ABSTRACT:Novel treatments that can improve outcomes of essential thrombocythemia (ET) are needed. In a phase 2 trial, participants with ET who required cytoreduction and had inadequate response to, or were intolerant of, ≥1 standard therapy received bomedemstat at a starting dose of 0.6 mg/kg per day, titrated to achieve a target platelet count (200 × 109/L to 400 × 109/L). Primary end points were safety and response, defined as a platelet count of ≤400 × 109/L without new thromboembolic events. Of 73 who received bomedemstat, at 24 weeks, 49 of 64 evaluable participants (77%) achieved a response. Durable reductions in platelet count (≤400 × 109/L for ≥12 weeks) were observed in 52 of 72 participants (72%). Durable reduction in white blood cell count (<10 × 109/L for ≥12 weeks) was observed in 61 of 72 participants (85%); of 10 participants with elevated white blood cell count at baseline, 9 had normal white blood cell count (<10 × 109/L) at week 24. Hemoglobin levels remained stable. After 24 weeks of treatment, a decrease in variant allele frequency of CALR, JAK2, or MPL was observed in 39 of 46 (85%) evaluable participants. By week 24, 2 of 73 participants (3%) had experienced ≥1 thrombotic event, and 15 of 73 (21%) experienced ≥1 hemorrhagic event. During overall treatment period, grade 3 or 4 adverse events (AEs) occurred in 34 of 73 participants (47%). AEs led to temporary treatment interruption in 29 participants (40%) and permanent discontinuation in 11 (15%). No participants died due to AEs. Bomedemstat had clinically relevant activity and manageable safety in participants with ET. This trial was registered at www.clinicaltrials.gov as #NCT04254978.

ABSTRACT:Secondary myelofibrosis (SMF) represents a late stage of polycythemia vera (PV) and essential thrombocythemia (ET), with overall survival (OS) currently defined by the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM). To identify additional myeloid neoplasm-associated cancer gene variants (CGVs) associated with SMF outcome, we evaluated next-generation sequencing panel testing in 644 patients within the MYSEC cohort. Overall, 429 (66.6%) patients reported at least 1 CGV, with ASXL1, TET2, and DNMT3A being the most frequently involved. Specific molecular profiles affected OS (P< .001): U2AF1, TP53, or SRSF2 variants (UTS; 9.3%; median OS, 4.1 years) and ASXL1 without UTS (25.3%; median OS, 8.4 years). By integrating these genetic signatures within the MYSEC-PM through penalized Cox regressions, we identified the following independent predictors (P< .0001 to .02): hemoglobin level <11 g/dL (1 point), circulating blasts ≥3% (2 points), platelet count <150 × 109/L (2 points), age (0.21 points/y), ASXL1 without UTS mutations (1 point), and any UTS mutations (3 points). Finally, we developed the MYSEC-molecular prognostic model (MYSEC-mPM) allocating 582 patients with SMF into 4 categories with different OS (P < .001): low (median OS, 18.0 years; score <14), intermediate-1 (8.8. years; score, 14-16), intermediate-2 (4.6 years; score, 17-18), and high risk (1.9 years; score ≥19). Additionally, in 381 patients with SMF and available cytogenetics, the MYSEC-mPM was implemented with complex/monosomal karyotype, generating the karyotype-enhanced MYSEC-kmPM. Our study shows that genomic and cytogenetic profiling improves survival prediction in SMF, outperforming the MYSEC-PM.

6521 Background: Intensive chemotherapy (IC; cytarabine plus an anthracycline) remains a standard first-line therapy for fit patients with acute myeloid leukemia (AML), a heterogeneous hematologic malignancy with poor long-term survival. IC induces composite complete remission (cCR) in ~60–70% of cases, and IC response variability persists within genetic/ELN risk strata. As emerging regimens increasingly challenge IC as a default therapy, biology-informed predictors are needed to identify patients unlikely to benefit from IC to avoid unnecessary toxicity. Mass spectrometry (MS)-based phosphoproteomics enables quantitative profiling of phosphopeptides (PPs) from patient samples, providing a functional readout of tumor biology. Thus, we sought to develop a PP-based clinically-deployable assay, orthogonal to genetic risk stratification, to predict response to IC in AML. Methods: 261 retrospective samples were collected from patients with newly-diagnosed AML (Table) treated with standard “7+3” IC in 9 centers in Europe, Australia, and North America. Response was assessed at the end of induction by the treating physician. Samples underwent phosphoproteomics using: 1) global MS for biomarker discovery or 2) targeted, clinically-compatible MS for validation. Predictive model performance was evaluated using rebalanced leave-one-out cross-validation. Results: During discovery, 3205 PPs were detected. Using Bayesian approaches, we identified an 80-PP multi-analyte signature of IC response (refractory vs cCR), and achieved an AUROC of 0.68 (95% CI 0.54-0.83). The signature was enriched for DNA damage signalling and repair (DNA-PK-S2612, ATM/cohesin, nucleotide excision and double-strand break repair proteins), and cellular stress pathways (phospho-p38, IL-16, AP-1/c-Jun). In an independent validation cohort, the targeted assay reliably detected the biomarker set and preserved its association with outcome (AUROC 0.69; 95% CI 0.53-0.84). Biomarker-based classification was associated with improved event-free survival (HR 0.45; 95% CI 0.26-0.78). Conclusions: We identified and validated a signature of response to IC in AML, and translated it into a targeted, clinically-deployable assay. This approach captures signaling states relevant to IC mechanisms of action that are not directly inferred from standard clinical or genetic variables. Ongoing analyses are evaluating its relationship to established genetic and ELN risk stratification. These findings support diagnostic phosphoproteomics and suggest functional biomarkers may complement existing approaches for treatment selection in AML. Cohort characteristics. Cohort Discovery Validation Median age at diagnosis (years, quartiles) 54 (23, 65) 59 (47, 68) Median diagnosis year (range) 2014 (1999, 2023) 2013 (2001, 2024) No of patients/samples 135/165 102/106 No of cCR/Refractory 94/41 79/23 PPs 3205 80

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.

Novel treatments that can improve disease course of essential thrombocythemia (ET) are needed. In this phase 2 trial, participants with ET who required cytoreduction and had inadequate response to or were intolerant of ≥1 standard therapy received bomedemstat at a starting dose of 0.6 mg/kg per day, titrated to achieve a target platelet count (200-400×109/L). Primary end points were safety and response, defined as a platelet count ≤400×109/L without new thromboembolic events. Seventy-three participants received bomedemstat. At 24 weeks, 49 of 64 evaluable participants (77%) had a response. Durable reductions in platelet count (≤400×109/L for ≥12 weeks) were observed in 52 of 72 participants (72%). Durable reduction in white blood cell count (<10×109/L for ≥12 weeks) was observed in 61 of 72 participants (85%); of 10 participants with elevated white blood cell count at baseline, 9 had normal white blood cell count (<10×109/L) at week 24. Hemoglobin levels remained stable. After 24 weeks of treatment, a decrease in variant allele frequency of CALR, JAK2, or MPL was observed in 39 of 46 (85%) evaluable participants. By week 24, 2 of 73 participants (3%) had experienced ≥1 thrombotic event and 15 of 73 (21%) experienced ≥1 hemorrhagic event. During overall treatment period, grade 3 or 4 adverse events (AEs) occurred in 34 of 73 participants (47%). AEs led to temporary treatment interruption in 29 participants (40%) and permanent discontinuation in 11 (15%). No participants died due to AEs. Bomedemstat had clinically relevant activity and manageable safety in participants with ET. Registration: NCT04254978 (Study of Bomedemstat in Participants With Essential Thrombocythemia [IMG-7289-CTP-201/MK-3543-003])

Myeloproliferative neoplasms (MPNs) are caused by acquired mutations in hematopoietic stem and progenitor cells (HSPCs). The acquisition of additional mutations like TP53 and the overall mutational burden influence a patient's risk of disease progression toward lethal post-MPN acute myeloid leukemia (AML). Recent technological advancements in linking single-cell gene expression with genotype have improved our understanding of tumor heterogeneity. However, current methodologies have limitations in simultaneously genotyping low-expression genes (such as JAK2) alongside other pathogenic loci. To address this, we developed a novel long read genotyping pipeline of cDNA transcripts called LOTR-Seq, which can genotype the full length of expressed transcripts of 30 genes at once. Using LOTR-Seq, we genotyped HSPCs at the JAK2V617 locus in 9,075 single cells from eight patients with chronic phase MPN (CP-MPN) and in 5,016 cells from four patients with post-MPN AML. We then linked the mutations to the single cell transcriptome of 29,712 JAK2V617F-driven CP-MPN cells and 16,895 post-MPN AML cells. In our analysis of post-MPN AMLs, we identified nine mutated loci across six genes (JAK2, IDH1/2, TP53, SRSF2, U2AF1) and linked these mutations to specific transcriptional phenotypes. Overall, LOTR-Seq provides novel insights into the evolution of post-MPN AML.

Somatic frameshift mutations in the gene encoding calreticulin (CALR) give rise to myelofibrosis and are classified as Type 1 (del52) or Type 2 (ins5) according to the degree of wildtype sequence retained adjacent to the neopeptide, with each type conferring different clinical outcomes. Targeting strategies specific for Type 1 vs Type 2 mutations would have enormous clinical utility in the treatment and prevention of myelofibrosis as responses to tyrosine kinase inhibitors are not durable nor mutation-specific. Here we show that dual targeting of Type 1 (del52) mutant CALR with two monoclonal antibodies directed against distinct epitopes in CALR have significant advantages compared to single agent treatment in the eradication of primary megakaryocyte progenitors in vitro and in a humanized ossicle microenvironment leading to improved survival in xenograft models. Dual targeting was superior in blocking constitutive STAT5 and ERK phosphorylation induced by del52 and prevented accumulation of JAK2 phosphorylation, overcoming ruxolitinib resistance. In contrast, Type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting but could be impacted by ruxolitinib triple combination. Together, our data demonstrate an ultra-precision medicine approach tailored to either Type 1 OR Type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signalling, with far-reaching implications for patient management.

Abstract Novel therapies are needed for myelofibrosis (MF), particularly after Janus kinase (JAK) inhibitor failure. This open-label, phase 1/2 study evaluated bomedemstat, an irreversible inhibitor of lysine-specific demethylase 1, in participants with MF refractory or resistant to, inadequately controlled by, or intolerant of approved therapies. Eighty-nine participants initially received bomedemstat at doses 0.25, 0.5, or 0.6 mg/kg orally once per day, titrated to achieve a target platelet count of ≥50 × 109/L to ≤75 × 109/L. Primary end points were safety and change in spleen volume. Hematologic response and change in symptom burden, bone marrow fibrosis score, and variant allele frequency (VAF) were exploratory. Eighty-seven (97%) participants experienced ≥1 any-cause adverse event (AE), most commonly thrombocytopenia (48%) and dysgeusia (36%); 62 (69%) participants experienced ≥1 grade 3 to 5 AE. Three participants (3%) experienced AEs that led to death; none were related to treatment. Of 35 participants with spleen volume data at week 24, 23 (66%) had a reduction in spleen volume; 9 (26%) had a reduction of ≥20%. Mean platelet and white blood cell counts normalized over 24 weeks; hemoglobin levels remained stable. Participants reported improvement in most symptoms, including fatigue. Of 35 participants with baseline and week 24 data, 8 (23%) had improved bone marrow fibrosis by ≥1 grade per central review, and 21 (60%) were stable. Of 36 participants with CALR, JAK2, or MPL mutations and data at week 24, 56% had a reduction in VAF. Bomedemstat had manageable safety and clinical activity in participants with MF in need of an alternative therapy. This trial was registered at www.ClinicalTrials.gov as NCT03136185.

JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).

Abstract Myelofibrosis (MF), a myeloproliferative neoplasm, was most commonly treated with hydroxyurea (HU) before approval of ruxolitinib (RUX), now the standard of care. Factors that influence real-world MF treatment patterns are not well understood. The METER study was a multi-country, retrospective chart review of MF treatment patterns, treatment effectiveness, and health care resource utilization. Of 997 eligible patients, 65.9% had primary MF, and 11.7% were transfusion dependent. Median time from diagnosis to the start of initial treatment (index date) was 29 days (interquartile range [IQR], 1-140). RUX was the most common first-line (1L) therapy (49.0%), followed by HU (40.2%); 48.5% of patients remained on 1L therapy through week 156. Seventy-seven patients underwent allogeneic stem cell transplantation; transplantation was uncommon at 1L, increasing from 2.2% at week 24 to 11.0% at week 156 in patients ≤70 years of age. Median overall survival was 79.1 months (95% confidence interval [95% CI], 70.8 to not estimable [NE]) in all patients, 142.3 months (95% CI, 74.1 to NE) for non-RUX patients, 77.6 months (95% CI, 64.2-85.9) for patients on RUX 1L therapy, and 72.6 months (95% CI, 62.0 to NE) for RUX 2L+ patients. Of patients who experienced ≥1 corresponding event, the median hospital length of stay (LoS; n = 520), intensive care unit LoS (n = 71), and number of transfusions (n = 375) were 16 days (IQR, 7-37), 5 days (IQR, 2-13), and 12 (IQR, 4-26), respectively. Despite improvements, there were numerous hospitalization and transfusion events among these patients in routine practice. This trial was registered at www.ClinicalTrials.gov as #NCT05444972.

Genomic profiling in patients with chronic-phase chronic myeloid leukemia (CP-CML) demonstrated somatic variants in blood cancer-related gene variants (CGVs) and rearrangements associated with the formation of the Philadelphia chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGAs). AGAs had a negative impact on failure-free survival (FFS) and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next-generation sequencing was performed on diagnostic samples of 315 patients consecutively enrolled in 4 clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% harboring CGVs and 18% with Ph-associated rearrangements (4% had both). Although the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to experience inferior outcomes. This result was largely attributable to patients with ASXL1 variants, observed in 7% overall. Patients harboring ASXL1 variants also had inferior outcomes compared with those with wild-type ASXL1 in terms of 12-month major molecular response (55% vs 83%; P = .001), 2-year FFS (61% vs 91%; P < .001), and notably, the development of treatment-emergent BCR::ABL1 kinase domain mutations at 2 years (35% vs 1%; P < .001). In multivariable models, both CGVs and ASXL1 variants were predictors of each outcome. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.

Figure showing X-ray crystal structure of pseudokinase domain inhibitor

While there have been outstanding improvements in the treatment of Chronic Myeloid Leukaemia (CML), some patients do not respond optimally or are entirely resistant to treatment. In many of these patients, the molecular basis for resistance to tyrosine kinase inhibitors (TKIs) is unknown, highlighting the need for further investigation. Various potential mechanisms of TKI resistance are being explored with the aim of identifying new therapeutic options. A growing body of evidence suggests that alterations in lipid metabolism are implicated in treatment resistance in a variety of cancers including CML. Intracellular lipid storage may play a protective role to facilitate drug resistance in cancers and subsequently could serve as a targetable vulnerability. Due to the single genetic driver of oncogenesis, CML is an excellent model disease for studying metabolic alterations in cancer that contribute to drug resistance and disease progression. Based on the need to identify adjuvant therapies for TKI-resistant CML, we have evaluated evidence of dysregulated lipid storage in CML and its potential as a therapeutic target. In addition to in vitro analysis, we discuss the outcomes of clinical studies of CML treated with therapeutics that target lipid storage both directly and indirectly. We also highlight key limitations in the current literature and identify priority areas for further investigation. Advancing our understanding of lipid metabolic pathways, including lipid storage, in CML may reveal actionable vulnerabilities and support the development of novel therapeutic strategies to overcome TKI resistance.

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with a high symptom and psychological burden, resulting in decreased quality of life (QoL). Patients with PV have an increased risk of cardiovascular (CV) complications, making regular monitoring crucial. The Landmark 2.0 survey was conducted worldwide among patients with PV and their treating physicians to identify any potential gaps in perceptions regarding PV management. Data were collected between April 2021 and April 2022 from physicians and patients across 11 countries. Overall, 133 physicians and 274 patients with PV participated in the survey. There were discrepancies between physicians and patients in reporting whether symptom assessments and basic CV assessments were conducted during routine visits (83% vs. 68% and 64% vs. 55%, respectively). Emotional assessments were not performed routinely (reported by 36% of physicians and 34% of patients). Patients attributed the highest impact on QoL to physical symptoms (67%); however, physicians were less likely to report highly prevalent symptoms such as bruising, difficulty sleeping, inactivity, and depression among the most common symptoms. While both physicians and patients aimed for symptom improvement, their treatment goals differed: physicians focused on managing hematocrit, preventing thrombotic events, and reducing spleen size, while patients focused on slowing down disease progression. Patient satisfaction with treatment was generally high but decreased in later therapy stages. Overall, these data underscore the disparity in patient–physician perceptions of PV management and treatment expectations, showing the gaps in communication and the need for greater patient education, as well as highlighting areas for potential improvement in clinical practice.

Somatic mutations in mitochondrial DNA (mtDNA) are not typically considered key oncogenic drivers of cancer, primarily because of a high synonymous to non-synonymous variant ratio. Here, we surveyed 248 matched diagnosis and remission samples from patients with chronic myeloid leukemia (CML) and found a 75% had mitochondrial mutations with a median number of 2 mutations per patient. mtDNA mutations were predominantly non-synonymous, enriched in the D-loop control region, and likely originated from replication and transcriptional errors. Functionally, mtDNA mutations were associated with reduced oxidative phosphorylation (OXPHOS), as measured by Seahorse analyser. This metabolic vulnerability could be phenocopied by treatment with the complex I inhibitor IACS-10759 in combination with the targeted tyrosine kinase inhibitor (TKI) imatinib, which significantly reduced the colony-forming potential of TKI resistant leukemic stem/progenitor cells (LSPCs). Strikingly, we show that mtDNA mutations were associated with increased sensitivity to imatinib therapy in the clinic. Patients with ≥3 mutations and patients with mutations in the D-loop showed significantly higher cumulative incidence of major molecular response at 24 months (90% vs. 68%, p = 0.004, and 89% vs 68%, p = 0.004 respectively). Single-cell RNA sequencing further revealed enrichment in non-synonymous mtDNA variants in LSPCs from TKI-sensitive patients, while TKI-resistant cells exhibited upregulated gene signatures related to glycerolipid and phospholipid metabolism and mitochondrial biogenesis. Together, our findings demonstrate that mtDNA mutations are key determinants of sensitivity to targeted therapy, rather than oncogenic drivers of leukemogenesis. Mechanistically, non-synonymous mtDNA mutations appear to restrict mitochondrial metabolic plasticity, with widespread implications for precision oncology. ### Competing Interest Statement The authors have declared no competing interest. We declare that data supporting the findings of this study are available within this manuscript and its supplementary information files. Supplementary information accompanies the manuscript on the Signal Transduction and Targeted Therapy website SAHMRI Mid-Career Seed Funding Grant, Adelaide Cancer Council SA National Health and Medical Research Council, 2007908 Contributing Haematologists Committee Research Grant, Adelaide National Medical Research Council Singapore, CIRG/1468/2017, MOH-000602, MOH-000059, CIRG16nov032 Leukemia & Lymphoma Synergistic Team Award with support from the Mike & Sofia Segal Foundation NHMRC Ideas Grants The Medical Research Future Fund

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL-3 receptor ternary complex forms higher-order assemblies, like those found earlier for the GM-CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL-3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine-receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism-based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.

TPS6587 Background: Lysine-specific demethylase 1 (LSD1) is an enzyme that regulates hematopoietic stem and progenitor cell proliferation and maturation. Bomedemstat (MK-3543) is an LSD1 inhibitor shown to have manageable safety and improve symptoms, durably reduce platelet and white blood cell (WBC) count, and reduce mutation burden in patients with essential thrombocythemia (ET) in a phase 2 study. Here, we describe the methodology of the randomized, double-blind, phase 3 Shorespan-007 study (NCT06456346), which has been designed to evaluate the efficacy and safety of bomedemstat compared with hydroxyurea in participants with ET naive to cytoreductive therapy. Methods: Key eligibility criteria include patients aged ≥18 years with an ET diagnosis per WHO diagnostic criteria for myeloproliferative neoplasms, an indication for cytoreductive therapy, no prior cytoreductive therapy, a bone marrow fibrosis score of 0 or 1, a platelet count of >450 × 10 9 /L, and an absolute neutrophil count of ≥0.75 × 10 9 /L. Key exclusion criteria include a documented increased risk of bleeding or an active infection necessitating systemic therapy. Approximately 300 participants will be enrolled. Participants will be randomly assigned 1:1 to bomedemstat at a starting dose of 50 mg/day by mouth titrated to a target platelet count of ≥150× 10 9 /L to ≤350 × 10 9 /L or hydroxyurea at a starting dose of 500 mg/day by mouth titrated per the approved product labeling. The primary end point is durable clinicohematologic response, defined as the following: a confirmed reduction of platelet count to ≤400 × 10 9 /L; absence of a WBC count elevation to >10 × 10 9 /L locally assessed to be due to ET; and, if WBC count is elevated to >10 × 10 9 /L at screening, a reduction of WBC count to ≤10 × 10 9 /L (confirmed by first subsequent visit a minimum of 2 weeks apart, starting by week 24 and maintained for ≥24 weeks to at least week 48; absence of any thrombotic or major hemorrhagic events or disease progression to myelofibrosis [MF] or myelodysplastic syndrome [MDS]/acute myeloid leukemia (AML) by week 52). Secondary end points include change in fatigue from baseline per the MFSAF v4.0, change in total fatigue score from baseline per the PROMIS Fatigue SF-7a scale, change in total symptom score from baseline per the MFSAF v4.0, duration of clinicohematologic response, duration of hematologic remission, incidence of thrombotic events, incidence of major hemorrhagic events, transformation to post-ET MF or MDS/AML, and safety and tolerability. Clinic visits will occur every 2 weeks for the first 12 weeks and every 4 weeks thereafter. Adverse events will be monitored throughout the study and for ≤30 days after treatment end and will be graded per NCI CTCAE v5.0. Recruitment for Shorespan-007 is ongoing or planned in sites in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT06456346 .