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Introduction Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined by relative monocytosis ≥ 10% and an absolute monocyte count (AMC) between ≥ 0.5 and < 1.0 x109/L. The 5th ed WHO and International Consensus Classifications lowered the AMC threshold to ≥ 0.5 x10/9L for CMML diagnosis, thereby incorporating OM-CMML (Khoury, 2022; Arber, 2022). However, prior reports differ as to whether OM-CMML is a distinct CMML subtype. This multi-center study compares the clinical, molecular, and survival features of OM-CMML with myelodysplastic (MD, WBC < 13.0 x109/L) and myeloproliferative (MP, WBC ≥ 13.0 x109/L) CMML with an AMC ≥1.0. Methods After IRB approval, patients with CMML from Mayo Clinic (n = 400, 47%) and MD Anderson Cancer Center (n = 449, 53%) were identified retrospectively. Analyses considered clinical, laboratory, and next generation sequencing parameters at diagnosis or first referral (in chronic phase). Categorical variables were compared by Fisher exact or Pearson χ2 tests and continuous variables by Mann-Whitney U or ANOVA tests. Survival was assessed via the Kaplan-Meier method with outcomes censored at allogeneic stem cell transplantation (alloSCT). P < 0.05 was considered significant. Calculations used BlueSky Statistics (v10.3.1). Results A molecularly annotated cohort of 849 patients with CMML (median age 71 years, 32% female, 90% white, median follow up 31 months [mo]) was categorized as OM-CMML (n = 57, 7%), MD-CMML (n = 394, 46%), and MP-CMML (n = 391, 46%). There were no differences in age or sex across subtypes. No clinical differences were observed between OM-CMML and MD-CMML, with similar hematologic parameters, karyotype distributions, Mayo-Molecular (Patnaik, 2014) or CPSS-Molecular (Elena, 2016) risk stratifications, and rates of leukemic transformation (12% vs 12%, p = 0.98) and death (35% vs 43%, p = 0.27). Cases of OM-CMML had lower WBC counts (median 4.4 vs 24.7 x109/L, p < 0.0001), fewer circulating immature myeloid cells (23% vs 57%, p < 0.0001) and fewer marrow blasts (median 3% vs 4%, p = 0.0065) than MP-CMML. Comparatively, OM-CMML cases were overrepresented in the lower-risk groups of the CPSS-Molecular and Mayo-Molecular models (p < 0.0001). Leukemic transformation (12% vs 20%, p = 0.015) and death (35% vs 52%, p = 0.034) rates were higher in the MP-CMML cohort. Molecular profiles were similar between OM-CMML and MD-CMML, including median number of genes mutated (3 vs 3, p = 0.88). Frequencies of ASXL1 (39% vs 38%, p = 0.91), SRSF2 (48% vs 43%, p = 0.49), DNMT3A (7% vs 5%, p = 0.60), and SF3B1 (4% vs 7%, p = 0.48) mutations were also similar. TET2 mutation frequency was higher in OM-CMML (70% vs 55%, p = 0.031) and occurred in isolation more frequently (12% vs 6%, p = 0.048) compared to MD-CMML. Neither median number of TET2 mutations (1 vs 2, p = 0.87), nor TET2 variant allele fractions (41% vs 44%, p = 0.19) were different between the two groups. Compared to OM-CMML, patients with MP-CMML were more likely to have mutations in ASXL1 (39% vs 56%, p = 0.017), EZH2 (0% vs 9%, p = 0.019), JAK2 (0% vs 9%, p = 0.019), NRAS (7% vs 25%, p = 0.0024), and SETBP1 (2% vs 13%, p = 0.021). RAS family (CBL, BRAF, KRAS, NRAS, PTPN11; 25% vs 54%, p < 0.0001) and signaling pathway (CSF3R, FLT3, JAK2, SH2B3; 2% vs 14%, p = 0.0078) mutations were also more frequent whereas spliceosome mutations (SF3B1, SRSF2, U2AF1, ZRSR2; 61% vs 46%, p = 0.033) were less frequent in MP-CMML. The median (95% CI) overall survival (OS) of OM-CMML patients was 44 (38 - not reached) mo compared to 45 (34 - 60) mo in MD-CMML (p = 0.76) and 23 (20 - 29) mo in MP-CMML (p < 0.0032). Similar results were obtained when comparing the acute leukemia-free survival (LFS) of the OM-CMML (41 mo), MD-CMML (39 mo), and MP-CMML (19 mo) groups. At last follow up (medians 42 and 62 mo, respectively), 33% of evaluable OM-CMML patients had progressed to MD-CMML and 28% of MD-CMML patients had progressed to MP-CMML. No patient with OM-CMML progressed directly to MP-CMML. Conclusions These data show that OM-CMML and MD-CMML are a relatively homogenous subset of patients with similar clinicomolecular profiles and survival outcomes. Although OM-CMML patients are more likely to have TET2 mutations in comparison to other CMML subtypes, they have similar rates of disease progression as MD-CMML. This validates recent modifications to CMML classification criteria, in which OM-CMML cases are included as bona fide CMML.

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.

AbstractThe current study was inspired by observations from exploratory analyses of an institutional cohort with chronic myelomonocytic leukemia (CMML; N = 398) that revealed no instances of blast transformation in the seven patients with plant homeodomain finger protein 6 (PHF6) mutation (PHF6MUT). A subsequent Mayo Clinic enterprise‐wide database search identified 28 more cases with PHF6MUT. Compared with their wild‐type PHF6 counterparts (PHF6WT; N = 391), PHF6MUT cases (N = 35) were more likely to co‐express TET2 (89% vs. 45%; p < .01), RUNX1 (29% vs. 14%; p = .03), CBL (14% vs. 2%; p < .01), and U2AF1 (17% vs. 6%; p = .04) and less likely SRSF2 (23% vs. 45%; p < .01) mutation. They were also more likely to display loss of Y chromosome (LoY; 21% vs. 2%; p < .01) and platelets <100 × 109/L (83% vs. 51%; p < .01). Multivariable analysis identified PHF6MUT (HR 0.28, 95% CI 0.15–0.50) and DNMT3AMUT (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation‐free survival with corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At median 20 months follow‐up, blast transformation was documented in none of the 33 patients with PHF6MUT/DNMT3AWT but in 6 (32%) of 19 with DNMT3AMUT and 74 (20%) of 374 with PHF6WT/DNMT3AWT (p < .01). The specific molecular signatures sustained their significant predictive performance in the context of the CMML‐specific molecular prognostic model (CPSS‐mol). PHF6MUT identifies a unique subset of patients with CMML characterized by thrombocytopenia, higher prevalence of LoY, and superior prognosis.

Abstract With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group–European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (&lt;10 g/dL for women and &lt;11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.