Prognostic Insights on PRE-Fibrotic Primary Myelofibrosis: A Clinical-Pathological Perspective in 762 Patients

Introduction

The 2022 WHO and ICC classifications confirmed pre-fibrotic PMF (pre-PMF) as a myeloproliferative neoplasm subtype with distinct histopathological and clinical-biological parameters, for which specific prognostic models are still lacking.

Aim

To identify the most relevant clinical, histological, and molecular data at diagnosis as predictors of outcome in pre-PMF patients (pts) in the real-world setting.

Methods

The present multicenter, retrospective study included 762 pre-PMF pts who were diagnosed in 7 Italian hematological centers between January 2000 and June 2023 and were followed for a minimum of 6 months. Baseline clinical characteristics and outcome measures (death, thrombotic complications, fibrotic progression, and leukemic evolution) were assessed. Follow-up information was updated in December 2023.

Results

Median age of the pts included in this study was 62.8 years; 48.3% were male.

All cases had no bone marrow fibrosis (MF-0, 28.6%) or only a slight increase in reticulin fibrosis (MF-1, 71.4%).

A driver mutation was found in 92.8% of cases: JAK2V617F in 69.9%, CALR in 20.1%, and MPLW515L/K in 2.8%; 55 (7.2%) pts were triple-negative.

After a median follow-up of 5.9 years, 168 (22.0%) pts died, 84 (11.0%) experienced fibrotic progression and 40 (5.2%) leukemic evolution. Thrombosis occurred before/at diagnosis in 137 (18.5%) and 64 (8.4%) pts, respectively, compared with 102 (13.4%) pts during follow-up.

The 5-, 10-, and 15-year overall survival (OS) rate was 90.9%, 74.5% and 60.1%, respectively. In details, 5-, 10-, and 15-year cumulative incidence of thrombosis was 9.6%, 16.0% and 23.1%, respectively, compared with 4.9%, 12.8% and 20.6% for fibrotic progression, and 2.5%, 6.1% and 8.6% for leukemic evolution.

In univariate analysis, factors associated with OS were female sex [Hazard Ratio (HR) 0.59, 95%CI 0.43–0.81], age at diagnosis (HR 2.66 per 10 years, 95%CI 2.25-3.15), previous thrombosis (HR 1.68, 95%CI 1.15–2.43), smoking habit, either former (HR 1.59, 95%CI 1.03–2.45) or current (HR 1.69, 95%CI 1.08–2.65), hypertension (HR 1.77, 95%CI 1.28–2.44) and diabetes (HR 2.02, 95%CI 1.37–2.98), hemoglobin (Hb) level (HR 0.81 per 1 mg/dL, 95%CI 0.75-0.86), white blood cell (WBC) (HR 1.06 per 1 x10⁹/L, 95%CI 1.04-1.08) and platelet (PLT) count (HR 0.95 per 100 x10⁹/L, 95%CI 0.90-1.00), peripheral blood (PB) blasts (HR 1.81 per 1%, 95%CI 1.33-2.48), LDH level (HR 1.08 per 100 IU/L, 95%CI 1.03-1.12), circulating CD34+ cells count (HR 1.07 per 10 x10⁶/L, 95%CI 1.05-1.10), spleen diameter (HR 1.06 per cm below left costal margin, 95%CI 1.00-1.12), CALR mutations (HR 0.46, 95%CI 0.29–0.72), in particular type 1 (HR 0.35, 95%CI 0.19-0.65), presence of cytogenetic abnormalities (HR 1.81, 95%CI 1.15–2.84), and MF-1 reticulin fibrosis (HR 1.51, 95%CI 1.06–2.13). Moreover, we confirmed the prognostic relevance of IPSS, DIPSS, and DIPSS-plus (data not shown). The same was also for IPSET-Thrombosis [intermediate risk (IR) vs low risk (LR), HR 2.77, 95%CI 1.36-5.64; high risk (HR) vs LR, HR 5.18, 95%CI 2.79-9.64] and revised IPSET [LR vs very low risk (VLR), HR 3.66, 95%CI 1.23-10.87; IR vs VLR, HR 17.3, 95%CI 5.99-49.8; HR vs VLR, HR 17.1, 95%CI 6.28-46.8].

In multivariable analyses adjusted for gender and age at diagnosis, the following variables were confirmed to be associated with OS: diabetes (HR 1.70, 95%CI 1.15–2.51), Hb level (HR 0.83, 95%CI 0.77-0.89), WBC count (HR 1.05, 95%CI 1.03-1.07), PB blasts (HR 1.81, 95%CI 1.36-2.41), LDH level (HR 1.12, 95%CI 1.06-1.17), circulating CD34+ cells count (HR 1.06, 95%CI 1.04-1.09), spleen diameter (HR 1.16, 95%CI 1.09-1.24), CALR mutations (HR 0.54, 95%CI 0.34–0.85), in particular type 1 (HR 0.42, 95%CI 0.22-0.79), presence of cytogenetic abnormalities (HR 1.57, 95%CI 0.99–2.49), and MF-1 reticulin fibrosis (HR 1.54, 95%CI 1.08–2.19).

Discussion

In clinical practice, existing tools for overt PMF are often extended for prognosis and management guidance in pre-PMF. However, the daily concerns in pre-PMF management usually lie more in the prevention of thrombo-hemorrhagic episodes.

Therefore, a risk stratification scheme based on clinical-pathological and molecular factors dedicated to pre-PMF would be needed, as it could help physicians not only with prognostication, but also in guiding management decisions.

Updated analyses, including data on HMR mutations, will be presented.