Abstract: The approved dose of bosutinib in chronic phase CML is 400 mg QD in first-line and 500 mg QD in later-line treatment. However, given that gastrointestinal (GI) toxicity typically occurs early after treatment initiation, physicians often tend to start therapy with lower doses although this has never been tested systematically in prospective trials in the Western world. The Bo sutinib Do se Optimization (BODO) Study, a multicenter phase II study, investigated the tolerability and efficacy of a step-in dosing concept of bosutinib (starting at 300 mg QD) in chronic phase CML patients in 2 nd or 3 rd line who were intolerant and/or refractory to previous TKI treatment. Of 57 patients included until premature closure of the study due to slow recruitment, 34 (60%) reached the targeted dose level of 500 mg QD following the 2-weekly step-in dosing regimen. While the dosing-in concept failed to reduce GI toxicity (grade II–IV, primary study endpoint) to  〈  40% (overall rate of 60%; 95% CI: 45–74%), bosutinib treatment (mean dosage: 403 mg/day) showed remarkable efficacy with a cumulative major molecular remission (MMR) rate of 79% (95% CI: 66 to 88%) at month 24. Of thirty patients refractory to previous therapy and not in MMR at baseline, 19 (64%) achieved an MMR during treatment. GI toxicity did not significantly impact on patient-reported outcomes (PRO) and led to treatment discontinuation in only one patient. Overall, the results of our trial support the efficacy and safety of bosutinib after failure of second-generation TKI pre-treatment. Trial registration: NCT02577926.

Abstract: Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2 , which were associated with normal karyotypes (NK) and concomitant mutations in IDH2 , RUNX1, BCOR, ASXL1 , and SRSF2 . Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL , and NPM1 . Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.

Abstract: Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by expansion of the granulocytic, erythrocytic, and megakaryocytic lineages in the bone marrow and peripheral blood, and in most cases, by the presence of a JAK2 mutation. Survival of patients with PV is decreased compared with age-matched controls, and this is mainly due to thromboembolic complications followed by progression to post-PV myelofibrosis and acute leukemia. While no curative treatment exists, cytoreductive treatment with hydroxyurea (HU) or ropeginterferon is approved in EU for first-line therapy, and ruxolitinib (RUX) is approved in EU and US for second-line therapy in patients with HU intolerance or resistance. The current futility analysis assesses the efficacy of ruxolitinib in newly-diagnosed PV treated within the Ruxo-BEAT trial. Methods: This clinical trial entitled "Ruxolitinib versus Best Available Therapy in patients with high-risk Polycythemia Vera or high-risk Essential Thrombocythemia" (Ruxo-BEAT; NCT02577926) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV and ET. Patients in first-line PV and in first and later lines ET are randomized in a 1:1 manner to receive either RUX or best available therapy (BAT). Crossover from BAT to RUX is possible in eligible patients after 6 months. Patients with PV in the RUX arm receive a starting dose of 10 mg bid and may increase their dose up to 20 mg bid. Primary endpoint is the rate of complete clinicohematologic response rate (CHR) at month 6 as defined by Barosi et al Blood 2009. Secondary endpoints include differences in the absence of phlebotomies, spleen size, patient-reported outcomes, and survival. This is a pre-specified futility analysis of RUX in the PV arm, after 50 PV patients had been enrolled. Of the 50 patients, 28 patients with newly-diagnosed PV were randomized into the RUX arm and were analyzed (a maximum of 6 weeks of HU, anagrelide, or interferon therapy was allowed). The PV arm would have to be closed if no favorable trend were observed for RUX for any of the following variables: (1) improvement (decrease) in the hematocrit level during 6 months of treatment, (2) improvement (decrease) of the JAK2V617F allele burden during 6 months of treatment, or (3) improvement of one of the following three symptom variables assessed by physician´s judgement or via MPN Symptom Assessment Form (MPN-SAF) during 6 months of treatment: pruritus, night sweats, or bone pain. Differences between screening (Hct) or baseline (all other variables) and end of month 6 (all variables) were calculated using Fisher´s exact test (for physician-assessed pruritus and night sweats) or the Wilcoxon matched-pairs signed rank test (all other variables). Results: 28 patients received RUX for at least 6 months. After 6 months, the mean hematocrit level decreased from 45.9+/-5.6% to 41.0+/-5.0% (mean+/-SD) (p=0.0003). The number of phlebotomies calculated per year decreased from 4.2+/-3.9% to 0.96+/-2.1 (p=0.0009). Mean JAK2V617F allele burden decreased from 50.2+/28.4% to 44.0+/-28.5% (p=0.0039). The percentage of patients, as assessed by the physician, with pruritus or night sweats decreased from 41% to 26% (trending with p=0.13), and from 30% to 11% (p=0.02), respectively. The points reported by patients themselves on the MPN-SAF survey for pruritus decreased from 2.7+/-3.0 to 1.3+/-1.5 (p=0.0095) and there was a strong trend for reduction of night sweat points (from 3.1+/-3.6 to 1.6+/-2.4; p=0.0579), while the points for bone pain remained unaltered (2.0+/-2.8 to 1.4+/-2.2; p=0.215). Conclusion: Treatment with ruxolitinib in first line PV is efficient regarding the above-mentioned endpoints. Recruitment of our trial will be ongoing. In order not to weaken the study´s statistical power, comparison of both arms was not performed. Disclosures Koschmieder: Ariad: Consultancy, Honoraria, 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, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Foundation: Research Funding; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Isfort:Mundipharma: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Hexal: Other: Travel reimbursement; BMS: Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Schafhausen:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Equity Ownership, Honoraria. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Platzbecker:Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Döhner:CTI Biopharma: Consultancy, Honoraria; Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Jost:Abbvie: Consultancy, Patents & Royalties: Royalty payments for the drug compound ABT-199, Research Funding; Bohringer: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Celgene: Other: Travel Support; Novartis: Research Funding. von Bubnoff:Novartis: Research Funding. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Crysandt:Amgem: Other: travel grant; celgene: Other: travel grant; Pfizer: Other: travel grant; Gilead: Other: travel grant; Incyte: Membership on an entity's Board of Directors or advisory committees. Gezer:AMGEM: Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Merck: Consultancy; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Janssen: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Research Funding. OffLabel Disclosure: Ruxolitinib as first-line treatment in newly-diagnosed PV

Abstract: Introduction: Ph-negative myeloproliferative neoplasms (MPN) represent a heterogeneous group of hematological malignancies which differ in various aspects such as clinical manifestation, underlying genetic aberrations, cytomorphological features and life expectancy. However, across all subtypes, patients (pts) with MPN often suffer from severe symptoms, resulting in an impairment of the quality of life (QoL). Methods: The German Study Group for MPN (GSG-MPN) Bioregistry is a non-interventional prospective study including pts of at least 18 years with diagnosis of Ph-negative MPN according to WHO criteria (2008) having provided written informed consent. The Bioregistry study also includes assessment of QoL at baseline and on an annual basis, with all pts completing the standardized MPN-SAF-TSS questionnaire (German version) and an additional item indicating pts' subjective overall QoL on an 11-point Likert scale. Total scores range from 0 to 90 and were calculated if at least 6 items were answered (Emanuel RM et al., J Clin Oncol. 2012; 30 (33): 4098-103.)). Clinical variables, as documented in the registry, included comorbidities, reported symptoms as assessed by the physician, bleeding, and thromboembolic events (TEE). For statistical analysis, standard descriptive methods, Spearman correlation coefficient, Wilcoxon test/Kruskal-Wallis test for significance testing, and Kendall´s tau-b statistics were used. Results: 1,403 pts who had completed at least six items of the QoL assessment at baseline were included in this analysis. Median age at diagnosis was 58 years (interquartile range [IQR] 22), 98% were Caucasian, 50% were female. 494 pts were diagnosed with essential thrombocythemia (ET, 35%), 444 pts with polycythemia vera (PV, 32%), 302 pts with primary myelofibrosis (PMF, 22%), 83 pts with MPN-unclassifiable (MPNu, 6%), 43 pts with post-ET-myelofibrosis (pET-MF, 3%) and 37 pts with post-PV-myelofibrosis (pPV-MF, 3%). The most common complaint reported via the MPN-SAF-TSS was fatigue, occurring in more than 80% of the pts in all entities except MPNu (77%). More than 50 % of pts in each entity reported to suffer from early satiety, night sweats, concentration problems, or overall impairment of QoL. Table 1 summarizes all 9 symptoms and overall QoL from the questionnaire categorized by entity. Interestingly, the pts suffering from PET-MF reported the highest symptom burden, while PPV-MF pts showed the lowest overall symptom burden (median total QoL score of 23 vs. 16; p=0.01). The strongest correlations among the different symptoms were seen for fatigue and overall QoL (Spearman´s rho 0.57, p 〈 0.001) as well as concentration problems and overall QoL (Spearman´s rho 0.33, p 〈 0.001). Furthermore, the impact of variables such as age, comorbidities and TEE on QoL was assessed. Abdominal discomfort increased with age (rho = -0.14, p 〈 0.001). A history of TEE before baseline assessment correlated significantly with fatigue scores (Spearman rho= 0.07, p 〈 0.01) and with concentration problems (rho=0.07, p 〈 0.01). With an increasing number of TEE, scores for both of these items worsened over time (p 〈 0.01, respectively). Moreover, MPN-total score (MPN-TSS) was higher in pts with more comorbidities (Median: 18 (IQR:23), and 25 (27) for pts with 〈 3 versus ≥3 comorbidities, respectively, p= 0.017). Next, we compared data on 5 of the pts symptoms (reported in the questionnaire) to their assessment by the treating physician (only 5 items were available both in the questionnaire and in our registry database) in order to understand whether the "physician´s opinion" is congruent with the patient´s reported outcome in the questionnaire. While there were clear associations between the two data sources, there were also significant discrepancies, e.g., the physician did not indicate fatigue in about 20% of pts with self-assessed fatigue score of 〉 =6 points. The most concordant symptom was night sweats (further details in table 2). Conclusions: Most MPN pts suffer from a significant symptom burden which impairs their QoL. TEE influence fatigue and concentration problems. The perception of symptoms (particularly with respect to fatigue) differs between pts and treating physician which suggests that questionnaires should be used on a routine basis in order to faithfully reflect patient´s degree of suffering from MPN and/or treatment. Disclosures Isfort: Amgen: Other: i.e. travel support; Mundipharma: Other: i.e. travel support; Roche: Other: i.e. travel support; Incyte/Ariad: Consultancy; Pfizer: Consultancy, Honoraria, Other: i.e. travel support; BMS: Honoraria; Novartis: Consultancy, Honoraria, Other: i.e. travel support; Alexion: Other: i.e. travel support; Hexal: Other: i.e. travel support. Stegelmann:Novartis: Consultancy, Honoraria. Al-Ali:Gilead: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Alexion: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Goethert:BMS: Consultancy, Honoraria, Other: i.e. travel support; Incyte: Consultancy, Honoraria, Other: i.e. travel support; Pfizer: Consultancy, Honoraria; Novartis: Honoraria; Proteros Biostructures: Honoraria; AOP Orphan: Other: i.e. travel support. Haenel:Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria; Amgen: Honoraria. Platzbecker:Celgene: Research Funding. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy.

Abstract: Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.