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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.

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Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18years). Twenty-one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.

Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin−Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin−Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin− cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin− cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported&mdash, 281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months&mdash, 65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Summary Background 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. Methods In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18–60 years, with a diagnosis of polycythaemia vera according to 2008–16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov , NCT03003325 . Findings Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0–12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7–41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. Interpretation Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. Funding AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro

Background Generic formulations of imatinib mesylate have been introduced in Western Europe since 2017 to treat patients with chronic myeloid leukemia (CML). However, results on the safety and efficacy of generic formulations are contrasting. The aim of this study was to investigate the safety and efficacy of generic imatinib in CML patients treated in 12 Italian institutes. Methods This is an observational, retro-prospective analysis of patients with CML for whom the treatment was switched from brand to generic imatinib. We analyzed and compared the variation in quantitative PCR values before and after the switch, and the proportion of patients who maintained molecular response after changing from brand to generic imatinib. Adverse events (AEs) were also evaluated. Results Two hundred patients were enrolled. The median PCR value after the switch was reduced by 0.25 compared to the values before the switch. A significant difference was found between median PCR values before and after the switch in favor of generic imatinib (P = 0.003). Molecular responses remained stable in 69.0%, improved in 25.5%, and worsened in 5.5% of patients. AEs were similar in the pre- and post-switch periods; however, a significant difference was found in favor of generic imatinib for muscular cramps (P < 0.0001), periorbital edema (P=0.0028), edema of the limbs (P

Introduction. MPN-COVID is a European LeukemiaNet cohort study, launched in March 2020 in patients with myeloproliferative neoplasms (MPN) with COVID-19. The first cohort of 175 cases was analyzed at the end of first wave (July 2020) and results provided estimates and risk factors of overall mortality (Barbui T. Leukemia, 2021), thrombosis incidence (Barbui T. Blood Cancer J, 2021), and post-COVID outcomes (Barbui T. Blood Cancer J, 2021). In the second wave of pandemic (June 2020 to June 2021), case-fatality risk in the general population has been found variable across different countries, and no information is available in MPN patients with COVID-19 diagnosed during the second wave in comparison with those of the first wave. Methods. In an electronic case report form, we registered a total of 479 cases of ET (n=161, 34%), PV (n=135, 28%), pre-PMF (n=49, 10%) and overt MF (n=134, 28%), from 39 European hematology units (Italy, Spain, Germany, France, UK, Poland, Croatia). Of these, 304 were diagnosed COVID-19 during the second wave. Results. Patients in the second wave were significantly different from those in the first wave, including parameters such as age (median: 63 vs. 71 years, p Conclusions. This is the largest series of MPN patients who incurred COVID-19 from June 2020 onward, namely during the "second COVID-19 wave". Compared to the first wave, the second one recorded a lower overall COVID-19 severity, but Ruxolitinib discontinuation still remained a risk factor for a dismal outcome. Greater vulnerability of ET than PV in developing venous thrombosis was confirmed also during the second wave. This finding suggests that ET warrants a specific antithrombotic prophylaxis in addition to heparin. Figure 1 Figure 1. Disclosures Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iurlo: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sobas: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Fox: Novartis: Honoraria; Sierra: Honoraria. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Benevolo: Novartis: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau. Harrison: Gilead Sciences: 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, Speakers Bureau; Sierra Oncology: Honoraria; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kiladjian: Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Patriarca: Incyte: Honoraria; Takeda: Honoraria; Argenix: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Griesshammer: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Garcia Gutierrez: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Osorio: Janssen, Abbvie, Roche: Consultancy. Koschmieder: CTI: Membership on an entity's Board of Directors or advisory committees, Other; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Other: Travel support; Alexion: Other: Travel support; Karthos: Other: Travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Image Biosciences: Other: Travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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.

Introduction Malignancy can be heralded by unprovoked venous thromboembolism (VTE) but also by arterial thrombosis. To date it is unknown whether this association is present also in myeloproliferative neoplasms (MPN), in which arterial thrombosis is more frequent that venous thrombosis and solid tumors are reported with an increased frequency. The MPN-K nested case-control study addressed the impact of cytoreductive drugs on the risk of developing second cancer in MPN patients (Barbui T et al, Leukemia 2019); here we re-examined the study database to evaluate the frequency and type of vascular complications in MPN patients with second cancer excluding leukemia and to establish whether arterial and venous thrombosis during follow-up after diagnosis of MPN could predict the occurrence of a second cancer. Patients and methods Cases were patients with second cancer diagnosed concurrently or subsequent to the diagnosis of MPN. Controls were MPN patients without second cancer. For each case with second cancer, up to 3 cancer-free controls were matched by each center for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. Each set consisting of one case and their matched-controls had a similar observational period (from MPN diagnosis until the index date of diagnosis for the second cancer). The study included 647 cases with second cancer (carcinoma, non-melanoma-skin cancers, hematological secondary cancer and melanoma). The most frequent category was carcinoma (n=426, 65.8%). Cases were comparable with the 1,234 matched controls for demographics, type of MPN, and exposure to potential confounders such as mutational profile, abnormal karyotype and cardiovascular risk factors. The thrombotic events of interest were ischemic stroke, transient ischemic attacks, acute coronary syndromes, peripheral arterial thrombosis, deep venous thrombosis (including thrombosis of cerebral and splanchnic veins) and pulmonary embolism. Thrombosis had to be concurrent with or in the 2 years before MPN diagnosis or occurring after MPN diagnosis. The cumulative incidence of either arterial or venous thrombosis from MPN diagnosis was estimated by the Kaplan-Meier method and was compared between cases and controls using the log-rank test. A conditional logistic regression model estimated the Odds Ratio (OR) with 95% Confidence Interval (CI) of second cancer associated with the occurrence of thrombosis before/at diagnosis of MPN and during follow-up. Other covariates were patient age, cardiovascular risk factors, the JAK2V617F mutation, and treatment during follow-up. Results Approximately 20% of either MPN cases or controls had thrombosis before MPN or at diagnosis (19.8% vs. 21.1%, respectively, p=0.462). After a median observation time from diagnosis of MPN to an index date of 4.5 years (interquartile range 1.5-8.2) in cases and 3.7 years (interquartile range 1.5-7.5) in controls, cases showed a percentage of thrombosis higher than in controls (75/647, 11.6% vs. 100/1234, 8.1%, respectively, p=0.013). Approximately one-third of thrombosis preceding cancer occurred in the 12 months before the diagnosis of second cancer (22/75, 29.3%). The excess of thrombosis in cases was due to a higher frequency of arterial thrombosis (6.2% vs. 3.7%, p=0.015), whereas no significant difference was found for venous thrombosis (5.4% vs. 4.3%, p=0.277). While the cumulative incidence of venous thrombosis over time was similar among cases and controls (p=0.864), the cumulative incidence of arterial thrombosis was higher in cases with second cancer (p=0.006) (Figure 1). The excess of arterial thrombosis after MPN diagnosis was limited to cases with carcinoma (6.8% vs 3.9%, p=0.027). In a multivariable model, arterial thrombosis during the follow-up was confirmed to be an independent predictor factor for carcinoma, with an odds ratio of 1.97 (95%CI 1.14-3.41, p=0.015). Conclusions. These findings reveal an association of arterial thrombosis with subsequent second cancer (namely carcinoma) in MPN patients. A possible biological plausibility for this link may be related to an underlying common pathogenic mechanism such as an aberrant inflammatory response consistently found in MPN. This observation may have practical implications and suggests careful clinical surveillance for early diagnosis of second cancer in MPN patients with arterial thrombosis during the follow-up. Disclosures 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.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.

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.

Background: The main objective of this study is to gain further insights on how chronic myeloid leukemia (CML) patients involved in an interventional clinical trial with the purpose of reaching treatment free remission (TFR) phase, perceived and experienced TFR failure. TFR failure was defined for the individual patient as either not being eligible for drug discontinuation or as having relapse in the TFR phase with reintroduction of nilotinib treatment. Methods: Using a qualitative approach, out of 25 patients with CML who experienced TFR failure 14 were interviewed. Patients’ views and experiences were explored using in-depth interviews, analyzed using the Interpretative Phenomenological Analysis (IPA). Results: The analysis of the interviews revealed that the experience of the diagnosis seems to have been lived as a traumatic break that has created a dichotomy, like an ambivalence in the ways in which CML patients perceived and experienced the whole disease journey, with contradictory feelings of both positive and negative emotions (e.g., a diagnosis of cancer, that is something distressing and of being afraid of, but also with a treatment and a life expectancies of which being grateful). This ambivalence of feelings was found to give meaning to the way in which patients cognitively and emotionally experienced the different steps of their disease history. Thus, four main issues, corresponding to different steps of the patients’ journey, were identified: (1) the moment of the diagnosis, (2) the experience of the illness journey: disease and treatment, (3) the moment of “TFR failure,” and (4) the impact of disease, treatment and relapse on the patient’s life. Conclusion: This qualitative analysis helps in understanding patients’ perspective, both in terms of getting access to the inner subjective experience of having CML and its strict relationship with the involvement in a trial or its cessation. Clinicians should consider that the way in which CML patients feel engaged in a clinical trial, create expectancies about TFR or experience the TFR failure is linked to the process of coping with the diagnosis, which is characterized by ambivalence.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.

Background: Ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Based on the concern for an unfavourable cardiovascular toxicity profile, a dose reduction to 15 mg daily is currently recommended in CP patients after the achievement of treatment milestones. As more flexible approaches with TKIs dosage are increasingly adopted in clinical practice, identifying specific profiles of patients eligible for different treatment strategies, in order to improve the benefit/risk ratio, would be of particular interest. Aims: To update previous observations in an extended cohort of CML patients, resistant or intolerant to prior TKIs, describing the efficacy and toxicity of two different ponatinib schedules (de-escalated vs 15 mg starting dose). Secondly, to investigate whether specific subsets of CML patients were managed more successfully with one strategy. Methods: A retrospective analysis of CML-CP patients treated with ponatinib 15 mg, as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib, to reduce or to start therapy with a lower dose were indicated. Cytogenetic and molecular responses were evaluated according to the ELN2013 recommendations. Toxicities under ponatinib treatment leading to transient or definitive discontinuation were recorded. Results: 68 patients were included in this analysis. Median age at ponatinib start was 57 years (range: 28-87). The median time from CML diagnosis to ponatinib treatment was 4.6 years (range: 0.4-19). Most patients (70.6%) were treated with imatinib as frontline treatment. 30/68 patients (44%) received ponatinib as 4th or subsequent line of therapy. ABL1 mutations were detected in 18 (26.5%) patients (being 44% of them positive for the T315I mutation). 50/68 (73.5%) of cases had less than MR2 at the time of ponatinib initiation, with one third exhibiting primary refractoriness to all prior treatments. Resistance to prior TKIs was the reason for switch in 85% of patients treated with higher doses of ponatinib, while 13/26 patients starting with 15 mg were purely intolerant or intolerant and resistant (p= 0.001). No other significant differences between the two groups were identified. MR2, MR3 and MR4/MR4.5 rates were 78.6%, 59.6% and 28.6% in 42 patients treated with the "de-escalated" approach, respectively. First step of dose reduction was decided after a median time of 3.1 months, with a subsequent decrease to 15 mg after a median of 10 months. Dose modifications were guided mostly by adverse events (73%) and, less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 27 months (range: 2-81), with 5/42 patients discontinuing ponatinib (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). 4 deaths were registered, three after blast crisis and one for a fatal cardiovascular event. 26 patients started ponatinib 15 mg daily, with a median duration of treatment was 15 months (range: 2-58). MR2 was obtained in 77%, MR3 in 69.3% and MR4 in 46.2% of cases, respectively. MR3 or deeper responses were maintained in 80% of patients; 7/26 lost their best acquired response, with subsequent dose escalation to higher than 15 mg in 5/26 patients. Treatment discontinuation was necessary in 3 cases (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). Of note, patients with ABL mutations gained benefit only from the "de-escalated" approach, with response improvements in 10/14 of cases vs 0/4 in the "low dose" group. Similarly, a higher rate of at least a MR2 was obtained in primary refractory patients treated ab initio with higher doses of ponatinib (57.1 % vs 14.3 %). However, focusing only on pure intolerant patients, 15 mg starting dose was very effective, with all patients achieving at least a MR3 or deeper response. Summary/Conclusion: With the limits of the retrospective nature and small sample size, these data suggest that different dose strategies could be applied to specific subsets of CP-CML patients. While mutations or refractoriness to previous treatments should address towards a "debulking approach" with 45 or 30 mg ponatinib dose, intolerant or "low level resistance" cases could benefit from lower starting dose. Further investigation in larger prospective trials is warranted. Disclosures Castagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Pane:AMGEN: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Therapy with Tyrosine Kinase Inhibitors (TKIs) changed the fate of Philadelphia-positive Chronic Myeloid Leukemia (CML). At present, the therapeutic strategy aims to improve the management of the disease and the quality of life of the patients. In July 2015, we started a prospective multicentric randomized trial with the aim to validate the policy of the intermittent de-escalation treatment and to explore the impact of this strategy on the Quality of Life. To this purpose, CML patients older than 60 years in stable (≥2 years) MR3.0 or MR4.0 molecular response were randomized to receive a FIXED intermittent TKIs regimen (one month ON and one month OFF), as previously published (Russo D, Blood 2013; Russo D, BCJ 2015), versus a PROGRESSIVE intermittent TKIs regimen (one month ON and one month OFF for the 1st year; one month ON and two months OFF for the 2nd year; one month ON and three months OFF from the 3rd year) (OPTkIMA study, ClinicalTrials.gov: NCT02326311). Molecular monitoring was performed according to the 2015 ELN guidelines, every 3 months by RT-PCR on peripheral blood (Baccarani M,Blood 2013). In case of MR3.0 (MMR) loss, checked in two monthly consecutive RT-PCR analysis, patients were planned to exit the study and to resume TKIs daily. This first interim report have been focused on the patients who, by intention to treat, have completed the first year of the study for an historical comparison with the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). During the first year, both the patients randomized in the FIXED and in the PROGRESSIVE arms were given the TKIs treatment one month ON and one month OFF. Up to June 2018, 177 patients have been enrolled by 26 Italian Hematological Centers (first patient randomized in July 2015) and 121/177 patients (68%) completed the first year of OPTkIMA study. The median age was 71 years (range 60-89) and 64% of the patients were belonging to the Sokal intermediate/high risk goup. 96/121 (79%), 14/121 (12%) and 11/121 (9%) patients were receiving imatinib (IMA), nilotinib (NILO) and dasatinib (DAS), at the time of enrollment. Overall, 59/121 (49%) and 62/121 (51%) patients have been randomized in the FIXED and PROGRESSIVE arm, respectively. 41/62 patients (66%) randomly assigned to the PROGRESSIVE arm have entered the second year of therapy. 34/121 patients (28%) went out of the study during the first year. The reasons for protocol discontinuation were: informed consent withdrawn (2 cases), second cancer (4 cases), loss of MR3.0 (28 cases). (Table 1). Among the 28 patients who lost the MMR, 17 and 11 were in MR4.0 and MR3.0, respectively, when they were enrolled into the study. Thus the probability of loosing the MR3.0 while on OPTkIMA was 21,7% at one year (Figure 1). All the 28 patients resumed TKIs continuously and all obtained at least the MR3.0 response, within 6 months and are currently included in the study follow up. The intermittent treatment was well tolerated, with 4 serious adverse events (1 appendicitis, 1 atrial fibrillation, 1 cardiac failure, 1 hip fracture) and 3 adverse events (1 diarrohea, 1 pruritus and 1 fever), none of which have been considered treatement-related. None of the patients experienced the TKI withdrawn syndrome. According to this first interim report, we found that a policy of intermittent TKIs administration in elderly patients is safe and well tolerated. Analysis of patient-reported QoL outcomes is ongoing and will further add information on the overall treatment effectivness of the new PROGRESSIVE intermittent TKI administration. After the 1st year, 28/121 patients (23%) lost MR3.0 and all of them re-gained the major molecular response within 6 months from resumption of continuous treatment. The probability of MR3.0 loss while on OPTkIMA at 1 year was 21,7% and this is quite comparable with the 20% MR3.0 loss observed in the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). Disclosures Efficace: Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Research Funding; TEVA: Research Funding; AMGEN: Research Funding; Incyte: Consultancy; Amgen: Consultancy; TEVA: Consultancy; Orsenix: Consultancy. Abruzzese:Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai:Novartis: Consultancy; Pfizer: Consultancy.

Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41–76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3–106), the 3-year probability of overall survival and disease free survival was 54 +/− 14% and 46 +/− 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/− 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John Wiley & Sons, Ltd.