Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome.

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.

Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia.

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.

Peripheral blasts are associated with responses to ruxolitinib and outcomes in patients with chronic-phase myelofibrosis.

BACKGROUND: 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. METHODS: In 794 chronic-phase MF patients treated with RUX, we evaluated the impact of baseline percentage of PB on response (spleen and symptoms responses) and outcome (RUX discontinuation-free, leukemia-free, and overall survival). Three subgroups were compared: PB-0 (no PB, 61.3%), PB-4 (PB 1%-4%, 33.5%), and PB-9 (PB 5%-9%, 5.2%). RESULTS: At 3 and 6 months, spleen responses were less frequently achieved by PB-4 (P = .001) and PB-9 (P = .004) compared to PB-0 patients. RUX discontinuation-free, leukemia-free, and overall survival were also worse for PB-4 and PB-9 patients (P = .001, P = .002, and P < .001, respectively). CONCLUSIONS: Personalized approaches beyond RUX monotherapy may be useful in PB-4 and particularly in PB-9 patients.

Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX-IOL study.

Deferasirox (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.

Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives.

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.

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome.

BACKGROUND: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P = .004). CONCLUSIONS: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.

Second primary malignancy in myelofibrosis patients treated with ruxolitinib.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 109 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 109 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

Impact of comorbidities and body mass index on the outcome of polycythemia vera patients.

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.

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis.

BACKGROUND: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. METHODS: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. RESULTS: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2-risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 ×109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. CONCLUSIONS: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.

Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real-world data.

The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P < .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count <150 × 109 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High-risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1-0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow-up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib-treated patients and is associated with DIPSS and MYSEC-PM risk in PMF and SMF, respectively.

Disease-Specific Derangement of Circulating Endocannabinoids and N-Acylethanolamines in Myeloproliferative Neoplasms.

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.

Understanding how older age drives decision-making and outcome in Immune Thrombocytopenia. A single centre study on 465 adult patients.

We analysed the impact of older age on the management of immune thrombocytopenia (ITP) in 465 adult patients diagnosed between 1995 and 2017 and followed at our institution for a minimum of 12 months. Over a follow-up of 4248 patient-years, front-line corticosteroids therapy was required in 334 patients (71·8%), mainly (85·3%) within 1 year from diagnosis. Need for first-, second- and third-line therapy was comparable in younger and older (age ≥65 years, n = 154) patients. Older patients presented more frequently with severe haemorrhages, started therapy with a higher platelet count and received lower dose front-line corticosteroids; thereafter, they were preferentially treated with mild immunosuppressive therapies/thrombopoietin-receptor agonists. Conversely, younger patients were more frequently treated with rituximab and splenectomy, achieving higher rates of complete responses. Incidence rates of ≥grade 2 complications were: 2·87 (haemorrhages), 1·55 (infections) and 0·66 (thromboses) per 100 patient-years. Older age (P = 0·01) and active haemorrhages at diagnosis (P = 0·01) significantly predicted grade ≥2 haemorrhages during follow-up. Older age (P = 0·01), male gender (P = 0·01), and thrombopoietin receptor agonist use (P = 0·02) were significantly associated with a higher probability of thrombosis over time. Older age is a significant driver of diagnostic/therapeutic strategy in ITP resulting in different responses and complications rates.

Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib.

The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early-PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia-free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.

Impact of comorbidities and body mass index in patients with myelofibrosis treated with ruxolitinib.

Comorbidities defined by the Charlson comorbidity index (CCI) and body mass index (BMI) are significantly associated with outcome in patients who receive continuous treatment with tyrosine kinase inhibitors. We evaluated the impact of CCI and BMI on responses, drug-related toxicities, and outcome in a cohort of 402 patients with myelofibrosis (MF) treated with ruxolitinib in 23 European Hematology Centers. Comorbidities were evaluable in all 402 patients. A higher (≥ 3) CCI did not correlate with a lower spleen reduction at any time (p = 0.68) or symptoms' response (p = 0.11), but influenced the onset of anemia during the first 3 months of treatment and later (p = 0.02 and p = 0.03, respectively) in patients without anemia baseline. BMI was evaluable in 380 patients and did not correlate with differences in spleen and symptoms response (p = 0.57 and p = 0.49, respectively). A higher CCI and a lower BMI correlated also with a reduced overall survival (p < 0.001 and p = 0.02, respectively). The achievement of a spleen response at 6 months could counterbalance the negative impact of comorbidities, while patients who were underweight when starting ruxolitinib and did not achieve a spleen response at 6 months were projected to the worse outcome. In MF patients treated with ruxolitinib, BMI and comorbidities did not influence the achievement of spleen/symptom responses, but they contributed to the early identification of patients who deserve a strict monitoring during treatment.

Ruxolitinib in elderly patients with myelofibrosis: impact of age and genotype. A multicentre study on 291 elderly patients.

Ruxolitinib is a JAK1/2 inhibitor that may control myelofibrosis (MF)-related splenomegaly and symptoms and can be prescribed regardless of age. While aging is known to correlate with worse prognosis, no specific analysis is available to confirm that ruxolitinib is suitable for use in older populations. A clinical database was created in 23 European Haematology Centres and retrospective data on 291 MF patients treated with ruxolitinib when aged ≥65 years were analysed in order to assess the impact of age and molecular genotype on responses, toxicities and survival. Additional mutations were evaluated by a next generation sequencing (NGS) approach in 69 patients with available peripheral blood samples at the start of ruxolitinib treatment. Compared to older (age 65-74 years) patients, elderly (≥75 years) showed comparable responses to ruxolitinib, but higher rates of drug-induced anaemia and thrombocytopenia and worse survival. Nonetheless, the ruxolitinib discontinuation rate was comparable in the two age groups. Number and types of molecular abnormalities were comparable across age groups. However, the presence of high molecular risk (HMR) mutations significantly affected survival, counterbalancing the effect of aging. Indeed, elderly patients with <2 HMR mutated genes had a comparable survival to older patients with ≥2 HMR mutations. Given that responses were not influenced by age, older age per se should not be a limitation for ruxolitinib administration. NGS analysis of HMR mutations also confirmed a strong predictive value in elderly patients.

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.

Epidemiological trends of pediatric IBD in Italy: A 10-year analysis of the Italian society of pediatric gastroenterology, hepatology and nutrition registry.

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 /105 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.

The diagnostic role of Next Generation Sequencing in uncovering isolated splenomegaly: A case report.

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.