Epidemiology and disease characteristics of myelofibrosis: a comparative analysis between Italy and global perspectives.

Myelofibrosis (MF) is a clonal disorder of hematopoietic stem cells characterized by altered bone marrow function and fibrosis. The aim of this narrative review is to report on the most recent epidemiologic data and to discuss features of MF and current strategies for the management of this condition in clinical practice. MF features covered by our review will include: characteristics of patients with MF; myeloproliferative and myelodepletive phenotypes; MF-associated thrombosis and bleeding; risk of infections; prefibrotic and overt PMF; secondary MF. Finally, we will discuss a few aspects of MF management in clinical practice and suggest strategies for its optimization and standardization. The focus of our paper is on Italy, but relevant data from other countries will also be reviewed.

FRACTION: protocol of a phase II study of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment of the German MPN study group (GSG-MPN).

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

Evans syndrome: Disease awareness and clinical management in a nation-wide ITP-NET survey.

Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.

Liver and spleen shear-wave elastography in the diagnosis and severity staging of myeloproliferative diseases and myelofibrosis.

AIMS: Spleen and liver stiffness, investigated by VCTE (Vibration-Controlled Transient Elastography), have been associated with marrow fibrosis in patients with myeloproliferative neoplasms (MPNs). Tissue stiffness can be assessed by shear wave point (pSWE) and bidimensional elastography (2DSWE). Spleen stiffness (SS) values were higher in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET). We aimed to identify SWE differences between MPN patients and healthy volunteers; to evaluate specific SWE features in patients with MF, PV and ET; to establish a correlation with bone marrow fibrosis in patients with myeloproliferative disease. METHODS: Patients with myeloproliferative disease and healthy volunteers performed evaluation of spleen and liver stiffness (LS) by pSWE and 2DSWE. RESULTS: A total of 218 subjects were included: 143 with myeloproliferative disease (64 MF, 29.4%, 33 PV, 15.1% and 46 ET, 21.1%), and 75 (34.4%) healthy volunteers. Compared to volunteers, MF patients had greater spleen (pSWE 40.9 vs. 26.3 kPa, p < 0.001; 2DSWE 34.9 vs. 20.1 kPa, p < 0.001), and liver stiffness (pSWE 7.72 vs. 5.52 kPa, p < 0.001; 2DSWE 6.96 vs. 5.01 kPa, p < 0.001). In low (0-1) (n = 81, 60.4%) versus high-grade bone marrow fibrosis (2-3) (n = 42, 39.6%), is evident a higher median stiffness in patients with higher grades of fibrosis both for liver (pSWE 5.2 vs. 6.65 kPa; 2DSWE 5.1 vs. 6.05 kPa) and spleen (pSWE 27.2 vs. 37.9 kPa, 2DSWE 21.7 vs 30.75 kPa-p < 0.001 in both). CONCLUSION: SWE evaluation distinguishes MF patients from HV and ET/PV and may help in MPN diagnosis. LS and SS values are associated with bone marrow fibrosis grade.

Clinical outcomes of ruxolitinib treatment in 595 intermediate-1 risk patients with myelofibrosis: The RUX-MF Real-World Study.

BACKGROUND: Ruxolitinib (RUX) is a JAK1/2 inhibitor approved for the therapy of myelofibrosis (MF) based on clinical trials including only intermediate2-high risk (INT2/HIGH) patients. However, RUX is commonly used in intermediate-1 (INT1) patients, with scarce information on responses and outcome. METHODS: The authors investigated the benefit of RUX in 1055 MF patients, included in the "RUX-MF" retrospective study. RESULTS: At baseline (BL), 595 (56.2%) patients were at INT1-risk according to DIPSS (PMF) or MYSEC-PM (SMF). The spleen was palpable at <5 cm, between 5 and 10 cm, and >10 cm below costal margin in 5.9%, 47.4%, and 39.7% of patients, respectively; 300 (54.1%) were highly symptomatic (total symptom score ≥20). High-molecular-risk (HMR) mutations (IDH1/2, ASXL-1, SRSF2, EZH2, U2AF1Q157) were detected in 77/167 patients. A total of 101 (19.2%) patients had ≥1 cytopenia (Hb < 10 g/dL: n.36; PLT <100 x 109/L: n = 43; white blood cells <4 x 109/L: n = 40). After 6 months on RUX, IWG-MRT-defined spleen and symptoms response rates were 26.8% and 67.9%, respectively. In univariate analysis, predictors of SR at 6 months were no HMR mutations odds ratio [OR], 2.0, p = .05], no cytopenia (OR, 2.10; p = .01), and blasts <1% (OR, 1.91; p = .01). In multivariate analysis, absence of HMR maintained a significant association (OR, 2.1 [1.12-3.76]; p = .01). CONCLUSIONS: In INT1 patients, responses were more frequent and durable, whereas toxicity rates were lower compared to INT2/high-risk patients. Presence of HMR mutations, cytopenia, and peripheral blasts identified less-responsive INT1 patients, who may benefit for alternative therapeutic strategies.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.

Real-life use of ropeg-interferon α2b in polycythemia vera: patient selection and clinical outcomes.

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.

ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Investigation of Serum Albumin as a Dynamic Treatment-Specific Surrogate for Outcomes in Patients With Myelofibrosis Treated With Ruxolitinib.

PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.

Prednisone vs high-dose dexamethasone in newly diagnosed adult primary immune thrombocytopenia: a randomized trial.

ABSTRACT: A debate exists regarding which type of corticosteroids (standard-dose prednisone [PDN] or high-dose dexamethasone [HD-DXM]) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged ≥18 but ≤80 years, platelet count of ≤20 or >20 but <50 × 109/L, and bleeding score of ≥8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410.

Ropeginterferon phase 2 randomized study in low-risk polycythemia vera: 5-year drug survival and efficacy outcomes.

In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.

Incidence of blast phase in myelofibrosis patients according to anemia severity at ruxolitinib start and during therapy.

BACKGROUND: Anemia is frequently present in patients with myelofibrosis (MF), and it may be exacerbated by treatment with the JAK2-inhibitor ruxolitinib (RUX). Recently, a relevant blast phase (BP) incidence has been reported in anemic MF patients unexposed to RUX. METHODS: The authors investigated the incidence of BP in 886 RUX-treated MF patients, included in the "RUX-MF" retrospective study. RESULTS: The BP incidence rate ratio (IRR) was 3.74 per 100 patient-years (3.74 %p-y). At therapy start, Common Terminology Criteria for Adverse Events grade 3-4 anemia (hemoglobin [Hb] <8 g/dL) and severe sex/severity-adjusted anemia (Hb <8/<9 g/dL in women/men) were present in 22.5% and 25% patients, respectively. IRR of BP was 2.34 in patients with no baseline anemia and reached respectively 4.22, 4.89, and 4.93 %p-y in patients with grade 1, 2, and 3-4 anemia. Considering the sex/severity-adjusted Hb thresholds, IRR of BP was 2.85, 4.97, and 4.89 %p-y in patients with mild/no anemia, moderate, and severe anemia. Transfusion-dependent patients had the highest IRR (5.03 %p-y). Progression-free survival at 5 years was 70%, 52%, 43%, and 27% in patients with no, grade 1, 2, and 3-4 anemia, respectively (p < .001). At 6 months, 260 of 289 patients with no baseline anemia were receiving ruxolitinib, and 9.2% had developed a grade 3-4 anemia. By 6-month landmark analysis, BP-free survival was significantly worse in patients acquiring grade 3-4 anemia (69.3% vs. 88.1% at 5 years, p < .001). CONCLUSIONS: This study highlights that anemia correlates with an increased risk of evolution into BP, both when present at baseline and when acquired during RUX monotherapy. Innovative anemia therapies and disease-modifying agents are warranted in these patients.

A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis.

Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the "RUX-MF" retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients (p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 109/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0-1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Predictors of Response to Hydroxyurea and Switch to Ruxolitinib in HU-Resistant Polycythaemia VERA Patients: A Real-World PV-NET Study.

In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.

Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study.

Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0-1 were considered low-grade fibrosis (LGF) and grades 2-3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment.

Immune Thrombocytopenia Onset and Relapse During the COVID-19 Pandemic. A Monocenter Study.

Background And Objectives: Several infections and vaccinations can provoke immune thrombocytopenia (ITP) onset or relapse. Information on ITP epidemiology and management during the Covid-19 pandemic is scarce. In a large monocenter ITP cohort, we assessed the incidence and risk factors for: 1) ITP onset/relapse after Covid19 vaccination/infection; 2) Covid19 infection. Methods: Information on the date/type of anti-Covid-19 vaccine, platelet count before and within 30 days from the vaccine, and date/grade of Covid-19 was collected via phone call or during hematological visits. ITP relapse was defined as a drop in PLT count within 30 days from vaccination, compared to PLT count before vaccination that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count <30 ×109/L with ≥20% decrease from baseline. Results: Between February 2020 and January 2022, 60 new ITP diagnoses were observed (30% related to Covid-19 infection or vaccination). Younger and older ages were associated with a higher probability of ITP related to Covid19 infection (p=0.02) and vaccination (p=0.04), respectively. Compared to Covid-19-unrelated ITP, Infection- and vaccine-related ITP had lower response rates (p=0.03) and required more prolonged therapy (p=0.04), respectively. Among the 382 patients with known ITP at the pandemic start, 18.1% relapsed; relapse was attributed to Covid-19 infection/vaccine in 52.2%. The risk of relapse was higher in patients with active disease (p<0.001) and previous vaccine-related relapse (p=0.006). Overall, 18.3% of ITP patients acquired Covid19 (severe in 9.9%); risk was higher in unvaccinated patients (p<0.001). Conclusions: All ITP patients should receive ≥1 vaccine dose and laboratory follow-up after vaccination, with a case-by-case evaluation of completion of the vaccine program if vaccine-related ITP onset/relapse and with tempest initiation of antiviral therapy in unvaccinated patients.

Circulating extracellular particles from severe COVID-19 patients show altered profiling and innate lymphoid cell-modulating ability.

Introduction: Extracellular vesicles (EVs) and particles (EPs) represent reliable biomarkers for disease detection. Their role in the inflammatory microenvironment of severe COVID-19 patients is not well determined. Here, we characterized the immunophenotype, the lipidomic cargo and the functional activity of circulating EPs from severe COVID-19 patients (Co-19-EPs) and healthy controls (HC-EPs) correlating the data with the clinical parameters including the partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) and the sequential organ failure assessment (SOFA) score. Methods: Peripheral blood (PB) was collected from COVID-19 patients (n=10) and HC (n=10). EPs were purified from platelet-poor plasma by size exclusion chromatography (SEC) and ultrafiltration. Plasma cytokines and EPs were characterized by multiplex bead-based assay. Quantitative lipidomic profiling of EPs was performed by liquid chromatography/mass spectrometry combined with quadrupole time-of-flight (LC/MS Q-TOF). Innate lymphoid cells (ILC) were characterized by flow cytometry after co-cultures with HC-EPs or Co-19-EPs. Results: We observed that EPs from severe COVID-19 patients: 1) display an altered surface signature as assessed by multiplex protein analysis; 2) are characterized by distinct lipidomic profiling; 3) show correlations between lipidomic profiling and disease aggressiveness scores; 4) fail to dampen type 2 innate lymphoid cells (ILC2) cytokine secretion. As a consequence, ILC2 from severe COVID-19 patients show a more activated phenotype due to the presence of Co-19-EPs. Discussion: In summary, these data highlight that abnormal circulating EPs promote ILC2-driven inflammatory signals in severe COVID-19 patients and support further exploration to unravel the role of EPs (and EVs) in COVID-19 pathogenesis.