De Stefano, Valerio

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

Abstract We examined the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), and monocyte (AMC) counts, on overall (OS), leukemia‐free (LFS), and myelofibrosis‐free (MFFS) survival in essential thrombocythemia (ET). Informative cases ( N = 598; median age 59 years; females 62%) were retrospectively accrued from a Mayo Clinic database: JAK2 59%, CALR 27%, triple‐negative 11%, and MPL 3%; international prognostic scoring system for ET (IPSET) risk high 21%, intermediate 42%, and low 37%; 7% (37/515) had abnormal karyotype and 10% (21/205) adverse mutations ( SF3B1/SRSF2/U2AF1/TP53 ). At median 8.4 years, 163 (27%) deaths, 71 (12%) fibrotic, and 20 (3%) leukemic transformations were recorded. Multivariable analysis resulted in HR (95% CI) of 16.5 (9.9–27.4) for age > 70 years, 3.7 (2.3–6.0) for age 50–70 years, 2.4 (1.7–3.3) for ANC ≥8 × 10 9 /L, and 1.9 (1.4–2.6) for ALC <1.7 × 10 9 /L. The corresponding HR‐based scores were 4, 2, 1, and 1, resulting in an new 4‐tiered AgeAncAlc (AAA; triple A) risk model: high (5–6 points; median survival 8 years; HR 30.1, 95% CI 17.6–54), intermediate‐2 (4 points; median 13.5 years; HR 12.7, 95% CI 7.1–23.0), intermediate‐1 (2–3 points; median 20.7 years; HR 3.8, 95% CI 2.3–6.4) and low (0–1 points; median 47 years). The AAA model (Akaike Information Criterion [AIC] 621) performed better than IPSET (AIC 647) and was subsequently validated by an external University of Florence ET cohort ( N = 485). None of the AAA variables predicted LFS while ALC <1.7 × 10 9 /L was associated with inferior MFFS ( p = .01). Adverse mutations ( p < .01) and karyotype ( p < .01) displayed additional prognostic value without disqualifying the prognostic integrity of the AAA model. This study proposes a simple and globally applicable survival model for ET, which can be used as a platform for further molecular refinement. This study also suggests a potential role for immune‐related biomarkers, as a prognostic tool in myeloproliferative neoplasms.

Abstract The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

AbstractThe recent association of cerebral venous thrombosis (CVT) with COVID‐19 vaccinations prompted the current retrospective review of 74 cases of CVT (median age = 44 years, range 15–85; 61% females) associated with myeloproliferative neoplasms (MPNs), seen at the Mayo Clinic, Catholic University of Rome, and University of Florence, between 1991 and 2021. Disease‐specific frequencies were 1.3% (39/2893), 1.2% (21/1811) and 0.2% (3/1888) for essential thrombocythemia, polycythemia vera and primary myelofibrosis, respectively. Cerebral venous thrombosis occurred either prior to (n = 20, 27%), at (n = 32, 44%) or after (n = 22) MPN diagnosis. A total of 72% of patients presented with headaches. Transverse (51%), sagittal (43%) and sigmoid sinuses (35%) were involved with central nervous system hemorrhage noted in 10 (14%) patients. In all, 91% of tested patients harbored JAK2V617F. An underlying thrombophilic condition was identified in 19 (31%) cases and history of thrombosis in 10 (14%). Treatment for CVT included systemic anticoagulation alone (n = 27) or in conjunction with aspirin (n = 24), cytoreductive therapy (n = 14), or both (n = 9). At a median follow‐up of 5.1 years (range 0.1–28.6), recurrent CVT was documented in three (4%) patients while recurrent arterial and venous thromboses and major hemorrhage were recorded in 11%, 9% and 14%, respectively. Follow‐up neurological assessment revealed headaches (n = 9), vision loss (n = 1) and cognitive impairment (n = 1). The current study lends clarity to MPN‐associated CVT and highlights its close association with JAK2V617F, younger age and female gender. Clinical features that distinguish COVID vaccine‐related CVT from MPN‐associated CVT include, in the latter, lower likelihood of concurrent venous thromboses and intracerebral hemorrhage; as a result, MPN‐associated CVT was not fatal.

Abstract The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis‐free survival (MFS) in WHO‐defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy ( n = 718); Mayo Clinic, USA ( n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy ( n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3–4.9), male sex (2.1, 1.2–3.9), palpable splenomegaly (2.1, 1.2–3.9), CALR 1/1‐like or MPL mutation (3.4, 1.9–6.1) and JAK2 V617F variant allele frequency > 35% (4.2, 1.6–10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: “high molecular risk” category included patients with JAK2 V617F VAF >35%, CALR type 1/1‐like or MPL mutations; all other driver mutation profiles were assigned to “low molecular risk” category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years ( p < 0.001; HR 6.1; 95% CI 3.2–11.7); Mayo Cohort, 16% vs. 7% at 10 years and 44% vs. 25% at 20 years ( p < 0.001; HR 2.5; 95% CI 1.6–4.1); and Rome cohort 7.8% vs. 4.6% at 10 years and 31.2% vs. 7.1% at 20 years ( p = 0.007, HR 2.7; 95% CI 1.3–5.8). The present study provides practically useful risk signals for fibrotic transformation in ET and facilitates identification of patients who require close monitoring and appropriate counseling.

Abstract Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)–defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis–derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.