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Background The phase 3b, randomised, open-label RESPONSE-2 study in patients with inadequately controlled polycythaemia vera without splenomegaly showed superiority of the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib versus best available therapy for the primary endpoint of haematocrit control at week 28. Here, we present secondary endpoints of the RESPONSE-2 study after 5 years of follow-up. Methods RESPONSE-2 was an open-label, randomised, phase 3b study done at 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and Canada. Patients (aged >= 18 years) with polycythaemia vera without splenomegaly, who were intolerant of, or resistant to hydroxyurea, with an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) to receive ruxolitinib or best available therapy for up to 80 weeks. Patients received oral ruxolitinib at a starting dose of 10 mg twice a day or best available therapy. Patients assigned to best available therapy could cross over to ruxolitinib at week 28 if the primary endpoint was not met, or after week 28 and up to week 80 if best available therapy was ineffective or not tolerated. Patients receiving ruxolitinib at week 80, including crossover patients, could continue ruxolitinib treatment up to week 260. We assessed secondary endpoints at week 260, including durable haematocrit control, median duration of haematocrit control, median haematocrit level over time, number of phlebotomies, and overall survival. Analyses were based on the intention-to-treat principle This study is registered with ClinicalTrials.gov , NCT02038036 and was completed on April 7, 2020. Findings Patients were enrolled between March 25, 2014 and Feb 11, 2015. 149 patients were randomly assigned to ruxolitinib (n=74) or best available therapy (n=75). The median follow-up was 67 months (IQR 65-70). At randomisation, best available therapy regimens included hydroxyurea (n=38), interferon or pegylated interferon (n=9), pipobroman (n=5), lenalidomide (n=1), or no treatment (n=22). Between weeks 28 and 80, 58 (77%) of 75 patients in the best available therapy group crossed over to ruxolitinib; no patients continued best available therapy after week 80 per protocol. 97 patients received ruxolitinib until week 260, including 59 (80%) of 74 patients in the ruxolitinib group and 38 (66%) of 58 patients in the crossover groups. At week 260, 16 (22%; 95% CI 13-33) of 74 patients in the ruxolitinib group had achieved durable haematocrit control, with estimated median duration not reached (NR; 95% CI 144 to NR). Median duration of haematocrit control was not reported for patients in the best available therapy group due to the small number of responders by week 80. During the 5-year follow-up, median haematocrit level among patients in the ruxolitinib group remained below 45%. 60 phlebotomies were required among 74 patients in the ruxolitinib group in 260 weeks, and 106 phlebotomies among 75 patients in the best available therapy group in 80 weeks. 5-year overall survival was 96% (95% CI 87-99) in the ruxolitinib group and 91% (80-96) in the best available therapy group. The most common grade 3-4 adverse events (exposure-adjusted per 100 patient-years) in the ruxolitinib group (n=74) and best available therapy group (n=75) were hypertension (eight [2.4%] vs three [5.6%]), thrombocytopenia (one [0.3%] vs three [5.6%]), and thrornbocytosis (0 vs four [7.5%]). Exposure-adjusted rates of any-grade thromboembolic events were 1.5% per 100 person-years (five of 74 patients) in the ruxolitinib group and 3.7% per 100 person-years (two of 75 patients) in the best available therapy group. No treatment-related deaths occurred during the study. Interpretation 5-year results from the RESPONSE-2 study support the use of ruxolitinib as a second-line therapy of choice for patients with inadequately controlled polycythaemia vera without splenomegaly. Copyright (C) 2022 Elsevier Ltd. All rights reserved., Novartis, Novartis.

We investigated the neutrophil-to-lymphocyte ratio (NLR) as a predictor of thrombosis in polycythemia vera (PV). After a median follow-up of 2.51 years, of 1508 PV patients enrolled in the ECLAP study, 82 and 84 developed arterial and venous thrombosis, respectively. Absolute counts of total leukocytes, neutrophils, lymphocytes, platelets, and the NLR were tested by generalized additive models (GAM) to evaluate their trend in continuous scale of thrombotic risk. Only for venous thrombosis, we showed that baseline absolute neutrophil and lymphocyte counts were on average respectively higher (median: 6.8 × 109/L, p = 0.002) and lower (median: 1.4 × 109/L, p = 0.001), leading to increased NLR values (median: 5.1, p = 0.002). In multivariate analysis, the risk of venous thrombosis was independently associated with previous venous events (HR = 5.48, p ≤ 0.001) and NLR values ≥5 (HR = 2.13, p = 0.001). Moreover, the relative risk in both low- and high-standard risk groups was almost doubled in the presence of NLR ≥ 5. These findings were validated in two Italian independent external cohorts (Florence, n = 282 and Rome, n = 175) of contemporary PV patients. Our data support recent experimental work that venous thrombosis is controlled by innate immune cells and highlight that NLR is an inexpensive and easily accessible prognostic biomarker of venous thrombosis.

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity.

The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis-free survival (MFS) in WHO-defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3-4.9), male sex (2.1, 1.2-3.9), palpable splenomegaly (2.1, 1.2-3.9), CALR 1/1-like or MPL mutation (3.4, 1.9-6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6-10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: "high molecular risk" category included patients with JAK2V617F VAF >35%, CALR type 1/1-like or MPL mutations; all other driver mutation profiles were assigned to "low molecular risk" category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p

Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disorder characterized by the overproduction of red blood cells. It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second-line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management.To gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy, and vaccines.In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas.While helping to provide greater understanding of treatment patterns for patients with PV in Italy, our survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV.

Myeloproliferative disease Enfermedad mieloproliferativa Malaltia mieloproliferativa The study was supported by a research grant by the COVID “3 × 1 project”, BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe.

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase myeloproliferative neoplasm (MPN‐BP). Pre‐leukemic phenotype included essential thrombocythemia (ET)/post‐ET myelofibrosis (34%), polycythemia vera (PV)/post‐PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty‐nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre‐leukemic PV/post‐PV myelofibrosis phenotype (p

Calreticulin (CALR), an endoplasmic reticulum–associated chaperone, is frequently mutated in myeloproliferative neoplasms (MPNs). Mutated CALR promotes downstream JAK2/STAT5 signaling through interaction with, and activation of, the thrombopoietin receptor (MPL). Here, we provide evidence of a novel mechanism contributing to CALR-mutated MPNs, represented by abnormal activation of the interleukin 6 (IL-6)-signaling pathway. We found that UT7 and UT7/mpl cells, engineered by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) to express the CALR type 1–like (DEL) mutation, acquired cytokine independence and were primed to the megakaryocyte (Mk) lineage. Levels of IL-6 messenger RNA (mRNA), extracellular-released IL-6, membrane-associated glycoprotein 130 (gp130), and IL-6 receptor (IL-6R), phosphorylated JAK1 and STAT3 (p-JAK1 and p-STAT3), and IL-6 promoter region occupancy by STAT3 all resulted in increased CALR DEL cells in the absence of MPL stimulation. Wild-type, but not mutated, CALR physically interacted with gp130 and IL-6R, downregulating their expression on the cell membrane. Agents targeting gp130 (SC-144), IL-6R (tocilizumab [TCZ]), and cell-released IL-6 reduced proliferation of CALR DEL as well as CALR knockout cells, supporting a mutated CALR loss-of-function model. CD34+ cells from CALR-mutated patients showed increased levels of IL-6 mRNA and p-STAT3, and colony-forming unit–Mk growth was inhibited by either SC144 or TCZ, as well as an IL-6 antibody, supporting cell-autonomous activation of the IL-6 pathway. Targeting IL-6 signaling also reduced colony formation by CD34+ cells of JAK2V617F-mutated patients. The combination of TCZ and ruxolitinib was synergistic at very low nanomolar concentrations. Overall, our results suggest that target inhibition of IL-6 signaling may have therapeutic potential in CALR, and possibly JAK2V617F, mutated MPNs.

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p=0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.

Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2P95-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, including JAK2 or MPL with myelofibrosis (OR = 26.9); TET2 with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); and STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients with SRSF2-JAK2 co-mutation, JAK2 dominance was invariably associated with clinical feature of MPN, whereas SRSF2 mutation was dominant in MDS/MPN. Within patients with SRSF2-TET2 co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype-phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories.

Prognostic modeling in myelofibrosis (MF) has classically pursued the integration of informative clinical and hematological parameters to separate patients' categories with different outcomes. Modern stratification includes also genetic data from karyotype and mutations. However, some poorly standardized variables, as peripheral blood (PB) blast count by morphology, are still included. In this study, we used multiparameter flow cytometry (MFC) with the aim of improving performance of existing scores. We studied 363 MF patients with available MFC files for PB CD34+ cells count determination at diagnosis. We adapted Ogata score to MF context including 2 parameters: absolute CD34+ cells count (/μL) and granulocytes to lymphocytes SSC ratio. A score of 1 was attributed to above-threshold values of each parameter. Accordingly, patients were categorized as MFC

The dysregulation of the JAK/STAT pathway drives the pathogenesis of myelofibrosis (MF). Recently, several JAK inhibitors (JAKis) have been developed for treating MF. Select mutations (MTs) have been associated with impaired outcomes and are currently incorporated in molecularly annotated prognostic models. Mutations of RAS/MAPK pathway genes are frequently reported in cancer and at low frequencies in MF. In this study, we investigated the phenotypic, prognostic, and therapeutic implications of NRASMTs, KRASMTs, and CBLMTs (RAS/CBLMTs) in 464 consecutive MF patients. A total of 59 (12.7%) patients had RAS/CBLMTs: NRASMTs, n = 25 (5.4%); KRASMTs, n = 13 (2.8%); and CBLMTs, n = 26 (5.6%). Patients with RAS/CBLMTs were more likely to present with high-risk clinical and molecular features. RAS/CBLMTs were associated with inferior overall survival compared with patients without MTs and retained significance in a multivariate model, including the Mutation-Enhanced International Prognostic Score System (MIPSS70) risk factors and cytogenetics; however, inclusion of RAS/CBLMTs in molecularly annotated prognostic models did not improve the predictive power of the latter. The 5-year cumulative incidence of leukemic transformation was notably higher in the RAS/CBLMT cohort. Among 61 patients treated with JAKis and observed for a median time of 30 months, the rate of symptoms and spleen response at 6 months was significantly lower in the RAS/CBLMT cohort. Logistic regression analysis disclosed a significant inverse correlation between RAS/CBLMTs and the probability of achieving a symptom or spleen response that was retained in multivariate analysis. In summary, our study showed that RAS/CBLMTs are associated with adverse phenotypic features and survival outcomes and, more important, may predict reduced response to JAKis.

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the cornerstone of curative approach to myelofibrosis (MF), although it is burdened by not negligible toxicity and mo...

Pre-fibrotic myelofibrosis (pre-PMF) and essential thrombocythemia (ET) are characterized by similarly increased rate of thrombotic events, but no study specifically analyzed risk factors for thrombosis in pre-PMF. In a multicenter cohort of 382 pre-PMF patients collected in this study, the rate of arterial and venous thrombosis after diagnosis was 1.0 and 0.95% patients/year. Factors significantly associated with arterial thrombosis were age, leukocytosis, generic cardiovascular risk factors, JAK2V617F and high molecular risk mutations, while only history of previous thrombosis, particularly prior venous thrombosis, was predictive of venous events. The risk of total thromboses was accurately predicted by the the international prognostic score for thrombosis in essential thrombocythemia (IPSET) score, originally developed for ET, and corresponded to 0.67, 2.05, and 2.95% patients/year in the low-, intermediate-, and high-risk categories. IPSET was superior to both the conventional 2-tiered score and the revised IPSET in this cohort of pre-PMF patients. We conclude that IPSET score can be conveniently used for thrombosis risk stratification in patients with pre-PMF and might represent the basis for individualized management aimed at reducing the increased risk of major cardiovascular events. Further refinement of the IPSET score in pre-PMF might be pursued by additional, prospective studies evaluating the inclusion of leukocytosis and/or adverse mutational profile as novel variables.

The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F− essential thrombocythemia and primary myelofibrosis patients, respectively, have “canonical” MPL exon 10 driver mutations W515L/K/R/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other “noncanonical” MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional consequences and relevance to disease are unknown. Here, we used a deep mutational scanning approach to evaluate all possible single amino acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba/F3 cells. We identified all currently recognized driver mutations and 7 novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all, of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.

The management of patients with myelofibrosis (MF) has dramatically changed since the introduction of ruxolitinib as a tailored treatment strategy. However, the perceptions about the use of this drug in clinical practice remain, at times, a matter of discussion. We conducted a survey about the diagnostic evaluation, prognostic assessment, and management of ruxolitinib in real-life clinical practice in 18 Italian hematology centers. At diagnosis, most hematologists do not use genetically or molecularly inspired score systems to assess prognosis, mainly due to scarce availability of next-generation sequencing (NGS) methodology, with NGS conversely reserved only for a subset of lower-risk MF patients with the aim of possibly improving the treatment strategy. Some common points in the management of ruxolitinib were 1) clinical triggers for ruxolitinib therapy, regardless of risk category; 2) evaluation of infectious risk before the starting of the drug; and 3) schedule of monitoring during the first 12 weeks with the need, in some instances, of supportive treatment. Further development of international recommendations and insights will allow the achievement of common criteria for the management of ruxolitinib in MF, before and after treatment, and for the definition of response and failure. Electronic supplementary material The online version of this article (10.1007/s00277-019-03847-z) contains supplementary material, which is available to authorized users.

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (15 × 10

Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

ROMEI, a prospective, observational study in patients with myelofibrosis receiving the oral JAK1/2 inhibitor ruxolitinib in real-world practice, assesses treatment adherence based on the 8-item Morisky Medication Adherence Scale (MMAS-8). Here, we present MMAS-8 results at week 24. Overall, 101 of 188 evaluable patients completed the questionnaire at every visit (full completers). Mean (±standard deviation) total MMAS-8 scores remained stable from week 4 to week 24 in the overall population (7.54 ± 0.77 and 7.67 ± 0.70, respectively) and full completers (7.53 ± 0.79 and 7.67 ± 0.73, respectively). Rates of low (MMAS-8 ˂6) or medium (MMAS-8 ≥ 6 to ˂8) adherence were 25–40% and 26–36%, respectively. Fifty-five full completers (54%) reported ≥1 change in adherence category (improvement and/or worsening), most of which were associated with unintentional behavior. The data suggest that one-third of patients receiving ruxolitinib may be undertreated due to non-adherence, potentially undermining disease control, and indicate a need for better interventions addressing noncompliance to oral therapies.

TO THE EDITOR: The discovery of prognostically informative mutations in patients with primary myelofibrosis (PMF)[1][1] prompted the development of mutation-enhanced risk scores.[2][2][⇓][3][⇓][4][⇓][5]-[6][6] Among these mutations, those in ASXL1 are invariably associated with adverse

Systemic mastocytosis (SM) is characterized by extreme heterogeneity of manifestations and prognosis. Several disease-related biomarkers, including clinical, hematological and molecular variables, have been correlated with prognosis. Although relevant, the mutation profile closely reflects the WHO classification that has per se prognostic value. High-risk mutations (HRM) are largely confined to advanced forms, and thus fail in providing information regarding progression and outcome in the not-advanced variants. In this work, we studied hematopoietic cells by multi-parameter flow cytometry (MFC) in order to highlight dysplastic traits that might provide insights into outcome. A score previously validated for myelodysplastic syndromes, with high reproducibility in standard diagnostics, was used. The application of an MFC score to a cohort of 71 SM cases, concurrently genotyped for configuring a HRM category, resulted in the identification of two separate patients' categories (MFC+ and MFC-) characterized by significantly different clinical and laboratory features at presentation. The extent of dysplasia by MFC tended to parallel WHO-category and genotype-related stratification. MFC+ patients had shorter survival compared to MFC- ones, for whom the incidence of progression and/or death was virtually null. Of note, MFC score remained prognostically informative in unadvanced subsets. Furthermore, the integration of MFC and HRM was an independent predictor for outcome, also overcoming WHO-categories in multivariate analysis for EFS. Our results support the use of MFC analysis in the evaluation of patients with SM, alone and in combination with HRM, for refinement of prognosis assessment.