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3169 Monocytosis Is an Independent Risk Factor for Survival in Essential Thrombocythemia - a Revised Triple-a Prognostic Score (AAA+A) Based on Age and Absolute Monocyte, Neutrophil, and Lymphocyte Counts

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
MPN, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Ayalew Tefferi, MD1, Giuseppe Gaetano Gaetano Loscocco2*, Maymona Abdelmagid, MD3*, Animesh D. Pardanani, MBBS, PhD3, Kebede Begna, MD3, Mrinal M. Patnaik, MD, MBBS4, Natasha Szuber, MD, MSc5, Alessandra Carobbio6*, Tiziano Barbui, MD7*, Kaaren K. Reichard, MD8, Paola Guglielmelli, MD9, Naseema Gangat, MBBS1 and Alessandro M. Vannucchi, MD2

1Division of Hematology, Mayo Clinic, Rochester, MN
2CRIMM, Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
3Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
4Mayo Clinic, Rochester, MN
5Institut universitaire d'hématologie-oncologie et de thérapie cellulaire, Université de Montréal, Montreal, QC, Canada
6Fondazione per la Ricerca Ospedale di Bergamo (FROM), Bergamo, Italy
7FROM Research Foundation ASST Papa Giovanni XXIII Bergamo, Bergamo, ITA
8Department of Pathology, Mayo Clinic, Rochester, MN
9University of Florence, Firenze, Florence, ITA

Background

Survival risk models in essential thrombocythemia (ET) include the International Prognostic Scoring System (IPSET; Blood 2012;120:1197) and the more recently described “triple-A” prognostic score that considers Age and absolute neutrophil (ANC) and lymphocyte (ALC) counts, as risk variables (AJH 2023;98:1829). Monocytosis, defined by absolute monocyte count (AMC) of ≥0.8 x 109/L, was recently reported to be associated with inferior survival in polycythemia vera (ASH 2024 abstract). The current study examined the prognostic contribution of monocytosis in ET, in the context of other clinical and genetic risk factors.

Methods

Study patients were recruited from Mayo Clinic (USA) databases, based on availability of information on ANC, ALC, and AMC (N=649). Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Mutations were screened by next-generation sequencing (NGS). Conventional statistical methods were employed (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA) and optimal cut-points for age, ANC, ALC, and AMC were determined by Receiver Operating Characteristic (ROC) analysis. Akaike Information Criterion (AIC) and ROC plots were used to estimate predictive accuracy of risk models.

Results

A total of 649 patients (median age 60 years; females 65%) were informative for AMC, ANC, and ALC, with median (range) values of 0.6 x 109/L (0.2-2.5), 5.7 x 109/L (1.5-26.5), and 1.9 (0.4-5.7), respectively. At presentation, IPSET risk distribution was low in 34%, intermediate 47%, and high 19%; triple-A risk distribution was low 21%, intermediate-1 50%, intermediate-2 13%, and high 16%; driver mutation distribution was 63.8% JAK2, 24.0% CALR, 3.7% MPL, and 8.5% triple-negative; median for platelets were 728 x 109/L, hemoglobin 13.9 g/dL, and leukocytes 8.5 x 109/L ; leukocytosis (leukocytes ≥11 x 109/L) was documented in 18.8% of patients, palpable splenomegaly 7%, arterial thrombosis (AT) history 14.5%, venous thrombosis (VT) history 9.2%, and major hemorrhage 7.8%.

At median follow-up of 7 years (range 0.02-31.4), 146 (22.5%) deaths, 52 (8%) fibrotic progressions, 22 (3.4%) leukemic transformations, 71 (11%) AT events, 36 (5.6%) VT events, and 64 (10%) major bleeds were recorded. In age-adjusted univariate analysis, higher AMC was significantly associated with inferior survival, with a ROC determined cutoff value of ≥0.8 x 109/L (N=154; 24%); significance was sustained (HR 2.3; p<0.01) during multivariable analysis (MVA) that also identified age >70 years (HR 16.6; p<0.01), age 50-70 years (HR 4.3; p<0.01), ANC ≥8 x 109/L (HR 1.9; p<0.01), ALC <1.7 x 109/L (HR 1.8; p<0.01), and AT history (HR 1.6; p=0.01). A similar MVA conducted on an external cohort from the University of Florence (N=514) confirmed the significant contribution from all of these risk variables, except AT (p=0.8).

An HR-based 4-variable prognostic model based on Age >70 years (4 points) or 50-70 years (2 points), AMC ≥0.8 x 109/L (1 point), ANC ≥8 x 109/L (1 point), and ALC <1.7 x 109/L (1 point), henceforth referred to as the AAA+A model, was subsequently developed using the Mayo Clinic cohort and validated by the Florence cohort: Low (0-1 points; N= 180; median not reached), intermediate-1 (2-3 points; N=266; median 21.6 years), intermediate-2 (4-5 points; N=151; median 12.2 years), and high (6-7 points; N=52; median 8.7 years); HR values were 2.1 for high vs. intermediate-2, 5.4 for intermediate-2 vs. intermediate-1, and 3.8 for intermediate-1 vs. low (p<0.001in all instances). The 20-year survival predictive performance of AAA+A (AIC 131; AUC 0.88) was superior to that of AAA (AIC 143; AUC 0.85) and IPSET (AIC 149; AUC 0.84). In MVA that included AAA+A risk variables, AMC ≥0.8 x 109/L (p=0.04) and ALC <1.7 x 109/L (p=0.06) appeared to affect leukemia-free survival and ANC ≥8 x 109/L (p=0.04) myelofibrosis-free survival. In univariate analysis, AMC ≥0.8 x 109/L was associated with AT (p=0.03) but not VT (p=0.14) history and showed borderline significance for venous (p=0.09) and arterial (p=0.07) thrombosis-free survivals; however, significance was lost during MVA.

Conclusions: Monocytosis is an adverse prognostic factor in ET and its inclusion as a risk variable enhances the predictive performance of the AAA risk model and is equally simple to apply worldwide. Analyses that include mutations will be presented at meeting.

Disclosures: Begna: Novartis: Membership on an entity's Board of Directors or advisory committees. Patnaik: Kura Oncology: Research Funding; Solu therapeutics: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Epigenetix: Research Funding; Polaris: Research Funding; StemLine: Research Funding. Guglielmelli: AOP: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gangat: DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Blueprint: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP: Honoraria, Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Honoraria, Membership on an entity's Board of Directors or advisory committees; IONCTURA: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH