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e18607 Background: Progression to myelofibrosis (MF) is associated with worse survival and influences treatment decisions, yet predictors of fibrotic progression in polycythemia vera (PV) and essential thrombocythemia (ET) remain poorly characterized. Methods: Patients with pathologically confirmed PV or ET were identified from a retrospective chart review. Demographics (age, sex, race, ethnicity), clinical features (thrombosis and bleeding history, performance status, symptom burden, organomegaly), bone marrow pathology (cellularity, trilineage hematopoiesis, megakaryocyte proliferation and atypia, fibrosis grade), molecular markers ( JAK2 , CALR , MPL , ASXL1 , EZH2 , TET2 , SRSF2 , IDH1/2 , SF3B1 , TP53 ), cytogenetics, laboratory values, and treatment history (phlebotomy, hydroxyurea, interferon, ruxolitinib) at first bone marrow biopsy were recorded. MF progression was defined as hematologist-confirmed transformation to MF. Kaplan-Meier analyses estimated median MF-free survival (MFS), defined as time to MF progression or death. Univariable followed by multivariable Cox proportional regression were performed to identify candidate MFS predictors. The proportional hazards assumption was assessed using Schoenfeld residuals. Hazard ratios (HR) with 95% confidence intervals (CI) were computed, with p<0.05 indicating statistical significance. Results: A total of 505 PV and 198 ET patients were identified. The majority were White (PV: 92%; ET: 86%). PV patients were predominantly male (54%) whereas ET patients were predominantly female (66%). MF progression occurred in 160 (32%) PV and 32 (16%) ET patients. Death was observed in 139 (28%) PV and 10 (5%) ET patients. Median MFS was 158.5 months (95% CI: 143.0-183.0) for PV and 308.0 months (95% CI: 175.0-NR) for ET. In PV, older age at diagnosis (HR 1.04; 95% CI: 1.02-1.07; p<0.001) and shorter time since PV or ET diagnosis to biopsy (HR 0.995; 95% CI: 0.990-0.999; p=0.048) independently predicted worse MFS. In ET, bone marrow hypercellularity (HR 5.67, 95% CI: 1.40-23.0, p=0.015) independently predicted worse MFS. Conclusions: PV patients demonstrated shorter MFS compared to ET. Older age at diagnosis in PV, whereas bone marrow hypercellularity in ET was significantly associated with fibrotic progression or death. Active surveillance of at-risk patients may facilitate early detection and timely treatment initiation. Disease Variable HR (95%CI) P-value PV Age at diagnosis 1.04 (1.02-1.07) <0.001 Time since PV or ET diagnosis to biopsy 0.995 (0.990-0.999) 0.048 ET Bone marrow hypercellularity 5.67 (1.40-23.0) 0.015

Abstract Background JAK inhibitors (JAKi) are small molecules that cross the placenta from early pregnancy.1 Evidence on the safety of in utero JAKi exposure remains limited, particularly regarding pregnancy outcomes, infant infections, vaccine responses, and early development.2, 3 Methods We conducted a multicenter retrospective study within the ECCO CONFER network, including pregnant women with inflammatory bowel disease (IBD) exposed to tofacitinib (TOFA), upadacitinib (UPA), or filgotinib (FILGO). Data were collected from 22 centers across 16 countries and included maternal characteristics, disease activity, medication patterns, and pregnancy and infant outcomes. Results Among 55 JAKi exposed pregnancies, 21 (38.2%) were unplanned and 30 (54.6%) had active disease. Nine women (16.4%) initiated JAKi during pregnancy. Overall, 38 (69.1%) received TOFA, 15 (27.3%) UPA, and 2 (3.6%) FILGO; 39 (70.9%) continued treatment throughout pregnancy. JAKi discontinuation in 1st-2nd trimester led to disease activity in 9/16 cases (56.3%). Maternal complication risk was low: no DVT or (pre) eclampsia occurred; three cases of premature rupture of membranes (GA 34–37) and four required hospitalizations due to infection or other complications. A total of 10 abortions occurred - five spontaneous (9.1%) and five induced (9.1%), including three due to concern about JAKi exposure. Among 45 live births, two infants (3.6%) were preterm, four (7.3%) small for gestational age, and two (3.6%) had Apgar &lt;7 at 5 minutes. No congenital abnormalities were reported. Infant follow-up findings are summarized in Table 1. One-third of breastfeeding women continued JAKi postpartum. A high adherence rate to the national immunization schedule was seen. Eight (19.5%) received the live BCG-vaccine within the first 30 days of life. No adverse events followed live or inactivated vaccines, and no malignancies were observed. Conclusion In this global cohort of JAKi-exposed pregnancies in women with IBD, maternal complication rates were low, and no increased risk of adverse outcomes among live births was identified. While disease activity was common, particularly following discontinuation of JAKi, infant outcomes - including development, infection risk, and vaccine response - were reassuring. These findings provide important preliminary safety data to inform decision-making regarding JAKi use in pregnancy, though prospective studies are needed to confirm long-term safety. References: 1.Fein KC, Arral ML, Kim JS, et al. Placental drug transport and fetal exposure during pregnancy is determined by drug molecular size, chemistry, and conformation. J Control Release 2023;361:29–39. 2.Torres J, Chaparro M, Julsgaard M, et al. European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis 2023;17:1–27. 3.Mahadevan U, Seow CH, Barnes EL, et al. Global Consensus Statement on the Management of Pregnancy in Inflammatory Bowel Disease. J Crohns Colitis 2025;epub ahead of print. Conflict of interest: Julsgaard, Mette: No conflict of interest Baunwall, Simon MD: No conflict of interest Seow, Cynthia: No conflict of interest Duricova, Dana: No conflict of interest Kane, Sunanda: No conflict of interest Zacharias, Neha: No conflict of interest Leong, Rupert: No conflict of interest Cremer, Anneline: No conflict of interest Kok, Klaartje: No conflict of interest Kagramanova, Anna Valeryevna: No conflict of interest Pipek, Barbora: No conflict of interest Candido, Kristina: No conflict of interest Cooney, Rachel: No conflict of interest Filip, Rafal: No conflict of interest Kiudelis, Vytautas: No conflict of interest Konečný, Michal: No conflict of interest Paramsothy, Sudarshan: No conflict of interest Pugliese, Daniela: No conflict of interest Oliveira Santana Silva, Genoile: Honoraria - Abbvie, Johnson & Johnson, Ferring, Takeda. Research - Abivax, Takeda, Johnson & Johnson, Roche, Sanofi, Polpharma. Advisory board - Abbvie, Johnson & Johnson, MSD. Savarino, Edoardo Vincenzo: No conflict of interest Smolovic, Brigita: No conflict of interest Vieujean, Sophie: No conflict of interest Wei, Shu Chen: No conflict of interest Mahadevan-Velayos, Uma: No conflict of interest

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Abstract Background Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide and a leading cause of anemia in the United States. Anemia accounts for over 800,000 Emergency department (ED) visits annually in the United States, many of which are for blood transfusions. Despite its burden, IDA remains underdiagnosed and undertreated. This study sought to characterize the incidence of iron deficiency in patients receiving a blood transfusion in the ED at a large academic medical center and to identify areas for improvement in diagnosis management.Methods We conducted a retrospective cohort study of adult patients with severe anemia who received at least one PRBC transfusion in our ED between January 1stand December 31st, 2021. Patients considered at risk for iron deficiency included those with a mean corpuscular volume (MCV) &lt; 80 fL on the day of the ED visit, a ferritin &lt; 40 ng/mL on the day of or with any recorded value prior to the ED visit, or an iron saturation &lt; 20% on the day of or with any recorded value prior to the ED visit. Patients with confirmed iron deficiency included those with ferritin levels &lt; 40 ng/mL or iron saturation &lt; 20% within 90 days prior to the ED visit. This 90-day period included labs checked on the day of the ED visit. We also collected B12 and folate levels to determine the incidence of B12 deficiency and folate deficiency, respectively, within 90 days prior to the ED visit. We defined B12 deficiency and those at risk for B12 deficiency as those with a B12 level &lt; 200 ng/L or with a B12 level 200-399 ng/L, respectively. We defined folate deficiency as having a folate level &lt; 4 mcg/L.Results: Four hundred and sixty-two patients accounted for 558 ED encounters for severe anemia requiring at least one PRBC transfusion. The median age of the cohort was 68 years. Within this cohort, we identified 210 (45%) patients at risk of iron deficiency and 136 (29%) patients with confirmed iron deficiency based on ferritin or iron saturation levels within 90 days of the ED visit. Among these patients with iron deficiency, 44/136 (32.5%) presented with an MCV &lt; 80 fL, 88/136 (65%) presented with an MCV 80-100 fL, and 10/136 (7.5%) presented with an MCV &gt; 100 fL. These findings show that iron deficiency does not always present with microcytosis. Fifteen (3%) of 462 patients had B12 deficiency and another 38/462 (8%) were at risk for B12 deficiency based on levels within 90 days of the ED visit. Two patients had folate deficiency based on levels within 90 days of the ED visit.Conclusions This study highlights the high prevalence of iron deficiency in patients presenting to the ED at a large academic medical center. Furthermore, relying on a low MCV level alone may lead to underdiagnosis of iron deficiency, underscoring the importance for a comprehensive assessment of iron stores when working up a patient with severe anemia. This study also suggests the need for further research to determine whether early identification and treatment of iron deficiency can reduce the frequency of ED visits for blood transfusions, decrease the number of PRBC units transfused, lower hospital admission rates, improve patient outcomes and reduce healthcare cost in our patient population.

Abstract Background: The coexistence of systemic mastocytosis (SM) and lymphoid neoplasms is rare and remains poorly defined. These cases are classified under SM with associated hematologic neoplasm (SM-AHN) in the WHO framework, though the ICC distinguishes SM with associated myeloid neoplasm (SM-AMN) as a separate entity. Emerging evidence points to SM with associated lymphoid neoplasms (SM-ALN) as a biologically distinct and clinically indolent subgroup (Aperna F et al, 2025). We performed a multisite retrospective study to characterize the clinico-molecular features and outcomes of SM-ALN. Methods: We conducted a retrospective analysis across Mayo Clinic sites, reviewing records from January 1980 to December 2024 to identify patients with SM-ALN. IRB approval was obtained. Of 22 cases identified, 4 were excluded due to co-occurring myeloid neoplasms. The final cohort included 18 patients. Variables analysed included age, sex, SM subtype, KIT mutation, symptoms, treatment, and survival outcomes. Results: Eighteen patients were included (median age: 61.5 years; range: 38–80; 11 female). Most had indolent SM (ISM, n=16); two had aggressive SM (ASM). SM preceded the lymphoid neoplasm in 4 cases (22%), followed it in 6 (33%), and was concurrent in 8 (44%). Low-grade lymphomas (n=12, 67%) included follicular lymphoma (n=2), CLL (, n=2), marginal zone (n=1), lymphoplasmacytic (n=1), and mantle cell (n=1). High-grade lymphomas (n=6, 33%) included diffuse large B-cell lymphoma (DLBCL, n=3), Hodgkin lymphoma (n=2), and T-cell acute lymphoblastic leukemia (n=1). SM-related symptoms were present in 16 of 18 patients (89%). The most common manifestations included dermatologic symptoms (rash/pruritus, 56%), systemic complaints (fatigue/weight loss, 39%), GI symptoms (17%), and anaphylaxis (6%). KIT D816V testing mutation was positive in 10 of 16 patients tested (63%). Tryptase was elevated (&gt;20 ng/mL) in 15 of 18 (83%). NGS data was available for 9 patients: among the two ASM cases, both harbored SRSF2 mutation; one also had JAK2, DNMT3A, RUNX1, TET2, and TP53, while the other carried DNMT3A and IDH1. Mutations observed in ISM cases included CCND3, CXCR4, NOTCH2, SF3B1, MYD88 L265P, ASXL1, and TET2. SM management was divided into two categories: (1) Conservative approach, including observation alone in 4 patients (22%) and symptomatic therapies such as antihistamines or leukotriene inhibitors in 7 (39%); and (2) Cytoreductive treatments, comprising avapritinib in 5 patients (28%), cladribine in 1 (6%), and imatinib in 1 (6%). Management of lymphoid neoplasms included intensive regimens such as R-CHOP and hyper-CVAD for high-grade subtypes (e.g., DLBCL and T-ALL), while indolent forms (e.g., CLL and follicular lymphoma) were treated with bendamustine-rituximab or observation depending on disease burden. Overall, 13 patients (72%) received systemic therapy. At a median follow-up of 81 months (6.7 years), 17 of 18 patients (94%) were alive and progression-free. Median OS and PFS were not reached. The sole death occurred in a patient with ASM, while all ISM cases remained alive. ASM was associated with a higher (though nonsignificant) risk of death (OR 33.0; 95% CI, 0.89–1220.9; p = 0.111). Among patients with high-grade lymphomas (n=5), 80% were alive at follow-up, compared to 100% with indolent lymphomas (n=13). Discussion: Our findings support SM-ALN as a clinically indolent and biologically distinct subset within SM-AHN. Most patients had ISM and low-grade lymphoid neoplasms, with favorable outcomes regardless of lymphoma subtype or diagnostic sequence. High-risk mutations were confined to ASM cases, reinforcing underlying biologic differences. These findings align with prior Mayo Clinic data showing longer survival in SM-ALN compared to SM-AMN (median OS 8.1 vs 2.0 years; p&lt;0.01). Treatment was primarily directed by the lymphoid malignancy, with limited need for cytoreduction in ISM. Larger, prospective studies are needed to confirm these observations and optimize management strategies. Limitations include the study's retrospective, single-center design and limited racial diversity. Multi-institutional studies are warranted to validate these findings and guide optimal management. Conclusion: SM-ALN is a rare but distinct SM subtype characterized by indolent behavior, favorable treatment responses, and prolonged survival. Recognition of this subset is critical to avoid over-treatment and to guide risk-adapted management strategies.

Abstract Introduction A 2017 survey by the American Society of Hematology found a widespread perceived shortage of classical hematologists in the US, which was compounded by a low trainee interest in the field (&lt;5%) (Masselink LE, Blood Adv 2019). Recently, we reported that among hematologist/oncologists at the 64 National Cancer Institute (NCI)-designated cancer centers with clinical programs, only ~5% identify as classical hematologists, despite 15% of them including classic hematology (CH) patients in their practice (Go LT, Blood Adv, in press). However, there remains limited data on CH consult volumes at NCI-designated cancer centers (West CV, JCO Oncol Pract 2023). This study aimed to evaluate the volume and nature of CH outpatient consults at the Mayo Clinic Comprehensive Cancer Center (MCCC). Methods We reviewed electronic medical records to identify all completed outpatient consults in CH, malignant hematology (MH), and solid tumor oncology at MCCC in Rochester, Minnesota from January 1 to December 31, 2024. Consults were defined as either external or internal referrals for new patients seen in CH outpatient clinic. CH consults were further categorized by referral reasons and the type of physician (CH, MH, or fellow) performing the consultations. CH physicians were defined as those whose clinical practice primarily focuses on non-malignant hematologic conditions; one advanced practice provider (APP) was included in this group. Inpatient consults, electronic consults, and return visits were excluded. Results In 2024, a total of 17,153 outpatient consults were completed. Of these, 13.4% were CH, 30.5% were MH and 56.1% were solid tumor oncology. Among CH consults, the most common referral reasons were abnormal blood counts (68.3%), bleeding disorders (10.6%), thrombosis (11.8%), and other hematologic diagnoses (9.3%). Within abnormal blood counts, the leading indications were anemia (50.7%), thrombocytopenia (15.3%), leukopenia (11.0%), leukocytosis (9.1%), and pancytopenia (7.0%). Among bleeding disorders, the top reasons included suspected bleeding diathesis (49.4%), von Willebrand disease (24.5%), Hemophilia A (4.1%), Factor VII deficiency (3.7%), and platelet qualitative defect (3.4%). Thrombosis-related consults were most often for pulmonary embolism or deep vein thrombosis (43.2%), antiphospholipid syndrome (17.7%), thrombophilia (16.2%), portal vein thrombosis (4.1%), and splenic infarct (2.6%). The top ten referrals for a specific hematologic diagnosis were iron deficiency anemia (29.2%), pulmonary embolism or DVT (13.5%), immune thrombocytopenic purpura (10.3%), von Willebrand disease (6.9%), hemoglobinopathy (5.5%), antiphospholipid syndrome (5.5%), thrombophilia (5.1%), anemia of chronic kidney disease (2.4%), aplastic anemia (1.5%), and hereditary spherocytosis (1.4%). Of the 114 physicians at MCCC during the study period, 55 (48.2%) were medical oncologists, 54 (47.4%) primarily practiced MH, and only 5 (4.4%) were dedicated CH physicians. Despite comprising only 4.4% of the hematology/oncology workforce, CH physicians or fellows completed the majority (86.1%) of CH consults; MH physicians completed 13.8%. Conclusion CH consults represent a substantial portion of outpatient hematology referrals at MCCC, primarily for diagnostic evaluation of cytopenias or thrombotic/bleeding symptoms. However, a striking mismatch exists between CH physician representation (4.4%) and CH consult volume (13.4%). This imbalance has implications for quality, timeliness, and continuity of care for patients with non-malignant hematologic conditions. Our findings underscore the urgent need to expand recruitment and career development pathways in CH to address a huge clinical demand.

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome resulting from immune dysregulation. While diagnostic and therapeutic guidelines (e.g., HLH-2004) are established for pediatric HLH, adult-onset HLH remains both a diagnostic and therapeutic challenge, with limited characterization and sparse outcome data. Here, we conduct a single-institution retrospective cohort study to evaluate clinical features, causes, and prognostic markers associated with outcomes. Methods: We performed a retrospective chart review of all adult patients (≥18 years) first diagnosed with HLH across all Mayo Clinic sites between January 1, 2006 and July 1, 2025. Diagnosis was based on hematologist adjudication at time of care. Patients with prior diagnoses of HLH or HLH related to T-cell therapy (CAR-T) were excluded. Clinical and laboratory variables were extracted from electronic health records. The primary outcome was overall survival (OS), defined as time from diagnosis of HLH to death or last follow-up. OS was estimated using the Kaplan-Meier method. Multivariable analysis to identify independent predictors of mortality was performed using a Cox proportional hazards regression model, adjusting for age at diagnosis, sex, HLH etiology, and relevant clinical and laboratory parameters. Model discrimination was assessed using Harrell's concordance index (c-index). Descriptive statistics were summarized using median and interquartile range (IQR) for continuous variables and frequency with percentages for categorical variables. Results: A total of 203 patients diagnosed with HLH were included. The median age at diagnosis was 55 years (range 18-86). The cohort was predominantly male (n=130, 64%) and White (n=163, 80%). The majority of diagnoses occurred in more recent years, with 75 patients (36.9%) diagnosed between 2021–2025, 61 (30.0%) between 2016–2020, and 43 (21.2%) between 2011–2015. Prior to HLH diagnosis, 86 patients (42.4%) had a history of malignancy, 55 (27.1%) had a history of autoimmune disease, and 28 (13.8%) had a history of transplant. The most common HLH etiologies were malignancy-associated (n=99, 49%), infectious (n=51, 25%), and autoimmune (n=24, 12%), in addition to idiopathic (n=6, 3%), post-transplant lymphoproliferative disease or graft-vs-host disease (n=3, 1%), drug-induced (n=3, 1%), or primary HLH (n=1, 0.5%). The most common malignancies included T-cell (n=35, 17.2%) and diffuse large B-cell lymphoma (n=24, 11.8%). Forty-four cases (21.7%) were associated with Epstein-Barr virus (EBV), either through overt viremia or malignancies with EBV positivity on pathology report. Five patients (2.5%) had COVID-19–associated HLH and 2 (1.0%) were attributed to immune checkpoint inhibitors. Overall, 164 patients (80.8%) met the HLH-2004 diagnostic threshold of ≥5 out of 8 criteria, while 196 (96.6%) met the HLH-2024 ≥4 of 7 modified criteria. Among patients with available information, elevated ferritin was present in 197 of 198 (99.5%), fever in 185 of 202 (91.6%), cytopenias involving ≥2 lineages in 184 of 199 (92.5%), hemophagocytosis in 156 of 182 (85.7%), elevated sCD25 in 117 of 121 (96.7%), hypertriglyceridemia in 117 of 186 (62.9%), hypofibrinogenemia in 118 of 196 (60.2%), splenomegaly in 125 of 188 (66.5%), and impaired NK cell activity in 16 of 25 (64.0%). In addition, hepatomegaly was noted in 57 of 195 patients (29.2%). After a median follow-up of 58.3 months, median OS was 62 days (95% CI 40-110) from day of diagnosis. In a multivariable Cox proportional hazards model with moderate discrimination (c-index=0.75), after adjusting for age at diagnosis and sex, T-cell lymphoma–driven HLH (HR 1.78, 95% CI 1.05–3.00, p = 0.03) and elevated blood urea nitrogen (median 51.0 mg/dL, IQR 27.9–99.1; HR 2.07, 95% CI 1.37–3.13, p &lt; 0.005) were independently associated with shorter OS Conclusions: In this cohort of adult patients with HLH, malignancy was found to be the most common trigger for HLH. T-cell malignancies in particular were strongly correlated with poor survival. Elevated blood urea nitrogen at diagnosis also identified patients at significantly higher risk of death, consistent with other critical illnesses that can present with multi-organ failure. These findings emphasize the need for adult-specific prognostic tools incorporating disease etiology and organ dysfunction markers to better stratify risk and guide clinical management in adult-onset HLH.

Abstract Background and Significance: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with pathologic erythrocytosis, most often driven by somatic mutations in the JAK2 gene. A key treatment goal is maintaining hematocrit (HCT) below 45% to reduce thromboembolic complications. Current standard of care for patients diagnosed with PV, including phlebotomy (PHL) and cytoreductive therapies (CRT), can be burdensome, may lead to intolerable adverse effects, and often are associated with symptoms of iron deficiency. DISC-3405 is an investigational, novel, humanized immunoglobulin (Ig)G1 monoclonal antibody that targets transmembrane serine protease 6 (TMPRSS6, also known as matriptase 2) to stimulate endogenous production of hepcidin, a peptide hormone secreted by hepatocytes and the key regulator of iron homeostasis. In a randomized, placebo-controlled study in healthy volunteers (DISC-3405-101), DISC-3405 administered subcutaneously at doses between 37.5-300 mg was well-tolerated, resulted in dose-dependent pharmacokinetic (PK) profiles, significantly increased hepcidin production with corresponding reductions in serum iron levels, and reduced HCT (Liu et al, EHA 2025, PS2207). DISC-3405 is being developed as a potential treatment for patients with PV requiring HCT reduction, regardless of baseline risk or concurrent CRT. Study Design and Methods: This is a multi-center, open-label, 52-week Phase 2 study enrolling up to 20 patients with PV in the United States to assess the safety, tolerability, PK, pharmacodynamics (PD), and therapeutic effect of DISC-3405 on PV disease control as evidenced by HCT reduction and PHL requirements. After an observation period of 4-12 weeks, participants will be treated and followed for 52 weeks and dosed up to 300 mg every 2 weeks. After 52 weeks, participants can continue in an optional 2-year continuation phase where long-term safety and efficacy will continue to be assessed. The main efficacy endpoints of the study include the proportion of participants achieving therapeutic response, defined as absence of PHL eligibility; number of PHLs during the treatment period; and proportion of participants with HCT values &lt;45% throughout the study. PHL eligibility is defined as (1) HCT ≥45% and ≥3% (absolute change) of pre-treatment values or (2) HCT &gt;48%. Eligible participants include adults 18 or older who meet the 2022 World Health Organization diagnostic criteria for PV. Clinically acceptable laboratory values include HCT &lt;45% prior to Day 1 (dosing) or HCT &lt;48% if followed by a PHL within 2 weeks prior to first dose of study drug, white blood cells 4000/μL to 20,000/μL (inclusive), and platelets 100,000/μL to 1,000,000/μL (inclusive). Participants should have at least 3 PHL in 26 weeks or 5 PHL in the 52 weeks prior to screening, and at least 1 PHL within 12 weeks prior to screening. Participants receiving CRT must have been on the therapy for at least 6 months and on a stable PV treatment regimen, including hydroxyurea, interferon, or ruxolitinib, for at least 2 months. Participants treated with only PHL must have stopped CRT 6 months before screening. Key exclusion criteria include participants that require PHL at HCT levels &lt;45%, clinically significant thrombosis within 2 months prior to study treatment, active or chronic bleeding, estimated glomerular filtration rate of &lt;30 mL/min/1.73 m2, and history of invasive malignancies within the last 5 years, except localized cured prostate cancer and cervical cancer, or other malignancies deemed acceptable in discussion with the Sponsor. The study will enroll participants from approximately 15-20 sites in the United States. Additional details can be found at https://clinicaltrials.gov/study/NCT06985147.

Abstract Background: In 2022, Medicare alone spent $42.1 billion on prescription drugs, with antineoplastic and classical hematology drugs accounting for 44% and 8% of the total, respectively (2024 MedPAC Data Book). While antineoplastic drugs have been extensively studied, classical hematology drugs have received comparatively little attention. We analyzed US Food and Drug Administration (FDA) approvals of classical hematology drugs over the past 30 years and examined their per-patient costs and annual total US sales. Methods: We identified all classical hematology drugs (those prescribed by hematologist/oncologists for non-malignant indications) approved by the FDA from January 1, 1995 to December 31, 2024, including novel pharmaceuticals (synthesized from chemical compounds), biologics (derived from living organisms), and biosimilars (highly similar, but not identical, to biologics previously approved). Cost estimates for 2024 were based on wholesale acquisition costs (WAC), using annual WAC for continuous-duration treatments and typical course WAC for fixed-duration treatments. WAC and US gross sales data for 2024 were obtained from IPD Analytics (Aventura, FL). Results: A total of 98 classical hematology drugs were approved over the past 30 years—11% in 1995–2004, 26% in 2005–2014, and 63% in 2015–2024. These included pharmaceuticals (36%), biologics (54%), and biosimilars (10%). Six gene therapies received approval: 3 for hemophilia and 1 each for sickle disease, beta thalassemia, and sickle cell disease/beta thalassemia (dual indication). Common categories of indications included bleeding (31%), anemia (30%), neutropenia (9%), and thrombocytopenia (9%). Leading diagnoses were hemophilia (25%), chemotherapy-induced neutropenia (9%), thromboembolism (8%), paroxysmal nocturnal hemoglobinuria (PNH; 7%), anemia of chronic kidney disease (6%), iron deficiency anemia (6%), and immune thrombocytopenia (5%). The median cost for gene therapies was $2.9 million per treatment (range: $2.2 million–$3.5 million). Among non-gene therapies, median costs were $3,000 per course for fixed-duration treatments (range: $64–$378,000) and $467,000 annually for continuous-duration treatments (range: $2,400–$1.8 million). The most expensive fixed-duration treatments targeted hemophagocytic lymphohistiocytosis ($378,000/8-week course), while the most expensive continuous-duration treatments were for hemophilia (median: $630,000/year; range: $270,000–$853,000). Estimated 2024 US gross sales across all drugs exceeded $70 billion. Top-selling indications included thromboembolism ($43.5 billion), hemophilia ($6.9 billion), immune thrombocytopenia ($4.9 billion), PNH ($4.7 billion), chemotherapy-induced neutropenia ($2.8 billion), anemia of chronic kidney disease ($2.0 billion), and iron deficiency anemia ($1.8 billion). Total sales for all gene therapies combined were $143 million. Six drugs have been discontinued (year approved/year discontinued/reason): betrixaban (2017/2020/business), daprodustat (2023/2024/business), fidanacogene elaparvovec (2024/2025/business), oprelvekin (1997/2011/business), peginesatide (2012/2013/safety), and voxelotor (2019/2024/safety). There are limitations to our study. Some drugs have non-classical hematology indications (anticoagulants in atrial fibrillation; luspatercept in myelodysplastic neoplasm) and/or may also be prescribed by non-classical hematologists (erythropoiesis stimulating agents by nephrologists and medical oncologists). We were unable to disaggregate the sales data in these situations. Therefore, the annual sales for certain indications may be overestimated. Conclusions: Classical hematology drugs contribute substantially to US prescription drug spending, with over $70 billion in annual sales and medications for thromboembolism accounting for over half of the costs. Approvals have accelerated over the past three decades, doubling each decade. Biologics and biosimilars now represent two-thirds of approvals. Continuous-duration treatments, particularly for rare hereditary diseases like hemophilia, carry significant financial burden, with annual costs per patient often exceeding $0.5 million. In these conditions, if gene therapies demonstrate durable efficacy, they may prove to be cost-effective alternatives. As more gene therapies are developed, evaluating their long-term value relative to chronic high-cost treatments will be essential for shaping future reimbursement and access strategies.