Associate Editor Jason Gotlib introduces a comprehensive How I Treat series on chronic myeloid leukemia (CML) that focuses on the multidimensional aspects of CML care. All articles in the series use case vignettes to illustrate how recent advances in care can be applied to challenging clinical scenarios. Leyte-Vidal and Shah kick off the series with frontline treatments for the chronic phase of CML, while Soverini and Castagnetti focus on resistance and relapse. Abruzzese and Chelysheva discuss the challenges in management of CML during pregnancy. Mauro emphasizes the less common but critically important diagnosis and management of advanced phases of CML, which dovetails with the article by Chalandon, Simonetta, and Masouridi-Levrat focusing on the indication and use of hematopoietic stem cell transplantation for CML. In the last article, Chen, Suttorp, and Hijiya address the unique features of treatment of children and adolescents with CML.

Ruxolitinib and subsequent JAK2 inhibitors have improved care for some patients with the myeloproliferative neoplasms myelofibrosis, essential thrombocythemia (ET), and polycythemia vera, but major problems remain and there is much to do. This Review Series, curated by Associate Editor Jason Gotlib, covers 3 areas where exciting advances are occurring. Gotlib’s editorial sets the scene for these by summarizing where we are in 2026 and lessons from how we got here. Constantinescu, Vainchenker, and Pecquet discuss how new ways to switch off JAK signaling are delivering a suite of new small-molecule drugs with potential. Salzman and Mullally review the biology of calreticulin mutations in myelofibrosis and ET and how multiple different modalities can be brought to bear against this mutant surface protein, including monoclonal antibodies, bispecific T-cell engagers, and cellular and vaccine therapies. Finally, Kremyanskaya, Ginzburg, and Hoffman outline the major recent progress being made in controlling excessive erythropoiesis through pharmacological modulation of iron metabolism.

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.

While TP53 mutations in myeloproliferative neoplasms (MPN) are associated with an increased risk of leukemic transformation, not all patients carrying a TP53 mutation progress. To better risk-stratify MPN patients with TP53 mutations, we analyzed data from 1540 patients treated at four specialized cancer centers. Among them, 1429 had wildtype TP53 and 111 had mutations in the TP53 gene. At first MPN diagnosis, 32% had polycythemia vera, 39% had essential thrombocythemia, and 25% had primary myelofibrosis. Among all MPN patients with TP53 mutations, presence of fibrosis in the bone marrow (hazard ratio (HR): 3.84, 95% CI: 1.98-7.43), multi-hit TP53 mutation status (HR: 2.74, 95% confidence interval (CI): 1.52-4.97), and higher PHANTM score (HR: 1.87, 95% CI: 1.02-3.42) were associated with worse OS in a multivariable analysis. Based on these variables, we developed a risk model to identify TP53-mutated MPN patients who are at high risk for inferior OS. Median OS from time of TP53 detection was 0.5 years in high-risk patients, compared to 2.3 years for patients with intermediate risk and 6.3 years for patients with low risk. This scoring system may help refine risk stratification for chronic phase MPN patients harboring TP53 aberrations.

ABSTRACT:Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHNs; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200 mg once daily, starting dose) with >4 years follow-up from the fully enrolled PATHFINDER study. End points included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population median follow-up, 49 months), 83 were response-evaluable. ORR was 73% (95% confidence interval, 63-83). Median DOR was 58 months; PFS, 51 months, and OS, 62 months. Disease progression occurred in 21 of 107 patients (20%), predominantly in SM-AHN and largely driven by the AHN. Reductions in objective biomarkers of disease were observed. Most frequent (≥30% patients) treatment-emergent adverse events (TEAEs; any grade; grade ≥3) were thrombocytopenia (58%; 31%); periorbital edema (57%; 6%), anemia (54%; 33%), peripheral edema (48%; 2%), and diarrhea (36%; 5%). Adverse events of special interest were cognitive effects (34%; 8%) and intracranial bleeds (4%; 2%). Eleven (10%) patients experienced TEAEs leading to death, of which 1 was deemed related to avapritinib by the principal investigator. With 4-year follow-up, patients with AdvSM treated with avapritinib experienced deep and durable responses and a favorable benefit-risk profile. This trial was registered at www.ClinicalTrials.gov as #NCT03580655.

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE:We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS:The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS:As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS:Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

Abstract Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort ( n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80–1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p <0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia ( n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.

Acute leukemias of the myeloid lineage most commonly show myeloid and/or monocytic differentiation. Leukemias with erythroid, megakaryoblastic, and basophilic differentiation are more rare but are well documented. In contrast, acute leukemia showing marked morphologic and immunophenotypic features of eosinophilic differentiation is not a defined entity. When acute leukemias do show a prominent population of cells with eosinophilic differentiation, the eosinophil populations typically show morphologic features of mature eosinophils and the eosinophilic population may be clonally related to the neoplastic cells or may be reactive. In this case report, we describe an unusual case of acute myeloid leukemia evolving from a myelodysplastic neoplasm with low blasts in which the predominant cell population in the peripheral blood and bone marrow were cells with round nuclei and immature chromatin with prominent eosinophilic granules and immunophenotypic features suggestive of maturation arrest at an eosinophilic promyelocyte-like stage. At the time of leukemic transformation, molecular studies showed acquisition of NRAS G13R, NRAS Q61K, and KRAS G12R mutations in addition to the TET2 variants (N582fs and E1357X), del(20q), and 7q- abnormalities detected in the antecedent myelodysplastic neoplasm. No PDGFRA, PDGFRB, FGFR1, JAK2, or FLT3 rearrangements were detected by FISH or in sequencing assays. BCR::ABL1 testing was also negative. Whole-genome sequencing did not detect additional abnormalities to explain the differentiation block. In summary, this is, to our knowledge, the only reported case of an acute leukemia in which the immature cells themselves demonstrate morphologic and immunophenotypic features of eosinophilic promyelocytes.

BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease driven by the KIT D816V mutation, can often cause debilitating dermatologic symptoms. OBJECTIVE:Assess improvement of ISM-related skin manifestations after treatment with avapritinib, a highly selective KIT D816V inhibitor, vs placebo in Part 2 of the PIONEER study (NCT03731260). METHODS:Patients with moderate to severe ISM received avapritinib 25 mg once daily (n = 141) or placebo (n = 71). Endpoints included skin lesion area and pigmentation at week 24, skin mast cell burden, and change in symptoms. RESULTS:Mean percent reduction in lesional surface area was -36.6% with avapritinib vs -1.8% with placebo in the most affected area; 86% vs 0% had improved skin lesion color. Mean percent change in skin mast cell burden decreased with avapritinib (-22.1%) vs placebo (10.1%). Avapritinib vs placebo significantly improved skin symptom domain score (mean change -7.2 vs -2.8; P < .0001), including the individual skin symptoms itching, flushing, and spots. Avapritinib was well tolerated. LIMITATIONS:Photography was optional, so analysis population for lesion area and color were smaller (n = 111) than the overall study population (n = 212). CONCLUSION:Avapritinib treatment improved dermatologic symptoms, decreased skin lesion size, normalized skin lesion color, and reduced skin mast cell burden in patients with ISM.

Background Patients with indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, often have lifelong debilitating symptoms. Anaphylaxis is a common feature of the disease seen in up to half of patients. The effects of KIT D816V-targeted therapy on the incidence of anaphylaxis are unknown. Methods We describe anaphylaxis events occurring in the study population of PIONEER (NCT03731260) during the 12-week screening and/or 24-week treatment period. This study had previously demonstrated the efficacy and safety of the oral, highly selective, KIT D816V inhibitor avapritinib compared with placebo in patients with moderate-to-severe ISM. Results In total, 13/212 (6.1%) patients in PIONEER experienced anaphylaxis during screening or treatment (6 during screening, 5 during treatment, and 2 during both screening and treatment). Baseline demographics, clinical characteristics, and known triggers varied. During the randomized, placebo-controlled treatment period, 4/141 (2.8%) avapritinib-treated patients and 3/71 (4.2%) placebo-treated patients experienced anaphylaxis. Conclusions Larger studies with longer-term follow-up are required to further confirm the effects of avapritinib on anaphylaxis in patients with SM.

Systemic mastocytosis (SM) is a spectrum of hematologic disorders characterized by accumulation of atypical mast cells (MCs) in extracutaneous organs. SM with an associated hematologic neoplasm (SM-AHN), the most frequent subtype of advanced SM, is predominantly associated with myeloid neoplasms, consistent with shared clonal architecture. Because of its rarity and heterogeneity, robust outcome data aligned with contemporary classifications are needed to inform risk stratification. We analyzed the 10th data wave of the European Competence Network on Mastocytosis registry (34 European centers and 1 US center). SM and AHN diagnoses followed the 2022 World Health Organization classification. Baseline characteristics and overall survival (OS) were compared between patients with myeloid SM-AHN and SM without AHN (SM-no-AHN). Within SM-AHN, outcomes were analyzed by SM component (advanced: aggressive SM [ASM] or MC leukemia [MCL] vs. non-advanced: bone marrow mastocytosis, indolent SM, or smoldering SM) and AHN subtype. Among 3,925 patients with SM, 467 (11.9

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.

Introduction Avapritinib (Ava) is a potent, selective KIT D816V inhibitor indicated for adult patients (pts) with advanced systemic mastocytosis (AdvSM) based on results from the PATHFINDER (NCT03580655) and EXPLORER (NCT02561988) studies. MARS is a prognostic tool classifying AdvSM pts into low-, intermediate-, and high-risk groups based on age (>60 years), anemia (hemoglobin <10 g/dL), thrombocytopenia (platelet count <100x10⁹/L), and the presence and number of SRSF2, ASXL1, or RUNX1 (S/A/R) mutations. Prior retrospective analyses of overall survival (OS) showed a hazard ratio (HR) of 0.19 for Ava vs midostaurin (Mido) in frontline (1L) therapy and 0.34 for Ava vs best available therapy (BAT) in second or later-lines (2L+) of treatment in AdvSM, regardless of MARS (Reiter et al., ASH 2024). MARS-defined intermediate- and high-risk pts face particularly poor prognoses, making it essential to evaluate treatment outcomes in this underserved population. This analysis builds on the earlier work, comparing OS between intermediate- and high-risk MARS pts treated with Ava (200 mg/day starting dose) in the PATHFINDER trial and those treated with BAT in real-world (RW) clinical practice. Methods Data from the PATHFINDER trial (median follow-up: 38.0 months) and a RW retrospective chart review study (NCT04695431) conducted at six global sites, were used to compare OS between pts treated with 1L Ava vs 1L Mido, and 2L+ Ava vs 2L+ BAT, which was predominantly Mido and cladribine (Clad). Analyses were restricted to lines of therapy (LOTs) in the combined cohorts of MARS- intermediate- or high-risk (score >1) pts. Subgroup analyses were conducted among pts with SM with an associated hematologic neoplasm (SM-AHN). Inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences in key prognostic covariates; covariate balance was confirmed by standardized mean differences <0.1. IPTW-weighted Cox proportional hazards models were used to compare OS between cohorts. Results 1L analysis. Ava (n=24) vs Mido (n=43); mean age 70.3 vs 70.9 years; mean follow-up 33.1 vs 22.5 months. Before weighting, more Ava pts had anemia (75.0% vs 60.5%) and fewer had an elevated serum tryptase level at baseline (≥125 ng/mL: 62.5% vs 72.1%). Distributions of AdvSM subtypes were similar between the cohorts (SM-AHN: 79.2% vs 79.1%; Aggressive SM [ASM]: 12.5% vs 14%; Mast Cell Leukemia [MCL]: 8.3% vs 7.0%). IPTW-weighted median OS was not reached (NR) (95% confidence interval [CI]: not estimable [NE], NE) in the Ava cohort, and 26.8 months (95% CI: 14.4, 49.8) in the Mido cohort. In IPTW-weighted Cox analysis, OS was significantly longer in Ava vs Mido pts (HR [95% CI]: 0.08 [0.02, 0.29]; p<0.001). 1L SM-AHN subgroup. Ava (n=19) vs Mido (n=34); IPTW-weighted median (95% CI) OS was NR (NE, NE) in the Ava cohort, and 22.1 months (13.0, 61.5) in the Mido cohort. After adjustment, OS was significantly improved in Ava vs Mido pts (HR [95% CI]: 0.09 [0.02, 0.36]; p<0.001). 2L+ analysis. Ava (n=41) vs BAT (n=55, 71 LOTs); mean age 71.0 vs 67.3 years; mean follow-up 28.4 vs 17.6 months. Common 2L+ BAT agents included Mido (47.5%), Clad (34.4%), and hydroxyurea (8.2%). Before weighting, more Ava vs BAT LOTs had elevated serum tryptase at baseline (78.0% vs 63.4%) and received prior treatment with tyrosine kinase inhibitors (85.4% vs 46.5%). Fewer Ava vs BAT LOTs had ≥1 S/A/R mutation (56.1% vs 66.2%); distributions of AdvSM subtypes were similar (SM-AHN: 70.7% vs 70.4%; ASM: 17.1% vs 14.1%; MCL: 12.2% vs 15.5%). IPTW-weighted median (95% CI) OS was 50.2 months (50.2, NE) in the Ava cohort, and 14.8 months (13.2, 32.6) in the BAT cohort. In IPTW-weighted Cox analysis, OS was significantly longer in Ava vs BAT pts (HR [95% CI]: 0.28 [0.13, 0.61]; p=0.001). 2L+ SM-AHN subgroup. Ava (n=29) vs BAT (n=38, 50 LOTs); IPTW-weighted median (95% CI) OS was 50.2 months (23.0, NE) in the Ava cohort, and 13.2 months (7.7, 27.5) in the BAT cohort. After adjustment, OS was significantly improved in Ava vs BAT pts (HR [95% CI]: 0.31 [0.13, 0.74]; p=0.008). ConclusionsAmong the combined cohort of MARS intermediate- and high-risk AdvSM pts, avapritinib was associated with significantly improved OS compared to midostaurin in the 1L setting and BAT in the 2L+ setting, including in the SM-AHN subgroup. This analysis further characterizes the survival benefit of avapritinib, and supports treatment decisions, in this traditionally underserved patient population.

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/ MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Background: Essential thrombocythemia (ET) and myelofibrosis (MF) are driven by mutations in calreticulin (mutCALR) in ~30% of patients (pts) and result in substantial morbidity and mortality. INCA033989 (‘989‘), a novel, fully human, Fc-silenced, IgG1 monoclonal antibody, selectively inhibits oncogenic signaling and proliferation of cells expressing mutCALR and thrombopoietin receptor. This mechanism of action has the potential to selectively eliminate malignant cells and restore healthy hematopoiesis. 989 is currently being studied in 2 phase 1 first-in-human trials (NCT05936359; NCT06034002) in pts with ET or MF. This analysis describes the baseline molecular characteristics and preliminary molecular responses to 989. Methods: Comprehensive clinicogenomics and histological analyses were undertaken using 3 approaches. A targeted NGS panel (Archer® VariantPlex® Core Myeloid panel) containing 37 genes associated with myeloid malignancies was used to analyze whole blood and bone marrow aspirate samples at enrollment and longitudinally to characterize the somatic mutation landscape and molecular dynamics following treatment. Molecular response (MR) was defined as a 20% reduction (best overall response) in mutCALR VAF between baseline and post-treatment. In addition, single-cell multi-omic analysis (TapestriTM) was conducted in a subset of pts on peripheral blood mononuclear cells using a custom panel to assess 47 cell surface proteins and 37 genes. Immunohistochemistry (IHC) using an antibody specific for mutCALR was performed on bone marrow biopsies at enrollment and post-treatment. Semi-automated annotation of mutCALR-positive and negative megakaryocytes (MKs) was performed, and counts were normalized to the total MK population determined by nuclei count. Data cutoff was based on a biospecimen collection date of May 2025. Results: 110 enrolled pts had evaluable genomic data, 51 and 59 with ET and MF, respectively. The frequencies of pts with mutCALR Type-1, Type-2, Type-other were 55%, 29%, 16% (ET) and 58%, 24%, 19% (MF), respectively. The mean (range) of mutCALR VAF at enrollment for ET was 0.33 (0.12-0.75) and MF was 0.38 (0.30-0.85). Only 5 pts (5%) had a VAF >0.5 suggesting loss of heterozygosity, and all had Type-2 mutations. A strong correlation was noted between mutCALR VAF of bone marrow and peripheral blood samples (R2=0.97). Co-occurring (nondriver) somatic variants were identified in 33% of ET pts and 83% of MF pts. The range for co-occurring variants per pt was 0-3 for ET and 0-9 for MF. The most frequently mutated gene in ET pts was TET2 (16%), while ASXL1 (42%), TET2 (31%), and EZH2 (12%) were frequent in MF. In ET, a hematologic response at any time occurred in 41/51 pts (80%) with longitudinal VAF data available for 39 of the 41 patients. Of these 39 patients, 37 (95%) had a reduction of mutCALR VAF (range 2%-91%) and 22 (56%) achieved MR. 16/41 (39%) achieved an IWG/ELN-defined durable peripheral blood count remission. Of these 16 patients, 14 (88%) achieved MR and their baseline VAF ranged from 0.22 to 0.34. In MF, 27 pts had evaluable spleen response and longitudinal VAF data available. Of these 27 pts, 10 (37%) had at least a 25% spleen volume reduction at week 24; all 10 pts had a VAF reduction (range 6.9%-33%) and 5 achieved MR. 21 MF pts had evaluable anemia response and longitudinal VAF data. Of these 21 pts, 12 (57%) had a major or minor anemia response; all 12 pts had a VAF reduction (range 5%-27%) and 4 (33%) had MR. Single-cell analysis in a subset of ET and MF pts revealed selective reductions in mutCALR+ hemopoietic stem/progenitor cells (HSPCs) by the end of cycle 3. Bone marrow IHC analysis of ET and MF pts showed a decrease in the density of total MKs including a decrease in the percentage of mutCALR+ MKs and a concomitant increase in the percentage of mutCALR-negative MKs.Conclusions: Pts with MF had higher mutCALR VAF than pts with ET and were more likely to have co-occurring somatic mutations at enrollment. Correlation between clinical response and post-treatment VAF reduction was observed in both ET and MF, with more frequent MRs achieved in ET. Post-treatment MR occurred over a range of baseline VAFs, which included patients with co-occurring variant(s). A rapid and selective reduction in mutCALR+ HSPCs and MKs was observed within 4 months of 989 treatment and correlated with clinical responses, suggestive of potential disease modification and recovery of normal hematopoiesis.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by red blood cell overproduction. In the phase 2 REVIVE study (NCT04057040), rusfertide was superior to placebo in achieving hematocrit (Hct) levels <45% and reducing or eliminating the need for therapeutic phlebotomy (PHL) in patients (pts) with PV who were PHL dependent prior to study entry (Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35). During the open-label extension portion of REVIVE (Part 3), combining rusfertide and PHL with or without cytoreductive therapy (CRT) controlled erythrocytosis, provided long-term control of Hct, and was associated with a greater than 8-fold reduction in the estimated annual PHL rate (Gerds AT, et al. Blood. 2024;144(Suppl. 1):4559). Pts who participated in REVIVE Part 3 were eligible to transition to the open-label phase 2 THRIVE extension study (NCT06033586) and receive up to 2 additional years of rusfertide treatment. Our objective is to present initial results describing the long-term durability of response and safety profile of rusfertide in pts with PV who participated in REVIVE and transitioned to THRIVE. Pts with PV who participated in REVIVE, completed ≥12 months of rusfertide therapy, and had an end-of-treatment visit were eligible to transition to THRIVE. Pts who enrolled in THRIVE continued to receive subcutaneous rusfertide once weekly with or without CRT. Median Hct and the number of PHLs each pt received were assessed in all pts who received ≥1 dose of rusfertide and had ≥1 efficacy assessment on study. Safety data were also collected, including treatment-emergent adverse events (AEs), serious adverse events (SAEs), non-PV malignancies, and thromboembolic events (TEs). New-onset AEs (ie, AEs that were reported in THRIVE but not REVIVE) were also recorded. Forty-six/58 pts (79%) who enrolled in Part 3 of REVIVE transitioned to THRIVE. At the data cutoff date (27 May 2025), 44 of the 46 pts (96%) who enrolled in THRIVE remained on study. Median (range) age was 58 (27-77), and the majority were male (74%). More than half (57%) had high-risk PV; 54% of pts were on concurrent CRT. Median (range) treatment duration in THRIVE was 48 (22-66) weeks; median (range) treatment duration in REVIVE and THRIVE combined was 198 (154-267) weeks, or 3.8 (3.0-5.1) years. At baseline, mean (standard deviation [SD]) Hct was 42.3% (3.7) in THRIVE. At Week 60, mean (SD) Hct was 43.0% (4.2). In addition, mean hemoglobin and erythrocyte levels remained stable throughout THRIVE. Prior to study entry in REVIVE, the mean (SD) annualized PHL rate (ie, PHL/year) for the 46 pts who eventually rolled over to THRIVE was 9.2 (5.2) PHL/year. The mean (SD) annualized PHL rate during REVIVE Part 3 and THRIVE was 0.6 (0.8) and 0.7 (1.1) PHL/year, respectively. Overall, the most common AEs in the pts who participated in REVIVE and THRIVE were Grade 1-2 injection site reactions (87%), fatigue (59%), COVID-19 (50%), pruritus (44%), arthralgia (39%), dizziness (35%), anemia (30%), paresthesia (28%), headache (26%), abdominal pain and nausea (24% each), and diarrhea, dyspnea, and upper respiratory tract infection (22% each). In THRIVE, the most common new-onset AEs were anemia (20%) and fatigue (15%). Twelve pts (26%) had a prior history of non-PV cancer. Six pts (13%) had a new-onset cancer event, including basal cell carcinoma (n=3; 7%), squamous cell carcinoma (n=2, 4%), non-invasive bladder cancer (n=1, 2%), and multiple myeloma (n=1; 2%). Of these 6 pts, 5 (83%) had a prior history of non-PV cancer. Nine pts (20%) had a history of TEs prior to enrolling in REVIVE. One patient with cardiovascular risk factors and a TE prior to enrollment in REVIVE had a new-onset TE of cerebrovascular accident in THRIVE. Overall, there were no TEs in pts with low-risk PV in either REVIVE or THRIVE. After transitioning to THRIVE, continued treatment with rusfertide with or without CRT demonstrated consistent, long-term Hct control with reduced therapeutic PHLs compared to baseline. With a median of 3.8 years of treatment, rusfertide's safety profile was consistent with prior observations. Protagonist Therapeutics, Inc.

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