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.

BACKGROUND:Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype. AIMS AND METHODS:Prognostic correlates of cytopenic phenotype were explored in 886 ruxolitinib-treated patients with primary/secondary MF (PMF/SMF) included in the RUX-MF retrospective study. Cytopenia was defined as: leukocyte count <4 × 109 /L and/or hemoglobin <11/<10 g/dL (males/females) and/or platelets <100 × 109 /L. RESULTS:Overall, 407 (45.9%) patients had a cytopenic MF, including 249 (52.4%) with PMF. In multivariable analysis, high molecular risk mutations (p = .04), intermediate 2/high Dynamic International Prognostic Score System (p < .001) and intermediate 2/high Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (p < .001) remained associated with cytopenic MF in the overall cohort, PMF, and SMF, respectively. Patients with cytopenia received lower average ruxolitinib at the starting (25.2 mg/day vs. 30.2 mg/day, p < .001) and overall doses (23.6 mg/day vs. 26.8 mg/day, p < .001) and achieved lower rates of spleen (26.5% vs. 34.1%, p = .04) and symptom (59.8% vs. 68.8%, p = .008) responses at 6 months compared with patients with the proliferative phenotype. Patients with cytopenia also had higher rates of thrombocytopenia at 3 months (31.1% vs. 18.8%, p < .001) but lower rates of anemia (65.6% vs. 57.7%, p = .02 at 3 months and 56.6% vs. 23.9% at 6 months, p < .001). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in patients with cytopenia and the proliferative phenotype (p < .001), whereas cumulative incidence of leukemic transformation was similar (p = .06). In Cox regression analysis adjusted for Dynamic International Prognostic Score System score, survival was significantly shorter in patients with cytopenia (p < .001). CONCLUSIONS:Cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and worse outcome. These patients should be considered for alternative therapeutic strategies.

The presence of peripheral blasts (PB) is a negative prognostic factor in patients with primary and secondary myelofibrosis (MF) and PB ≥4% was associated with a particularly unfavorable prognosis. Ruxolitinib (RUX) is the JAK1/2 inhibitor most used for treatment of MF‐related splenomegaly and symptoms. Its role has not been assessed in correlation with PB.

SummaryDeferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The ‘RUX‐IOL’ study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX–DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1–71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX‐ or DFX‐related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion‐independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX–DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician's expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP.

Introduction: The present study aimed at evaluating Italian epidemiological trends of pediatric inflammatory bowel diseases (IBD) over the period 2009-2018.Materials and methods: Data from 1969 patients enrolled in the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition Registry, by 49 pediatric IBD centers throughout the country, were analyzed, comparing three different time intervals (2009-2012, 2013-2015, 2016-2018).Results: The number of new IBD diagnoses ranged from 175 to 219 per year, evenly distributed over the examined period of time. From 2009 to 2018, the minimal incidence ranged from 1.59 to 2.04 /10 5 inhabitants aged < 18 years, with an overall slight predominance of ulcerative colitis (UC) over Crohn's disease (CD) (ratio: 1.1). Mean diagnostic delay was 6.8 months for CD and 4.1 months for UC, with a significant reduction for CD when comparing the three-time intervals ( p = 0.008). The most frequent disease locations according to the Paris classification were ileocolonic for CD (41.3%) and pancolitis for UC (54.6%).Conclusions: The minimal incidence rate in Italy seems to have stabilized over the last two decades, even if it has increased when compared to previous reports. UC is still slightly more prevalent than CD in our country. Diagnostic delay significantly decreased for CD, reflecting an improved diagnostic capacity. (c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

New diagnoses and relapses of primary immune thrombocytopenia (ITP) have been reported following SARS-CoV-2 infection and vaccination. In a large monocenter cohort, we assessed: 1) incidence, risk factors and outcome of newly diagnosed ITP and ITP relapses after SARS-CoV-2 infection/vaccination; 2) incidence and risk factors for SARS-CoV-2 infection in the ITP cohort. After IRB approval, 1142 ITP patients (pts) followed at our Hematology Center from 1982 to Feb 2022 were registered in an electronic database. Between Feb 2020 (pandemic start) and Feb 2022, 60 pts were newly diagnosed with ITP. Among the 1082 pts with ITP diagnosis prior to Feb 2020, 297 (27.4%) were deceased before the pandemic start and 403 (37.2%) were untraceable. Taken together, 442 ITP (60 newly and 382 previously diagnosed) pts were included in this study. Information on SARS-CoV-2 infection/vaccination, platelet (PLT) count, and ITP therapy, was collected via phone call/e-mail or during routine medical visits. Laboratory data were verified through health electronic records. Risk factors for ITP relapse included sex, age, vaccine type, previous splenectomy, comorbidities (CCI), active disease (ongoing ITP therapy and/or PLT <100 x109/L), other immune diseases and ITP relapse to previous vaccine doses. Newly diagnosed ITP was considered infection-related (inf-ITP) or vaccine-related (vax-ITP) if the onset occurred <30 days from infection or vaccination, respectively. ITP relapse (rel-ITP) was defined as a drop in PLT count (<30 days from vaccination/infection) that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count <30 x109/L with ≥20% decrease from baseline. Eighteen (30%) out of 60 newly diagnosed pts had SARS-CoV-2-related ITP. Inf-ITP was diagnosed in 5 pts (8.3%). Compared to the 55 pts whose ITP was not related to Sars-CoV-2 infection, Inf-ITP pts were younger (median, 41.9 vs 70.2 yrs, p=0.02). ITP outcome was comparable in inf-ITP and other newly diagnosed pts, in terms of response to fist-line steroids (p=0.09), no. of therapeutic lines (p=0.9), and no. of pts still on therapy (p=0.9) at 6 months from diagnosis. Vax-ITP was diagnosed in 13 (21.7%) pts after the first (no.4, 30.8%), second (no.4, 30.8%) or third vaccine dose (no.5, 38.4%). Vaccines were: Comirnaty (53.8%), Vaxzervria (23.1%) or Spikevax (23.1%). Compared to the 47 pts whose ITP was not related to Sars-CoV-2 vaccine, Vax-ITP pts were older (median, 74 vs 55 yrs, p=0.04). ITP treatment duration was longer in Vax-ITP pts (median, 150 days vs 54 days in no Vax-ITP pts, p=0.04); 53.8% of vax-ITP pts were still on therapy 6 months after diagnosis (vs 23.4%, p=0.03). Between Feb 2020 and Feb 2022, 69/382 (18.1%) had a relapse of ITP. In 36/69 pts (52.2%), relapse was related to SARS-CoV-2 infection (1 case) or vaccination (35 cases out of 360 pts who received ≥1 vaccine dose, 9.7%). Ten pts experienced multiple relapses (46 total cases). Post-vaccine relapse occurred in 3.3%, 4.7%, and 5.4% of these 35 pts after the 1st, 2nd, and booster dose, respectively (p=0.65). In multivariate analysis (MVA), active disease at the time of the 1st and the 2nd vaccine dose was associated with Rel-ITP (Odds ratio, OR 10.81, p=0.002; OR 6.88, p=0.001, respectively). After booster, active disease (OR 9.90, p<0.001) and previous Rel-ITP (OR 5.33, p=0.007) was associated with relapse (Fig.1). No major bleeding occurred in newly diagnosed and relapsed pts. Overall, 89/442 (20.1%) ITP pts had a SARS-CoV-2 infection (g≥3 in 10.1%). In MVA with death as competing risk, ≥2 vaccine doses (SHR 0.18; p<0.001) was associated with a lower risk of SARS-CoV-2 infection. SARS-CoV-2 is a risk factor for ITP onset, with 30% of new diagnoses being related to infection/vaccination. In older pts, the risk of vax-ITP is higher, and ITP requires more prolonged therapy, suggesting closer hematological monitoring. Also, >50% of total ITP relapses were related to SARS-CoV-2, mainly occurring after vaccination and regardless of vaccine dose. Thus, strict hematological monitoring may be recommended after all doses. In pts with active disease at vaccination and/or previous ITP relapse after vaccine, the completion of the vaccine program and subsequent laboratory follow-up should be personalized. Notably, vaccination confirmed to be the most protective factor against SARS-CoV-2 infection also in ITP pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: Around 30% of Myelofibrosis (MF) either primary (PMF) or secondary to polycythemia vera/essential thrombocythemia (SMF) may present a myelodepletive phenotype (MyD) (ie, thrombocytopenia, leukopenia, anemia). Pts with MyD MF represent a challenging population, as prognosis is poorer compared to pts with myeloproliferative (MyP) MF and therapeutic options, including the JAK1/2 inhibitor ruxolitinib (RUX), are limited or must be given at reduced doses. Aims: In light of the upcoming new drugs that may be used in MyD MF, we explored prognostic correlates of MyD phenotype in RUX-treated MF pts. Methods: After IRB approval, the “RUX-MF” retrospective real-world study collected 801 chronic phase MF pts treated with RUX in 26 Hematology Centers. MyD was defined as: WBC <4×109/L and/or Hb <11/<10 g/dL (males/females) and/or PLT <100×109/L with no increase of other blood cells (WBC >15×109/L, Hb >16.5/>16 g/dL in males/females, Plt >450×109/L). 219 (27.3%) had a MyD MF, including 140 (17.5%) PMF and 79 (9.8%) SMF. Spleen and symptoms response (SR/SyR) were defined according to IWG-MRT criteria. NGS mutational analysis was available for 167 pts. Results: In multivariable analysis (MVA), PMF diagnosis (p=0.001) and unfavorable karyotype (p=0.01) confirmed their significant association with MyD. In PMF pts, MyD was due to leukopenia, anemia and thrombocytopenia in 7.1%, 52.2% and 9.3%, respectively; in SMF, corresponding figures were 5%, 51.9% and 11.4%. Two or more cytopenias were found in 31.4% and 31.7% of PMF and SMF patients, respectively. In MVA, lower peripheral blast count (p=0.03), higher TSS (p=0.04) and BM fibrosis grade ≥2 (p=0.03) confirmed their association with MyD in PMF pts. In univariate/MVA, MyD SMF patients were more likely to have higher peripheral blast count (p=0.003/p=0.04), a higher MYSEC-PM risk (p<0.001/p=0.001), and to be triple negative (p=0.005/0.03). RUX starting, median at 3 months, and median overall dose was more frequently ≤10 mg BID in MyD than in MyP pts (44.9% vs 67.5%, p<0.001; 39.5% vs 59.9%, p<0.001; 34.9% vs 57.3%, p<0.001, respectively). This was confirmed also in PMF and SMF separately. The rate of SR was comparable in MyD and MyP patients. However, SR at 3 and 6 months was lower in pts with PLT<100 x 109/l (p=0.02). In SMF, MyD pts had lower rates of SR (10.8% vs 28.0% at 3 mos, p=0.004; 20.0% vs 33.1% at 6 mos, p=0.05). SyR was significantly lower in MyD MF (51.9% vs 62.5% in MyP at 3 mos, p=0.01; 59.8% vs 71.0% at 6 mos, p=0.008). In particular, anemia and thrombocytopenia were significantly associated with lower SyR. After a median RUX exposure of 2.3 yrs (0.1-12.6), 364 (45.4%) pts stopped RUX, 110 (13.7%) had a blast phase and 366 (45.7%) died. After competing risk analysis, the cumulative incidence of RUX discontinuation was higher in MyD MF patients overall (p<0.001), only PMF (p=0.03) and only SMF (p<0.001) (Fig.1a). Incidence of RUX stop was significantly higher in MyD patients with ≥2 cytopenias (p=0.03). Leukemia-free survival was not influenced by MyD/MyP phenotype (Fig.1b). In Cox regression analysis adjusted for DIPSS score, OS was significantly shorter in MyD vs MyP MF (median, 4.5 vs 5.7 yrs; p=0.03) (Fig.1c). This was confirmed considering only SMF patients (p=0.02). Image:Summary/Conclusion: MyD phenotype is associated with baseline high-risk clinical and molecular features, with lower responses to RUX, particularly in case of low PLT count, and higher risk of drug discontinuation and death. Newer strategies are warranted in this setting.

Background: Ruxolitinib (RUX) use and discontinuation are risk factors for severe COVID-19 and death in MPN patients (pts). In pts on RUX therapy, predictors for COVID-19 disease and survival (OS) to COVID-19 are unknown. Aims: The aims of this study were to distinguish RUX-treated pts at higher risk of COVID-19 and to assess prognostic factors for OS. Methods: We performed a sub-analysis of the RUX-MF and the PV-ARC observational studies that include consecutive adult pts with myelofibrosis (MF) and polycythemia vera (PV), respectively. Overall, 815 MF and 172 PV pts treated with RUX outside clinical trials have been registered. At pandemic start, 494 pts (359 MF and 135 PV) on RUX were included in this analysis. Results: Among 66 (13.6%) pts (PV n=11, MF n=55) with COVID-19 from Feb 2020 to Jan 2022, 1 (1.5%), 14 (21.2%), 9 (13.6%), 17 (25.8%), 4 (6.1%) and 21 (31.8%) pts had an asymptomatic, mild, moderate, severe, critical, and fatal infection, respectively; 42 (63.7%) were hospitalized. Overall, 14, 38 and 14 infections were observed during the 1st (Feb-Jun 2020), 2nd (Jul 2020-Jun2021) and 3rd (Jul 2021-Jan 2022) wave of the pandemic, with an overall incidence rate of 10.2 per 100 pt-yrs. Incidence rates in the 3 waves were 8, 10.2 and 7 per 100 pt-yrs respectively. Hospitalized cases were significantly less frequent during the 3rd wave (35.7% vs 64.3%/73.7% in the 1st/2nd wave, p=0.04). Overall, 283/390 evaluable pts (72.6%) received ≥1 dose of Comirnaty vaccine (19/66 COVID-19 pts; 5, 7 and 7 pts had received 1, 2 or 3 vaccine doses, respectively). At COVID-19 diagnosis, RUX was reduced in 10 (15.1%) pts and discontinued in 9 (13.6%) pts, comparably in MF and PV. In the total cohort, COVID-19 infection was more frequent in pts with MF (15.3% vs. 8.2% PV pts, p=0.04), with ≥1 comorbidity (15% vs. 8.7%, p=0.04). Also, COVID-19 infections after vaccine availability were more frequent in unvaccinated pts (37.4 vs. 6.3%, p<0.001). COVID-19 requiring hospitalization was more frequently observed in pts ≥70 yrs (12.2% vs. 6.8% in pts <70 yrs, p=0.04), and without COVID-19 vaccine (32.4% vs. 2.9%, p<0.001). No additional predictors for COVID-19 were noted analyzing MF and PV separately. In COVID-19 pts, hospitalized cases had a significantly lower median platelet count (275 vs. 168 x109/L, p=0.02), were receiving lower RUX doses (33.3% <10 mg BID vs. 8.3%, p=0.02) and more frequently presented comorbidities (40.5% vs. 13.6%, p=0.03) compared to outpatients. MF vs. PV, median hemoglobin levels, age≥70 yrs and sex were not associated with hospitalization. MF pts who were not in spleen response at COVID-19 infection had higher risk of hospitalization (73% vs. 44.4% in responders, p=0.04). After multivariable Cox analysis including previous anti-SARS-Cov-2 vaccine, need for hospitalization, age≥70 and male sex, OS to COVID-19 was significantly improved in pts who had previously received anti-SARS-Cov-2 vaccine (HR=0.10, p=0.02) (Fig.1), in pts with COVID-19 not requiring hospitalization (HR=0.19, p=0.03) and in patients <70 yrs (HR=0.38, p=0.03). The COVID-19 wave did not impact OS (p=0.53). Image:Summary/Conclusion: Among RUX-treated pts, lower RUX doses, comorbidities and no spleen response are significant predictors of hospitalization. Vaccine was the most protective factor against COVID-19 disease, hospitalization, and mortality. RUX-treated pts, regardless of MPN type, should be sensitized to adherence to the vaccine program and prioritized for antiviral therapy in case of infection.

Introduction: The outcome of patients (pts) with myelofibrosis (MF) who discontinue ruxolitinib (RUX) is poor with scarce therapeutic possibilities (Palandri et al, 2020). However, some evidences suggest that pts may respond to a rechallenge of RUX after drug stop (Gerds et al, 2018). Aims: To investigate in a real-world context: 1) frequency and reasons for rechallenge; 2) therapeutic effects of rechallenge; 3) impact of rechallenge on overall survival (OS) Methods: After IRB approval, a clinical database was created in 20 European Hematology Centers including now retrospective data of 703 MF pts who started RUX from Jan 2011 to Nov 2019. Only chronic phase (CP) pts who stopped RUX for ≥14 days and survived ≥30 days after discontinuation were included. A specific survey collected clinical/laboratory data at RUX stop and at rechallenge, reasons for discontinuation and treatments before rechallenge. OS was estimated from the date of the first/only RUX discontinuation to last contact (log-rank test). Results: A total of 219 CP pts was evaluable for this study. In 60 (27.4%) pts, RUX was re-challenged for ≥14 days after the first discontinuation (RUX-again), while 159 (72.6%) pts discontinued RUX permanently (RUX-stop). The median time from RUX start to stop was of 16.5 and 12.3 mos for RUX-again and RUX-stop pts, respectively (p=0.41). At RUX start, characteristics of RUX-again were: median age 67y (24-88); males 61.7%; PMF 53.3%; median Hb 10.2 g/dl; median PLT/WBC: 249/12.6 x109/l; median RUX starting dose: 15mg BID. Baseline characteristics of RUX-again and RUX-stop pts were comparable. In the 60 RUX-again pts, reasons for discontinuation included loss of/inadequate response (18 pts, 30%) and toxicity (42 pts, 70%). Toxicity included G3-4 thrombocytopenia (38.1%), anemia (26.2%), infections (21.4%), other (14.3%). Conversely, RUX-stop pts discontinued RUX mainly due to loss of/inadequate response (75 pts, 47.2%), while intolerable toxicity occurred in 69 pts (43.4%) (p=0.004) and other causes in 9.4%. At first RUX discontinuation, 35.7% of RUX-again pts presented with large (>10 cm) splenomegaly; median Total Symptoms Score (TSS) was 10 (TSS>20 in 30.4% of pts). The median duration of temporary RUX discontinuation was 2 mos (range 0.5-71.1). During RUX stop, 65% of RUX-again pts did not receive any therapy, 15% received only palliation (steroids, hydroxyurea), while 11.7% switched to investigational agents, 3.3% underwent splenectomy and 5% allogeneic transplantation. Compared to disease status at first RUX stop, at RUX restart there was a significant increase of pts with large splenomegaly and high TSS, while the PLT count was higher and RUX dose significantly lower (Table 1). The median duration of RUX rechallenge was 7.5 mos (0.5-72.7). During the rechallenge, 44.6% and 48.3% pts improved spleen and symptoms, and there was a significant increase in pts with TSS reduction (p=0.01); 8 pts (13.3%) continued RUX with stable/worsening spleen size and improvement in TSS. Conversely, 26.8% and 20% of pts had increase in spleen size and in symptoms, respectively. While Hb levels remained stable, PLT count significantly decreased during rechallenge (p<0.001). At last contact, 51.7% of RUX-again pts had permanently discontinued RUX. The reasons for temporary discontinuation had no impact on the reduction of spleen/symptoms during rechallenge and on OS. However, comparing RUX-again and RUX-stop pts, RUX-again pts showed a better OS, with a median survival of 41.1 mos and 23.7, respectively in the 2 cohorts (Fig. 1). Conclusions: This real-world study highlights that RUX rechallenge is quite common in CP-MF pts, involving almost 30% of treated pts, particularly when the discontinuation is due to toxicity. The temporary discontinuation, while improving PLT count, generally caused a significant increase in disease burden. After rechallenge, almost 50% of pts achieved clinical responses regardless of reason of first discontinuation. This residual disease control activity, that correlated with improved OS, should be weighed up also given the new therapeutic possibilities available in these pts. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Incyte: Honoraria; Pfize: Honoraria; Novartis: Honoraria. Crugnola:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Heidel:CTI: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Pane:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Many diseases can induce splenomegaly, however, about 5% of splenomegalies are idiopathic. When there is no underlying treatable cause, and the splenomegaly significantly affects the quality of life, splenectomy is the best therapeutic choice. A 67-year-old woman had idiopathic and asymptomatic splenomegaly. The increase in splenomegaly resulted in hypersplenism with cytopenia and symptoms related to abdominal discomfort. The patient underwent splenectomy which led to clinical improvement. A histological examination showed the presence of hematopoietic tissue. Peripheral blood Next Generation Sequencing with the myeloid panel SOPHiA Genetics showed the following mutations: ASXL1, SRSF2, KRAS and TET2. Three out of these four mutations were also found in the splenic tissue. Next Generation Sequencing could be useful in the diagnosis of splenomegalies associated with myeloproliferative neoplasms otherwise defined as idiopathic, in order to address a therapeutic strategy.

Nerve growth factor (NGF), basic fibroblast growth factor (bFGF), dibutyryl cAMP and forskolin, known differentiating agents for pheochromocytoma PC12 cells, induced sustained activation of sphingosine kinase, the enzyme responsible for the formation of the sphingolipid second messenger, sphingosine-1-phosphate, which mediates the mitogenic effects of certain growth factors. In contrast, epidermal growth factor and insulin-like growth factor-1, which stimulate proliferation of PC12 cells, induced only small and transient increases in sphingosine kinase activity. Of the growth factors examined, NGF was the most potent activator of sphingosine kinase, inducing a 4-fold increase in Vmax. Sphingosine kinase activity induced by NGF, but not FGF, was blocked by the protein kinase inhibitor K252a when added simultaneously, with minimal effect when added after 60 min. Thus, activation of sphingosine kinase may have an important role in neural differentiation.

Abstract Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts. Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts. Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy. Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start. No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1). Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04). Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs. As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60). Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs. Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. Figure 1 Figure 1. Disclosures Latagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

In 816 patients with 2016 World Health Organization‐defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post‐PV myelofibrosis (PPV‐MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI < 25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 (p < 0.001), while overweight/obese patients were more frequently males (p < 0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p = 0.01) and hypertension (SHR: 1.77, p = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow‐up of 6.1 years, progression to PPV‐MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV‐MF (SHR: 0.38, CI95%: 0.15–0.94, p = 0.04) and better survival (hazard ratio [HR]: 0.42, CI95%: 0.18–0.97, p = 0.04). CCI ≥ 1 did not affect progression to PPV‐MF (p = 0.44) or survival (p = 0.71). The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted.

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered.