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Background Blast or accelerated phase myeloproliferative neoplasm (MPN-BP/AP) carries a dismal prognosis, with 3-year survival estimates of <5% (BCJ 2023;108). Patients with MPN-BP/AP were excluded from venetoclax (Ven) plus hypomethylating agent (HMA) clinical trials for acute myeloid leukemia (NEJM 2020;383:617). In the current retrospective study, we examined response patterns and long-term survival of newly-diagnosed MPN-BP/AP patients who received treatment with Ven+HMA, outside of clinical trials. Methods Newly-diagnosed patients with MPN-BP/AP treated with Ven+HMA at the Mayo Clinic, between March 2019 and May 2024, were retrospectively reviewed. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Cytogenetic and molecular studies were performed by conventional karyotype and next-generation sequencing, respectively. All patients received at least one cycle of Ven+HMA (azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5). Response was assessed according to the 2022 European Leukemia Net criteria (Blood 2022;140:1345). Standard statistical analyses were performed using JMP Pro (Version 17.1.0). Results Patient characteristics 70 patients (median age 73 years, 59% males, 48% splenomegaly >14 cm, 4% isolated myeloid sarcoma) with newly-diagnosed MPN-BP (n=58) or AP (n=12) received Ven+HMA with (n=13) or without (n=57) concomitant JAK2 inhibitor. Driver mutation distribution was 69% JAK2, 21% CALR, 6% MPL, and 4% triple negative. Mutations involved ASXL1 (31%), TP53 (28%), TET2 (28%), RUNX1 (25%), SRSF2 (18%), IDH2 (12%), U2AF1 (11%), DNMT3A (9%), IDH1 (7%), and K/NRAS (7%). Karyotype was abnormal in 50 (76%) of 66 informative cases, of which 28 (56%) were complex (CK). Median TP53 mutation variant allele frequency (VAF) was 30% (8-96%) and all evaluable cases displayed CK (n=18). Response and Survival Complete remission (CR; 21%) or CR with incomplete count recovery (CRi; 19%) was documented in 28 (40%) patients with residual MPN in 18 (64%) patients. Median response duration was 5.5 months (1-60 months). After a median follow up of 7 months (1-62 months), 48 (69%) deaths, 13 relapses (46%), and 15 (21%) allogeneic stem cell transplants (ASCT; 12 in CR/CRi) were recorded. Median overall survival (OS) was 9 months and was superior with ASCT (median 22 vs. 8 months; p=0.01). In univariate analysis, transplant-censored survival was superior with CR/CRi (12 vs. 5 months; p<0.01) and IDH1 mutation (33 vs. 8 months; p=0.04) and inferior with CK (7 vs. 10 months; p=0.05), TP53 mutation (5 vs. 10 months; p<0.01), post polycythemia vera myelofibrosis (post-PV MF) (3 vs. 9 months; p=0.01), and splenomegaly >14 cm (5 vs. 16 months; p<0.01). Multivariable analysis confirmed the negative survival impact of not achieving CR/CRi (HR 3.8; p<0.01) and presence of TP53 mutation (HR 4.0; p<0.01); median survival (1/3-year survival rate) was 3 months (10%/0%) in TP53 mutated patients not achieving CR/CRi (n=11) vs. 27 months (65%/28%) in TP53 unmutated cases achieving CR/CRi (n=19) (p < 0.01). Median survival in patients with TP53 mutations or CK who achieved CR/CRi (n=7; 7 months) was inferior to that in treatment responders without TP53 mutations or CK (n=18; 23 months; p=0.01). CR/CRi rates in the presence vs. absence of TP53 mutations were 42% vs. 39% (p=0.80) and of CK (25% vs. 50% (p=0.04). Importantly, responses in the presence of TP53 mutations or CK were too short-lived to allow successful bridging to ASCT (median 2 vs. 9 months; p<0.01). Additional predictors of inferior treatment response included splenomegaly >14 cm (24% vs. 53%; p=0.01), and post-PV MF (0% vs. 46%; p<0.01) while SRSF2 (67% vs. 34%; p=0.04) and IDH2 mutations (75% vs. 35%; p=0.03) were associated with favorable response. In multivariable analysis, CK (p=0.04) and splenomegaly >14 cm (p=0.01) remained independent predictors of inferior response. The use of concomitant JAK2 inhibitor therapy did not impact treatment response (CR/CRi 46% vs. 39%; p=0.62) or survival (median 9 vs. 8 months; p=0.71). Conclusions TP53 mutations and CK undermine the value of Ven+HMA, with or without concomitant JAK2 inhibitor, in enabling successful bridging of newly-diagnosed MPN-BP/AP to ASCT. An alternative treatment approach is advised, in the particular scenario, while the observed 3-year survival rate of 28%, in treatment responders without TP53 mutations, is encouraging.

Background A JAK2 mutation is detected in almost all patients with polycythemia vera (PV) and in ⁓50% of those with essential thrombocythemia (ET). The two diseases also share characteristic clinical and bone marrow morphological traits, suggesting they exist on a disease continuum rather than representing discrete entities. The objective of the current study was to compare clinical and genetic characteristics as well as long-term outcome between formally-defined PV vs. JAK2-mutated ET vs. JAK2-wild-type (WT) ET. Methods Study patients were retrospectively recruited from Mayo Clinic, USA databases (1967-2024). Diagnostic criteria were according to the International Consensus Classification (ICC; Blood 2022;140:1200). All study patients were fully annotated for JAK2, CALR, and MPL mutations while cytogenetic and additional next-generation sequencing (NGS)-derived mutation information was available in a subset of patients. Conventional statistical methods were employed for phenotypic comparisons and survival analysis. Results Among 2,010 study patients, 1,010 had PV, 617 (63%) JAK2-mutated ET, and 383 JAK2-WT ET (CALR 26%; MPL 3%; triple-negative 9%). Phenotypic comparisons revealed older age distribution in PV compared to JAK2-mutated ET (p=0.03) and the latter compared to JAK2-WT ET (p<0.01). Females were represented more in JAK2-mutated ET (69%), compared to both PV (49%; p<0.01) and JAK2-WT ET (54%; p<0.01). The frequencies of leukocytosis, palpable splenomegaly, constitutional symptoms, diabetes, hypertension, and abnormal karyotype were all significantly higher in PV, compared to both groups of ET, while JAK2-mutated compared to JAK2-WT ET displayed higher leukocyte count and incidence of hypertension. The incidences of arterial thrombosis at/prior to diagnosis were 14%, 16%, and 10% in PV, JAK2-mutated and WT ET, respectively (P=0.03), and venous thrombosis 14%, 13%, and 6% (p<0.01). After a median follow-up of 8.6 years, 632 (32%) deaths, 329 (16%) fibrotic progressions, 79 (4%) leukemic transformations, and 236 (12%) arterial and 202 (10%) venous thrombotic events were recorded, among all 2,010 study patients. Median overall survival was 19.3 years for PV vs. 17.8 years for JAK2-mutated ET vs. 23 years for JAK2-WT ET (p<0.01); however, the significant difference in favor of JAK2-WT ET was no longer apparent when analysis was adjusted for age and sex (p=0.15) and subsequently for other risk factors (p=0.86). All-inclusive multivariable analysis identified older age (p<0.01), male sex (p<0.01), higher leukocyte count (p<0.01), and arterial thrombosis history (p<0.01), but not the distinction between PV, JAK2-mutated, and JAK2-WT ET (p=0.9), to be independently associated with shortened survival. Leukemia-free survival was similar between PV and either JAK2-mutated (p=0.5) or JAK2-WT (p=0.1) ET. On the other hand, myelofibrosis-free survival was shorter in PV, compared to both JAK2-mutated (HR 1.8, 1.4-2.4; p<0.01) and JAK2-WT (HR 1.4. 1.0-1.8; p=0.03) ET. In multivariable analysis, older age (p<0.01), higher leukocyte count (p<0.01), PV vs. JAK2-mutated ET (HR 1.8; p<0.01), and JAK2-WT vs. JAK2-mutated ET (HR 1.6; p=0.01) were associated with a higher risk of fibrotic progression, with no difference noted between PV and JAK2-WT ET (p=0.4). Arterial thrombosis-free survival was similar between PV and JAK2-mutated ET (p=0.8). In univariate analysis, JAK2-WT ET vs. PV was associated with superior arterial thrombosis-free survival (p=0.02), but significance was lost when analysis was adjusted for arterial thrombosis history (p=0.1). Venous thrombosis-free survival favored JAK2-WT ET vs. PV (HR 0.3; p<0.01) and JAK2-mutated ET (HR 0.6; p=0.02) and the latter vs. PV (HR 0.6; p<0.01); the significant differences between PV and both groups of ET were sustained when analysis was adjusted for age, sex, and venous thrombosis history. Conclusions The current study highlights significant demographic and phenotypic differences between PV and JAK2-mutated ET. However, risk factor-adjusted overall, leukemia-free, and arterial thrombosis-free survival was not inferior in PV, compared to ET, regardless of the presence or absence of a JAK2 mutation in the latter. JAK2-WT ET was distinctly associated with a lower risk of venous thrombosis while JAK2-mutated ET appeared to be less vulnerable to fibrotic progression.

Background DISC-0974 is a monoclonal antibody that targets hemojuvelin, a co-receptor to BMP-SMAD signaling that stimulates hepcidin production. In healthy volunteers, DISC-0974 has been shown to be safe and induce dose-dependent decreases in serum hepcidin and corresponding increases in serum iron and absolute reticulocyte count (JCP 2024). Serum hepcidin level is abnormally elevated in myelofibrosis (MF) and is believed to contribute to iron-restricted erythropoiesis (AJH 2013:88:312). In an ongoing phase 1/2 study in MF (NCT05320198), DISC-0974 was well tolerated and associated with marked reduction in serum hepcidin levels and improvement in anemia (Blood 2023;142/DOI 10.1182). The current investigator-initiated laboratory correlative study examined the impact of mutations and baseline cytokine levels on anemia response to DISC-0974, in non-transfusion-dependent (nTD) patients with MF. Methods The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from Mayo Clinic patient records (Rochester, MN, USA). Study patients were selected from the aforementioned ongoing phase 1/2 study, based on availability of information on mutations and baseline cytokine levels. Definitions of nTD and anemia response criteria were according to the revised international working group (IWG) criteria (Blood 2024; in press): i) nTD was defined as the presence of ≤2 units transfused in the 12 weeks prior to enrollment; ii) a 12-week rolling average increase of hemoglobin by ≥1.5 or 1-1.4 g/dL is required for major and minor response, respectively. Mutation and cytokine analyses were performed according to institutional standard protocols; next-generation sequencing panel included 48 genes and cytokine panel 12 inflammatory cytokines. Results A total of 21 nTD patients with MF (median age 71 years; males 62%) were considered: 15 primary and 6 secondary. Driver mutation distribution was JAK2 52%, MPL 14%, and CALR-1 33%. DIPSS risk distribution was high (10%) and intermediate-2 (90%). Baseline median (range) values were 8.0 g/dL (range 7.1-9.5) for hemoglobin, 266 (41-1221) for serum ferritin, 79 (32-130) for serum iron, 32 (13-49) for transferrin saturation, and 59 (10-913) for serum erythropoietin. Karyotype was favorable (N=18) or unfavorable (N=2). Other mutations, included ASXL1 (N=5), SF3B1 (N=4), SRSF2 (N=1), U2AF1 (N=1), and “none of the above” (N=5). Elevated cytokines at baseline included TNF (90%), IL-18 (43%), IL-2R alpha (34%), IL-6 (24%), and MCP-1 (14%). DISC-0974 dose levels were 28 mg (N=2), 50 mg (N=7), 75 mg (N=7), and 100 mg (N=5). Twelve (60%) patients were on DISC-0974 monotherapy while 9 (40%) received concomitant ruxolitinib (N=5), pacritinib (N=1), or hydroxyurea (N=3). At median follow-up of 6 months (range 2-14), one (5%) patient has discontinued DISC-0974 for lack of response. Details on drug safety are summarized in another abstract (Gangat et al. ASH 2024). Per IWG criteria, 9 (43%) patients achieved major (MR) and 3 (14%) minor responses, resulting in an overall response (OR) rate of 57%. Two additional patients have surpassed the hemoglobin threshold for major response (≥1.5 g/dL) but have not yet met IWG criteria. OR and MR rates were higher in patients receiving DISC-0974 as monotherapy (OR 75% and MR 58%) vs. combined with JAK2 inhibitor or hydroxyurea (OR 33% and MR 22%) (p=0.05 for OR and 0.09 for MR), ASXL1 wild-type (N=15; OR 67% and MR 53%) vs. mutated (N=6; OR 33% and MR 17%) (p=0.16 for OR and 0.11 for MR), no ASXL1/SRSF2/U2AF1/SF3B1 (N=5; OR 100% and MR 80%) vs. at least one mutated (N=16; OR 44% and MR 31%) (p<0.01 for OR and 0.05 for MR). OR was also higher in the presence of elevated MCP-1 (p=0.05) or elevated IL-2R alpha (p=0.05) and MR in the presence of elevated IL-2R alpha (71% vs. 29%; p=0.06). Conclusions: The current study suggests that ASXL1 mutation might attenuate but not abrogate anemia response to DISC-0974, in MF. Elevated inflammatory cytokines in MF are often associated with increased hepcidin levels (AJH 2013:88:312) and this might explain their association with a higher response rate to DISC-0974, observed in the current study. Regardless, it is important to note that these observations represent preliminary data from a subset of patients from an ongoing clinical trial.

Background Absolute basophil count (ABC) might be increased in patients with myeloproliferative neoplasms and has been associated with poor prognosis in chronic myeloid leukemia (CML) and, possibly, primary myelofibrosis (PMF, Front. Oncol 2019;9:872). In a Mayo Clinic survey of 382 patients with BCR::ABL1-negative leukocytosis and ABC ≥0.09 x 109/L, 191 (50%) were associated with myeloid neoplasms, including 104 (27%) with CML, 23 (6%) essential thrombocythemia, 21 (6%) polycythemia vera (PV), and 18 (5%) PMF (AJH 2020;95:E216). Herein, we tapped into a well-characterized cohort of patients with PV, in order to describe the prevalence of basophilia, at specific ABC thresholds, and corresponding clinical, molecular, and prognostic correlates. Methods Study patients were retrospectively recruited from Mayo Clinic (USA) databases, after approval from IRB. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Study inclusion criteria included the availability of information on ABC and absolute eosinophil count (AEC). Mayo Clinic institutional reference range for ABC was 0.01 to 0.08 x 109/L and for AEC 0.03 to 0.48 x 109/L. “Eosinophilia” was defined as an AEC of ≥0.6 x 109/L. Basophilia was evaluated both at an ABC of ≥0.1 x 109/L and ABC of ≥0.3 x 109/L, the latter representing 3 x the upper limit of the normal reference range. Cytogenetic information obtained within one year of diagnosis was available in 270 patients. Next-generation sequencing information collected before disease transformation was available in 99 patients. Conventional statistical methods were employed for comparisons of groups and survival analysis (JMP Pro 17.0.0 software SAS Institute, Cary, NC, USA). Results Information on ABC and AEC, obtained within one year of diagnosis, was available in 478 patients (median age 66 years; males 51%). Median values at presentation were 10.6 x 109/L for leukocyte count, 453 x 109/L platelet count, and 17.3 g/dL hemoglobin level. Presenting symptoms included palpable splenomegaly 24%, pruritus 31%, arterial thrombosis 12%, and venous thrombosis 17%. Median and range values for ABC and AEC were 0.12 x 109/L (0-3.2) and 0.27 x 109/L (0-6.5), respectively. ABC was ≥0.3 x 109/L in 80 (17%) patients and ≥0.1 x 109/L in 315 (66%). AEC was ≥0.6 x 109/L in 68 (14.6%) patients. ABC≥0.3 x 109/L was associated with AEC ≥0.6 x 109/L (p<0.01), leukocytosis (p<0.01), and palpable splenomegaly (p=0.02), but not platelet count, pruritus, smoking history, diabetes, or arterial or venous thrombosis; in multivariable analysis, the association with leukocytosis, but not that with splenomegaly, was confirmed. At a median follow-up of 5.7 years (range 0.03-32.8), 132 (28%) deaths, 17 (3.6%) leukemic and 40 (8.4%) fibrotic progressions were documented. Post-diagnosis events also included arterial (7%) and venous (9%) thrombosis. In univariate analysis, neither ABC (p=0.8, 0.7, and 0.96) nor AEC (p=0.7, 0.6, and 0.8), evaluated as continuous variables, affected overall (OS), leukemia-free (LFS), or myelofibrosis-free (MFFS) survival, respectively. Similarly, eosinophilia at AEC ≥0.6 x 109/L did not appear to influence OS (p=0.99), LFS (p=0.6) or MFFS (p=0.5). On the other hand, although basophilia at ABC≥0.3 x 109/L did not affect OS (p=0.27), it was significantly associated with inferior LFS (HR 6.5, 95% CI 2.3-18.0; p<0.01) and MFFS (HR 2.3, 95% CI 1.2-4.5; p=0.01); the corresponding p values for ABC≥0.1 x 109/L were 0.7, 0.1, and 0.17. The detrimental impact of basophilia (ABC≥0.3 x 109/L) on LFS was confirmed (P<0.01) with multivariable analysis that included other clinical variables, including leukocytosis (NS), platelet count (NS), basophil percentage (NS), age (p<0.01), and palpable splenomegaly (p<0.01). Results were similar during multivariable analysis for MFFS with palpable splenomegaly (p<0.01), ABC≥0.3 x 109/L (p=0.03), and age (p=0.05) sustaining independent predictive value. The number of informative cases was too small to evaluate prognostic interaction with mutations and karyotype. Conclusions: Basophilia in PV is associated with palpable splenomegaly and leukocytosis and independently predicts leukemic and myelofibrotic transformation. Additional studies are needed to confirm these observations and examine prognostic interaction with mutations and karyotype.

Abstract The ZRSR2 gene is a member of the spliceosome gene family which are frequently mutated in myeloid neoplasms. ZRSR2 mutations (ZRSR2m) occur in less than 5% of MDS, CMML, and AML. Our study included 164 ZRSR2m patients (98.8% males) and 98 ZRSR2wt MDS control cohort. In the ZRSR2m group, there were 53 MDS (32%), 39 CCUS (24%), 33 MPN (20%), 23 MDS/MPN overlap (14%), 15 AML (9%), and 1 MPAL (0.6%). Most MDS patients were the low blast subtype (n=37, 70%). Twenty-seven MDS patients (51%), and 23 CCUS patients (59%) had absolute monocyte count ≥0.5 x109/L and 18 of 23 MDS/MPN overlap were CMML (78%). Mutations in ZRSR2 were spread across the entire gene. The median number of co-mutations was 2, with TET2 (51%) and ASXL1 (32%) being the most common. U2AF1 and SRSF2, previously described as mutually exclusive with ZRSR2, were found in 10.4% of patients. Median overall survival (OS) was 51 months, and significantly varied among MNs (p=0.004). ZRSR2m MDS patients had better mOS than the MDS control cohort with ZRSR2wt (35 vs 22 months, p=0.013). ZRSR2m patients with isolated TET2 co-mutation and higher hemoglobin showed improved survival, while patients with RUNX1m, higher WBC count showed worse OS.

AbstractTwo‐hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990–2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704–369 × 109/L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first‐trimester loss was predicted by prior fetal loss (43% vs. 18%; p < .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p < .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p < .01) risk scenarios. The benefit of aspirin therapy, in preventing first‐trimester loss, was significant in both JAK2‐mutated (18% vs. 50%; p < .01) and CALR‐mutated (8% vs. 43%; p < .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first‐trimester loss in ET, independent of driver mutation status or other risk factors.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS <15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold <0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a < 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age < 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .