001). Asciminib continued to cause fewer grade ≥3 adverse events (AEs; 59.6% vs 68.4%) and fewer AEs that led to treatment discontinuation (8.3% vs 27.6%) than bosutinib. This updated analysis also includes patients who switched to asciminib because of a lack of efficacy with bosutinib. Two of the 25 patients who switched achieved MMR by the end of study, suggesting that earlier incorporation of asciminib, before other TKIs, may improve responses, albeit modestly. These long-term results further solidify asciminib as the therapy of choice for patients with CML-CP who were previously treated with ≥2 previous TKIs. This trial was registered at clinicaltrials.gov as #NCT03106779.

Although SARS-Cov-2 outcomes have improved in the Omicron era, the synergistic or additive effects between SARS-CoV-2 Omicron variants and other microbiological agents in adult hematologic patients have been little explored. We aimed to characterize co-infection types, identify risk factors for co-infection and determine co-infection-related mortality in hematologic patients and recipients of cellular therapy with a first episode of SARS-CoV-2 infection in the Omicron era. Retrospective national Spanish registry analysis of 692 consecutive patients with hematological disease including receptors of cellular therapy from December 2021 to May 2023. The co-infection rate was 9

Platelets are key players in hemostasis and thrombosis. Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) in which the JAK2 V617F, MPL W515K/L, and CALR mutations determine differences in clinical phenotype, in particular the thrombotic risk and the risk of myelofibrosis. Here, we examined the proteome of platelets in ET by mass spectrometry (MS) in combination with functional assays to gain insights into platelet activation in ET. MS analysis revealed a different proteome in ET platelets with stoichiometric differences in mitochondrial proteins compared with normal platelets. The tricarboxylic acid cycle enzymes (TCA) were in general downregulated in ET platelets while glycolysis enzymes were upregulated changing modes in energy production. Acetyl salicylic acid (ASA) treatment increased levels of TCA enzymes in controls and restored them only partially in JAK2 V617F platelets. Interestingly, membrane CD36 was higher in CALR Type1 implicating lipid transport and fatty acid oxidation in platelet lifespan. Aggregation levels specifically in JAK2 V617F platelets were similar or lower to healthy controls while activation markers i.e. CD62P were higher in untreated CALR Type2 than controls and the rest of ET. In summary, analysis of platelet proteome in ET implicates mitochondrial activity in platelet activation and also identified differences between JAK2 V617F and CALR patients. Our study suggests that metabolic finetuning can be critical in the control of platelet reactivity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by funds from the Comunidad de Madrid, Atraccion de Talento (2016-T1/BMD-1051 and 2020-5A/BMD-19731 to P.P), the Stichting tegen Kanker (C/2014/302 to P.V) and Research Foundation_Flanders (FWO, G.0908.15 to P.V) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of the University Hospital Leuven (study number S53745), and the Hospital Clinico San Carlos (Madrid, C.P - C.I. 16/257-E_BS) gave approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw files and processed proteomics data of two independent experiments have been deposited to the ProteomeXchange Consortium via the PRIDE (13) partner repository with the dataset identifiers PXD052171 and PXD050550.