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In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p< 0.05) and better overall survival (p< 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.

There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5–1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p< 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n= 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P= .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P= .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P= .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.govas NCT03745378.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n= 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n= 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82–1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15–4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00–14.01), ruxolitinib (OR = 3.87, 95% CI 1.18–12.75), and for drug combination (OR = 3.47, 95% CI 1.55–7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.

Recently, the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) was introduced to assess prognosis in myelofibrosis (MF) secondary to polycythemia vera and essential thrombocythemia (post-PV and post-ET MF), replacing the International Prognostic Scoring System (IPSS) and/or Dynamic IPSS (DIPSS) that was applied for primary MF (PMF). In a cohort of 421 ruxolitinib (RUX)-treated patients (post-PV and post-ET MF: 44.2%), we evaluated the following: (1) disease phenotype, responses, and toxicity to RUX; and (2) performance of the MYSEC-PM in post-PV or post-ET MF. While the IPSS failed to correctly stratify post-PV or post-ET MF patients at diagnosis, the MYSEC-PM identified 4 risk categories projected at significantly different survival probability (P< .001). Additionally, the MYSEC-PM maintained a prognostic value in post-PV and post-ET MF also when used over time, at RUX start. Notably, the MYSEC-PM reclassified 41.8% and 13.6% of patients into a lower and higher risk category, respectively. Finally, patients at intermediate-1 risk had significantly higher spleen responses and lower hematological toxicities compared to higher risk patients. Compared to PMF, post-PV and post-ET MF presented a more hyperproliferative disease, with higher leukocyte and/or platelet count and hemoglobin levels both at diagnosis and at RUX start. Despite comparable response rates, post-PV and post-ET MF had lower rate of RUX-induced anemia and thrombocytopenia at 3 and 6 months. The study validates MYSEC-PM in post-PV and post-ET MF prognostication. Post-PV or post-ET MF represents a separate entity compared to PMF in terms of clinical manifestations and toxicity to RUX.

Up to 7% of adult patients with Hymenoptera venom allergy may suffer from a clonal mast cell disease. Patients with clonal mast cell disease and Hymenoptera venom anaphylaxis are commonly males, without skin lesions, and anaphylaxis is characterized by hypotension and syncope in the absence of urticaria and angioedema. A normal value of tryptase does not exclude a mastocytosis. The diagnosis of a mast cell disease leads to several therapeutic consequences concerning the treatment of Hymenoptera venom allergy as matter of fact these patients have to undergo long-life venom immunotherapy, to prevent further, potentially fatal severe reactions.

Up to 75% of patients with severe anaphylactic reactions after Hymenoptera sting are at risk of further severe reactions if re-stung. Venom immunotherapy (VIT) is highly effective in protecting individuals with ascertained Hymenoptera venom allergy (HVA) and previous severe reactions. After a 3- to 5-year VIT course, most patients remain protected after VIT discontinuation. Otherwise, a lifelong treatment should be considered in high-risk patients (eg, in mastocytosis). Several case reports evidenced that patients with mastocytosis and HVA, although protected during VIT, can re-experience severe and sometimes fatal reactions after VIT discontinuation.

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:Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria.

Palandri: Novartis: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Abbvie: Consultancy; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Heidel:Celgene: Consultancy; CTI: Consultancy; Novartis: Consultancy, Research Funding. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Pane:Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; 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:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. 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: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; 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. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo: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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galimberti:Incyte: Honoraria; Novartis: Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Gugliotta:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.

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).

IntroductionHydroxyurea (HU) is worldwide used in the current clinical practice as first line treatment in high risk patients with Polycythemia Vera (PV). However, its efficacy has been seldom evaluated in the real-life setting.

Introduction:Hydroxyurea (HU) is the most used cytoreductive therapy (tx) for patients (pts) with polycythemia vera (PV). However, many pts may have suboptimal responses (SubOR) and/or toxicity (TOX) to HU. After HU, Ruxolitinib (RUX) may achieve hematocrit (HCT) and spleen reductions, but other tx are also available, mainly busulfan (BUS) and interferons (IFN).

Apart from particle size distribution, spray velocity is one of the most important aerosol characteristics that influence lung deposition of inhaled drugs. The time period over which the aerosol is released (spray duration) is also important for coordination of inhalation. Respimat ® Soft Mist™ Inhaler (SMI) is a new generation, propellant-free inhaler that delivers drug to the lung much more efficiently than pressurised metered dose inhalers (pMDIs). The objective of this study was to compare the velocity and spray duration of aerosol clouds produced by Respimat® SMI with those from a variety of chlorofluorocarbon (CFC) and hydrofluoroalkane (HFA) pMDIs. All inhalers contained solutions or suspensions of bronchodilators. A videorecording method was used to determine the aerosol velocity. For spray duration, the time for generation of the Soft Mist™ by Respimat® SMI was initially determined using three different methods (videorecording [techniques A and B], laser light diffraction and rotating disc). Videorecording was then used to compare the spray duration of Respimat® SMI with those from the other inhalers. The Soft Mist™ produced by Respimat® SMI moved much more slowly and had a more prolonged duration than aerosol clouds from pMDIs (mean velocity at a 10-cm distance from the nozzle: Respimat® SMI, 0.8 m/sec; pMDIs, 2.0–8.4 m/sec; mean duration: Respimat® SMI, 1.5 sec; pMDIs, 0.15–0.36 sec). These characteristics should result in improved lung and reduced oropharyngeal deposition, and are likely to simplify coordination of inhaler actuation and inhalation compared with pMDIs.

Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.

Semenzato: Abbvie: Honoraria; Roche: Honoraria; Takeda: Honoraria. Pizzolo:janssen: Speakers Bureau; Abbvie: Speakers Bureau. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

H3K36 tri-methylation by SETD2 has been linked to a plethora of pathways critical for the regulation of a multitude of cellular processes, including transcription, DNA replication and DNA repair after damage, yet the functional implications of perturbed H3K36 tri-methylation by SETD2 mutations or non-genomic loss of function in leukemia are still unclear. We have previously reported that the HMC-1.1 and -1.2 mast cell leukemia (MCL) cell lines and many patients (pts) with advanced systemic mastocytosis (advSM) display H3K36Me3 deficiency as a result of non-genomic loss of function of SETD2. Proteasome inhibition restored SETD2 protein expression and H3K36me3, suggesting that a functional protein is produced but rapidly degraded. To understand the mechanisms underlying this phenomenon, we used an in silicoapproach to identify candidate SETD2-interacting proteins, followed by experimental confirmation by co-immunoprecipitation. We found that, after proteasomal inhibition, SETD2 co-immunoprecipitates with Aurora Kinase A (AKA). We also found that AKA was overexpressed and hyper-activated in pts with advSM compared to ISM pts and to a pool of healthy donors, and that AKA can phosphorylate SETD2. Both pharmacological inhibition by Danusertib and siRNA-mediated knock-down of AKA rescued SETD2 expression and activity, raising the hypothesis that phosphorylation by AKA might be implicated in proteasome-mediated degradation of SETD2. The new standard of therapy in advSM is midostaurin, that inhibits the activity of both wild‐type and D816V mutant KIT, as well as of various other kinases including AKA. Therefore we investigated if midostaurin effects may be addressed to AKA inhibition and consequent SETD2/H3K36me3 rescue. To this purpose, HMC-1 cells were treated with 5 µM midostaurin for 24 h and AKA, SETD2 and H3K36me3 expression were evaluated by western blotting. Treatment with midostaurin was able to inhibit AKA activity by about 60%, partially restoring SETD2 expression and H3K36Me3. Moreover, midostaurin treatment of HMC-1 cells at micromolar doses induced cytostatic but not cytotoxic effects as shown by cell growth curves performed in liquid medium and as confirmed by annexin V/PI staining and subsequent cytofluorimetric analysis of apoptotic cell death. Our observations in cell lines were confirmed in neoplastic mast cells collected from six patients with advSM before and after three months of midostaurin treatment. Western blotting showed that midostaurin treatment in vivo indeed results in a rescue of SEDT2 expression and activity, associated with a partial de-phosphorylation of AKA.

Palandri: Novartis: Consultancy, Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria; Teva: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Heidel:Novartis: Consultancy, Research Funding; Celgene: Consultancy; CTI: Consultancy. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Cuneo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latagliata:Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Novartis: Honoraria.

Palandri: Novartis: Consultancy, Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Bonifacio:Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Rumi:novartis: Honoraria, Research Funding. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. McMullin:Italopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Introduction:Hydroxyurea (HU) is the recommended treatment in patients (pts) with polycythemia vera (PV) at high thrombotic risk. In 2013, European LeukemiaNet (ELN) guidelines defined criteria for response to HU including hematology and clinical parameters (Barosi G, Blood 2013). Yet, estimates of ELN response rates and of their influence on clinical outcomes are lacking.

Introduction

BackgroundBosutinib is a 2ndgeneration tyrosine-kinase inhibitor (TKI) active in Chronic Myeloid Leukemia (CML) patients resistant or intolerant to frontline imatinib, dasatinib or nilotinib; the favourable toxicity profile makes bosutinib potentially useful in elderly patients, but at present there are no data in unselected cohorts of these subjects.

Papayannidis: Incyte: Honoraria; Shire: Honoraria; Novartis: Honoraria; Teva: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Bonifacio:Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Elena:Novartis: Consultancy; Pfizer: Consultancy. Valent:Deciphera: Honoraria, Research Funding; Blueprint: Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Cavo: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, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Soverini:Incyte: Consultancy.

Elli: Novartis: Membership on an entity's Board of Directors or advisory committees. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cilloni:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Trawinska:Novartis: Consultancy, Honoraria. Breccia:BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Palumbo:Janssen: Honoraria; Celgene: Honoraria; Teva: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Latagliata:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Pfizer: Honoraria.

Latagliata: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Annunziata:Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Elena:Novartis: Consultancy; Pfizer: Consultancy. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Sgherza:Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Iurlo:Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria. Breccia:Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria.

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis.

Introduction:Deferasirox (DFX) is the currently available iron-chelation therapy (ICT) for the management of iron overload (IOL), mainly in myelodysplastic syndromes; recently, two retrospective independent studies (Di Veroli, 2018; Elli, 2019) demonstrated that a treatment with DFX is feasible and effective also in the setting of myelofibrosis (MF). However, no data are still available regarding the concomitant use of DFX in patients (pts) treated with Ruxolitinib (Rux).

Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitolo:Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

Introduction.The 2016 WHO criteria identified early primary myelofibrosis (early-PMF) as an individual entity with different clinical/laboratory presentations and a significantly better outcome compared to overt PMF. No information is available on the therapeutic effects of ruxolitinib (RUX) in the context of each disease separately.

Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Foà:INCYTE: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Vitolo:Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau. Aversa:Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria.

Abruzzese: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Foà:CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau. Breccia:Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marchetti:Gilead: Consultancy; takeda: Speakers Bureau; amgen: Speakers Bureau; janssen: Speakers Bureau. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Soverini: Novartis: Consultancy; Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy. Pagano:Pfizer: Speakers Bureau; Gilead: Speakers Bureau; Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau. Gugliotta:Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Angelucci:Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC. Martinelli:Abbvie: Consultancy; Ariad/Incyte: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Next-Generation Sequencing (NGS)-based BCR-ABL1 kinase domain (KD) mutation screening has been shown to enable greater accuracy and sensitivity and straightforward identification of compound mutants (CM) as compared to Sanger sequencing (seq). However, the prevalence of CMs has never been assessed in prospective studies, and although in vitrodata suggest that many of them may be challenging for all tyrosine kinase inhibitors (TKIs) including ponatinib, attempts to correlate such data with in vivoresponses have never been made. To address these issues, we have reviewed the results of routine NGS-based BCR-ABL1 KD mutation screening performed over the past 3 years.

INTRODUCTION

Introduction.Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time.

Bonifacio: Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Pagano:Janssen: Speakers Bureau; Merck: Speakers Bureau; Gilead: Speakers Bureau; Basilea: Speakers Bureau; Pfizer: Speakers Bureau. Valent:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Soverini:Novartis: Consultancy; Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy.