Spleen and Liver Fibrosis Is Associated to Treatment Response and Prognosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Introduction: Spleen and liver stiffness, investigated by transient elastography (TE), have been associated with marrow fibrosis in patients (pts) with Ph-negative myeloproliferative neoplasms (MPNs) (Iurlo et al, Br J Haematol. 2015; Webb et al, Ultrasound Q. 2015). Morover, spleen stiffness was found to be greater in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET) (Benedetti et al, J Clin Med. 2020). Tissue stiffness can be assessed by ultrasound shear wave elastography (SWE), the two most common techniques being point SWE (pSWE) and bidimensional SWE (2D.SWE). Aims: The aims of this study are: 1) to identify TE differences between MPN pts and healthy volunteers (HV); 2) to evaluate specific TE features in pts with MF, PV and ET; 3) to assess whether spleen/liver stiffness may identify clinical-laboratory features associated with prognosis in MPNs Methods: In this monocentric study, MPN pts and HV received elastometric evaluation of spleen and liver stiffness by pSWE and 2D.SWE with an Esaote MyLab™9 ultrasound system. Spleen area, portal (PVD) and splenic vein diameter (SVD) were measured. Results: A total of 220 pts were included in this study: 142 (64.5%) MPN and 78 (35.5%) HV. MPN pts were affected by MF (63, 44.4%: 39 primary MF), PV (33, 23.2%) or ET (46, 32.4%). Compared to HV, MPN pts had greater median spleen maximal cross sectional area (79 vs 38 cm2, p<0.001), greater spleen stiffness (pSWE 31.3 vs 23.7 kPa, p<0.001; 2D.SWE 25.2 vs 18.7 kPa, p<0.001), and greater liver stiffness (pSWE 6.0 vs 4.9 kPa, p<0.001; 2D.SWE 5.4 vs 4.7 kPa, p<0.001). Additionally, PVD and SVD were significantly larger in MPNs than in HV (PVD 10.9 vs 9.2 mm, p<0.001; SVD 8 vs 6.3 mm, p<0.001). Comparing each MPN to HV, only MF retained all the significant differences; conversely, liver stiffness and PVD were comparable between ET/PV and HV. Clinical and laboratory features of MPN pts are shown in Tab 1. Compared to PV and ET pts, MF pts had higher spleen (p<0.001) and liver stiffness (p<0.001), larger PVD (p<0.001) and SVD (p<0.001). Conversely, ET and PV displayed comparable TE values. Notably, higher median spleen area (p<0.001), larger SVD (p=0.03) and PVD (p=0.02), higher liver (pSWE/2D.SWE, p<0.001/p=0.002) and spleen stiffness (pSWE/2D.SWE, p=0.01/p=0.001) were associated with increased marrow fibrosis grade. Grade 0-1 marrow fibrosis was present in 15 MF, 17 PV and 34 ET pts. Considering only these 66 MPN pts, spleen (40.8 vs 31.3/25.6 in PV/ET, p=0.006) and liver (6.5 vs 5.6/4.7 in PV/ET, p=0.01) stiffness was significantly higher in MF pts. Notably, increased spleen fibrosis was significantly associated with thrombotic history (32.2 vs 24.3 kPa in pts without previous thrombosis, p=0.02). Also, MPN pts with splanchnic vein thrombosis had higher spleen (pSWE: p<0.001; 2D.SWE: p<0.001) and liver stiffness (pSWE: p <0.001), and increased PVD (p=0.02) and spleen area (p=0003). In MF pts, TE data did not correlate with DIPSS risk category. However, a higher spleen stiffness (pSWE/2D.SWE, p=0.09/ p=0.03), liver stiffness (pSWE/2D.SWE, p=0.001/p=0.01), PVD (p=0.002), and SVD (p=0.01) were associated with larger spleen length by palpation. Also, a reduced SVD was associated with the presence of ≥1 high molecular risk mutation (HMR) (p=0.04). As expected, MF pts treated with JAK-inhibitors showed larger spleen area (143.8 vs 83.7 cm 2, p=0.01) and higher spleen stiffness (34.3 vs 24 kPa, p=0.01) compared to pts under cytoreductive therapy. However, pts in spleen response at the time of TE had lower median SVD/PVD (p=0.05/p=0.07) and reduced spleen stiffness (sSWE/2D.SWE: 31.5/25.9 vs 39.0/32.8 in non-responders, p=0.01/p=0.04) In ET/PV, TE data were comparable in pts with/without a complete hematological response. However, IFN was associated with enlarged spleen area and stiffness compared to cytoreduction. Conclusions: TE evaluation effectively distinguishes MF pts from HV and ET/PV, while ET/PV show relevant similarities to each other and to HV. TE data were significantly associated with prognostically relevant features including marrow fibrosis and history of thrombosis in all MPNs, and presence of large splenomegaly and HMR in MF. Finally, TE data were significantly associated with spleen response in MF. Overall, spleen/liver stiffness may help in correct MPN diagnosis, and may provide clinical guidance, being associated with known prognostic factors and treatment outcome. Figure 1 Figure 1. Disclosures Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau. Piscaglia: ESAOTE: Research Funding. Palandri: CTI: Consultancy; AOP: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees.

Stiffer Spleen Predicts Higher Bone Marrow Fibrosis and Higher JAK2 Allele Burden in Patients With Myeloproliferative Neoplasms

A total of 63 myeloproliferative neoplasms [MPN; 9 polycythemia vera (PV), 32 essential thrombocythemia (ET), and 22 myelofibrosis (MF)] underwent spleen stiffness (SS) measurement by vibration-controlled transient elastography equipped with a novel spleen-dedicated module. Higher SS values significantly correlated with grade 2-3 bone marrow (BM) fibrosis (p=0.035), with hemoglobin level <10 g/dl (p=0.014) and with white blood cells ≥10,000/μl (p=0.008). Median SS was significantly higher in MF patients compared to ET and PV (p=0.015). SS also correlated with higher JAK2 variant allele frequency (p=0.02). This study identifies SS as a potential noninvasive tool that reflects BM fibrosis and the mutational burden in MPN.

Comparsion of Liver and Spleen Elastometry Features

The review presents data on the comparison of the features of liver and spleen stiffness measurements and those on the impact of various conditions on the measurement results (the type of a sensor used, food intake, number of measurements, patient position, breathing phase, etc.). Literature has been sought in the PubMed and eLibrary databases. In particular, the liver and spleen stiffness values vary differently at the height of inspiration and expiration. This is due to organ engorgement with a change in intrathoracic and intraabdominal pressures, as well as to a reduction in splenic arterial flow during exhalation. The review gives published data on liver and spleen stiffness values in healthy volunteers. The spleen is a stiffer organ than the liver. The different liver and spleen stiffness is explained by the features of blood supply (the spleen receives the most blood supply from the intensive-flow artery; the liver does from the portal vein). The reasons for increasing the stiffness of these organs in both health and disease are described. Estimation of liver stiffness can be used to diagnose cirrhosis and portal hypertension. That of spleen stiffness can help in the diagnosis of portal hypertension and in the indirect diagnosis of the presence of esophageal varices and the nature of a splenic lesion.

Acoustic radiation force impulse imaging: normal values of spleen stiffness in healthy children

Background Acoustic radiation force impulse (ARFI) imaging is a noninvasive ultrasound elastography technique for evaluating tissue stiffness. The association of liver and spleen stiffness provides additional information in the assessment of portal hypertension. The technique and normal values of spleen stiffness by point shear wave elastography (p-SWE) in pediatrics have not been well documented. Objective Our aim is to describe the feasibility and normal ARFI elastography values in the spleen for healthy children and to compare measurements in two different probe positions (the axial and sagittal planes). Materials and methods Spleen p-SWE using ARFI values were measured with a 6C1 probe in 102 healthy children (age range: 8 weeks to 17 years) divided into four age groups. An average of nine (standard deviation: two) spleen stiffness measurements were taken during free breathing in each plane (axial and sagittal). The impact of age and measurement plane in the spleen was analyzed using multivariate models. Results There was no significant difference in spleen stiffness values taken at different ages, with an average of the medians of 2.43±0.31 m/s. There was no significant difference based on probe orientation: sagittal plane (median: 2.46±0.29 m/s) and axial plane (median: 2.43±0.32 m/s) with Student’s t-test P=0.18. The mean depth of measurement varied between 2.3 cm and 3.7 cm, according to age. Conclusion Normal spleen stiffness values using ARFI imaging in children do not vary with age and correspond to a median of 2.43 m/s. No significant difference was found when using different probe positions.

Assessing Baveno VI Criteria Using Liver Stiffness Measured with a 2D-Shear Wave Elastography Technique

The present study evaluates the performance of Baveno VI criteria, using liver stiffness (LS) assessed with a 2D-SWE elastography technique, for predicting high-risk varices (HRV) in patients with compensated advanced chronic liver disease (cACLD). A secondary aim was to determine whether the use of spleen stiffness measurements (SSMs), as additional criteria, increases the performance of the 2D-SWE Baveno VI criteria. Data were collected from 208 subjects with cACLD, who underwent abdominal ultrasound, liver and spleen stiffness measurements, and upper digestive endoscopy. HRV were defined as grade 1 esophageal varices (EV) with red wale marks, grade 2/3 EV, and gastric varices. A total of 35.6% (74/208) of the included subjects had HRV. The optimal LS cut-off value for predicting HRV was 12 kPa (AUROC-0.80). Using both LS cut-off value < 12 kPa and a platelet cut-off value > 150 × 109 cells/L as criteria to exclude HRV, 52/208 (25%) subjects were selected, 88.5% (46/52) were without EV, 9.6% (5/52) had grade 1 EV, and 1.9% (1/52) had HRV. Thus 98% of the subjects were correctly classified as having or not having HRV and 25% of the surveillance endoscopies could have been avoided. Using SS < 13.2 kPa and a platelet cut-off value > 150 × 109 cells/L as additional criteria for the patients that were outside the initial ones, 32.7% of the surveillance endoscopies could have been avoided.