Citations

Abstract Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib. Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patients Secondary Objectives: Hematologic response, symptom assessment Methods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1. Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1). Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents. Methods: Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using chi-square test for categorical data and ANOVA F-test for continuous variables. Results Hydroxyurea vs. HU Naive A total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p<0.001) and had a greater concentration of both high risk (24.9% vs. 11.4%, p=0.001) and intermediate risk (53.9% vs 38.4%, p<0.001) patients. They also had a higher rate of prior thrombosis (29.8% vs 11.3%, p<0.001) and leukopenia (10.1% vs. 3.0%, p<0.001). No differences were noted between gender, a history of prior hemorrhage, red blood cell transfusion requirements, or the presence of anemia/thrombocytopenia. In comparing symptom profiles, no significant differences were noted between TSS or individual symptoms with the exception of slightly more severe cough in HU patients (1.5 vs. 1.1, p=0.02, Figure 1). Anagrelide vs. Anagrelide Naive A total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p<0.001). No differences were noted between age, gender, risk scores, the presence of leukopenia/thrombocytopenia, a history of prior thrombosis or hemorrhage complications or red blood cell transfusion requirements. Additionally, there were no significant differences between TSS or individual symptom items (Figure 1). HU vs. Anagrelide A total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p<0.001) with a greater population of patients meeting high risk criteria (24.9% vs. 2.8%, p=0.002) and having a history of prior thrombosis (29.8% vs. 12.8%, p=0.02). Patients receiving anagrelide had a slightly longer disease duration (8.2 years vs. 6.0 years, p=0.0446). In comparing symptom profiles, no differences were noted in TSS or individual symptom items between cohorts. Discussion In this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Disclosures Kiladjian: Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Abstract BACKGROUND: Burkitt Lymphoma (BL) represents approximately 40% of all childhood and adolescent non-Hodgkin lymphoma (Miles/Cairo, BJH 2012). Children with relapsed or progressive BL develop chemoimmunotherapy-resistant disease and can rarely be cured with salvage therapy (Cairo et al, JCO 2012). Bruton's tyrosine kinase (BTK) is a regulator of normal B-cell development and is activated upon B-cell receptor (BCR) stimulation. Chronic active BCR signaling through BTK activation can be inhibited by the selective and covalent BTK inhibitor, ibrutinib (Young/Staudt et al, Nat Rev Drug Dicov 2013). Preclinical studies of ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) suggest that its inhibitory effect on cell proliferation is in the range of 1.0uM to 25.0uM (Herman et al, Blood 2011; Cinar et al, Leuk Res 2013), which is higher than the typical plasma concentration range in patients at the recommended dose of 560mg (<0.6uM) (Advani et al, JCO 2013). Despite these relatively high IC50 values in vitro, ibrutinib has been highly effective in the treatment of patients with refractory CLL and MCL (Byrd et al, NEJM 2013 and Wang et al, NEJM 2013). Ibrutinib was initially approved by the FDA (IMBRUVICA, USPI) for patients with MCL in November 2013 and CLL in February 2014, who have received at least one prior therapy. BL, however, is associated with tonic vs chronic active BCR signaling; while, both CLL and MCL have chronic active BCR signaling. These findings suggest that the antitumor activity of ibrutinib in BL, which is associated with tonic BCR signaling, may be less pronounced than in Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), CLL or MCL. OBJECTIVES: We hypothesize that ibrutinib may be a potential adjuvant agent in the treatment of BL. Therefore, we investigated the in vivo anti-tumor activity of ibrutinib in BL xenografted NSG mice. METHODS: Raji Burkitt lymphoma (BL) cells (ATCC) were exposed to ibrutinib (0-10uM, generously provided by Janssen R&D LLC) alone and in combination with dexamethasone (1uM) for 5 days and then MTS cell proliferation assay (Promega) was performed. The IC50 values were determined with CompuSynTM software (Chou and Martin, ComboSyn, 2005) based on data derived from MTS assay. Raji BL cells were stably transfected with a firefly luciferase expression plasmid (ffluc-zeo), kindly provided by Laurence Cooper MD, PhD. NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ, 6-8 weeks old) from Jackson laboratory were irradiated (2.5 Gy) and then mice were subcutaneously injected with one million ffluc-zeo tumor cells. Tumor progression and tumor burden were monitored by Bioluminescent Imaging system using the Xenogen IVIS-200 (Caliper Life Sciences). Mice were orally gavaged with either vehicle or ibrutinib (12.5mg/kg) for 10 days (once a day) at post-tumor cells injection. Analysis of survival rates were determined by the Kaplan-Meier method and differences evaluated by log-rank test using the Prism Version 6.0 software. RESULTS: Ibrutinib compared to control induced a significant dose-dependent decrease in cell proliferation in Raji BL cells (5uM, 0.561 ± 0.170, p<0.03, IC50=5.20uM) following 120 hours (5 days) of ibrutinib treatment. Interestingly, we observed a significant decrease in cell proliferation in Raji BL cells (5uM, 0.213 ± 0.078, p<0.002, IC=0.50 ± 0.374uM) following ibrutinib and 1uM dexamethasone combination treatment following 120 hours (5 days) of treatment. We observed a significant decrease of tumor progression by tumor luminescence signal intensity following ibrutinib treated Raji BL xenografted NSG mice at day 20 (12.5mg/kg, p<0.001 and 25mg/kg, p<0.05) and day 25 (12.5mg/kg, p<0.05 and 25mg/kg, p<0.05) compared to control (Figure 1A).Ibrutinib (12.5 mg/kg) treated mice (n=39) significantly prolonged survival compared to vehicle controls (n=28) (p<0.0001) (Figure 1B). CONCLUSIONS: Ibrutinib (12.5mg/kg) significantly decreased tumor progression and significantly increased survival in Raji BL xenografted NSG mice, suggesting that ibrutinib may be a potential adjuvant agent for therapy in the treatment of BL. Future studies will investigate the efficacy of combination therapy with ibrutinib on survival in BL xenografted NOD/SCID mice. Disclosures Galardy: Mission Therapeutics: Research Funding.

Abstract Introduction Individuals with the Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) have previously been shown to experience symptoms in excess to age and comorbidity matched peers. Although numerous assessments of symptom burden and quality of life have been utilized among MPN populations, including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS¨) fatigue scale, and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-10), there are currently no validated assessments of overall health. Developed by the EuroQol Group to assess heath status, the EQ-5D is an internationally validated self-assessment which may be useful in the assessment of health state among MPN patients (Annals of Medicine, 2001. 33:337-43). Methods The EQ-5D evaluates five dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression, on a scale from no problems to extreme problems and assesses patient reported health state via a numerical visual analogue scale (VAS) ranging from 0 to 100. The health state score is a composite score of these items ranging from 0 to 1.0, with higher scores indicating an improved health state. EQ-5D survey participants were essential thrombocythemia (ET) and polycythemia (PV) patients participating in the MAJIC United Kingdom (UK) trial. The MAJIC trial is a randomized, phase II study of best available therapy versus JAK inhibition in individuals with PV or ET who have been resistant or intolerant of cytoreduction with hydroxyurea /hydroxycarbamide. This study was one of the first Trials Acceleration Programme (TAP) trials and is funded by Leukaemia Lymphoma Research, with drug supplied by Novartis. Only baseline EQ-5D assessments taken at study enrollment were included in this analysis. Comparative analysis was preformed using the MPN-10 (J Clin Oncol.2012. 30:4098-103). Results: Participant Demographics: Sixty six patients with ET and 55 patients with PV completed the EQ-5D questionnaire. Median respondent age was 65 years old and half of respondents were female (54%). Average MPN duration was 10 years for ET and 9.2 years for PV. EQ-5D Scoring: Severe to extreme difficulties in the items of mobility, self-care, usual activities, pain/discomfort and anxiety/depression were common (Table 1).Patients with PV tended to have higher proportion of patients with severe to extreme difficulties in individual disease dimensions, higher VAS score, and worsened health state compared to their essential thrombocythemia counterparts, although these effects were not significant. Average VAS health score was 70.4 (+21.2) for ET and 66.5 (+19.6). When evaluating the health state composite score, the mean ET score was 0.74 (+0.32) and mean PV score was 0.66 (+0.28). EQ-5D Validation: The EQ-5D had excellent internal consistency (CronbachÕs alpha=0.87) and strong internal correlation. When evaluating external validity, strong correlations existed between the EQ-5D and the MPN-SAF TSS scales for dimensions of mobility, usual activities, pain and overall health state (many items with r >0.5 and p<0.001). Conclusions: The EQ-5D is a valid and accurate instrument for the brief assessment of health state among MPN patients. This instrument demonstrates excellent clinical utility in a large clinical study cohort and can be used in both clinical practice and trial settings. When comparing EQ-5D health state scores, ET and PV patients had worsened health than the general UK population age 60 to 69 (0.774; Med Decis Making. 2011.31(6)800-4), but similar health to individuals with other malignancies including breast cancer (0.760), prostate cancer (0.743), and lung cancer (0.689). Disclosures Mesa: NS Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: 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; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: 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, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: 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, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

Background: Despite treatment advances, multiple myeloma (MM) remains a condition with high unmet medical need as patients (pts) relapse and become resistant to therapy. MM pts experience a range of serious disease-related symptoms and side effects impacting their functioning and health-related quality of life (HRQL). The median overall survival (OS) has improved with the advent of new treatments in the last two decades, however, the impact of newer combination treatments on pt quality of life remains unknown (Beckner, N et al. Cancer Res. 2011;183:25; Bharat, N et al. J Clin Oncol 2019;37:15(suppl):8039). Venetoclax is a novel, orally bioavailable small molecule inhibitor of BCL-2 activity in MM. In the Phase 3 double-blind, randomized clinical trial (M14-031, BELLINI) progression free survival (PFS) was studied in relapsed/refractory (RR) MM pts receiving venetoclax or placebo in combination with bortezomib and dexamethasone. In addition, patient-reported outcomes (PRO) data focused on physical functioning, pain, and fatigue from BELLINI were evaluated to better understand the overall impact on pt HRQL of adding venetoclax to bortezomib and dexamethasone-based doublet therapy. Methods: The BELLINI Phase 3 study (NCT01794520) enrolled patients ≥18 y old with R/R MM who had received 1-3 prior lines of therapy. The study met its primary endpoint of PFS (HR 0.63, 95% CI=0.44-0.89) but higher risk of death (HR 2.027, 95% CI=1.04-3.95) was observed in the treatment arm compared with placebo, although the OS data are not yet mature (Kumar, S et al. EHA Library. Jun 16 2019;273254:LB2601). The secondary HRQL endpoints included in this study were pain severity, fatigue, physical functioning (PF), and global health status, which were measured using the Brief Pain Inventory-Short Form (BPI-SF), PROMIS Fatigue Short Form surveys, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Change from baseline to day 1 of each cycle visit (up to 25 cycles or last treatment visit) was assessed for each measure in both the treatment and placebo groups. Summary analyses compared mean and median scores between arms at each cycle. The treatment effect was evaluated in a mixed effect model controlling for the patient's baseline score, total visits (or cycles of treatment), age (<65 or ≥65), prior therapy lines, and prior proteasome inhibitor exposure. The model also included an interaction term examining treatment by visits. Results: The intention-to-treat (ITT) dataset included 194 pts (median age: 66y; 53% with 2 or 3 prior lines of therapy) in the treatment group and 97 pts (median age: 65y; 55% with 2 or 3 prior lines of therapy) in the placebo group (2:1 randomization). There was no clear evidence for an independent effect of treatment on PF (P=0.522). Pain scores across multiple measures showed a similar trend, with a statistically non-significant improvement of unadjusted average "Worst Pain" scores for the venetoclax group (P=0.289; Figure B). Non-inferiority in pain results were replicated by the pain subscale of the QLQ-30 (P=0.778), the BPI pain severity index (P=0.418), and the related BPI pain interference subscale score (P=0.603). Fatigue scores likewise demonstrated no significant differences between treatment arms whether using PROMIS Cancer Fatigue t-scores (P=0.442), raw scores (P=0.568), or the 3-item QLQ-C30 subscale (P=0.959), although there was a positive trend across cycle summary scores for the treatment group compared with the placebo group. Unadjusted QLQ-C30 PF subscale scores showed declines from baseline that were generally worse in the placebo group across 25 treatment cycles, although differences were smaller and non-significant in the adjusted model (Figure A). Conclusions: Comparable HRQL in pain severity, fatigue, and PF was observed in RRMM pts receiving venetoclax in combination with bortezomib and dexamethasone compared to pts receiving bortezomib and dexamethasone. The summary scores showed outcomes that were comparable or slightly improved for those randomized to the venetoclax combination. Results of concurrent measures of the same or associated concepts reinforced confidence in these results. Additional analyses of subgroups are ongoing (eg, t(11;14), BCL-2 expression status) and may provide further insights surrounding HRQL in these populations. Figure Disclosures Gasparetto: BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Popat:Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, 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; AbbVie: Consultancy, 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, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; sanofi: 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. de la Rubia:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, 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, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, 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, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Sanofi: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Maciel:Amgen: Other: funding for travel, teaching, participation in advisory boards; Janssen: Other: funding for travel, teaching, participation in advisory boards. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Harrison:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:AbbVie: Employment, Other: Stock/stock options. Karve:AbbVie: Employment, Other: stock/stock options. Ma:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Devine:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Benjamin:AbbVie: Employment, Other: stock/stock options.

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells and has shown synergistic activity with the proteasome inhibitor (PI) bortezomib (B) and dexamethasone (d). Ven ± d had encouraging clinical efficacy in both t(11;14) MM and in pts irrespective of genetic background when administered with B, with a tolerable safety profile in Phase 1 studies. Here, we provide updated efficacy and safety of Ven vs placebo (Pbo) + Bd in pts with relapsed/refractory (RR) MM, including subgroup analyses, in the BELLINI study. Methods: BELLINI (NCT02755597) was a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo + Bd in pts with RRMM who received 1 - 3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. Cycles 1-8 were 21-day with B 1.3 mg/m2 on Days 1, 4, 8, 11 + d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. Cycles 9+ were 35-day with B 1.3 mg/m2 on Days 1, 8, 15, 22 + d 20 mg Day 1, 2, 8, 9, 15, 16, 22, 23. The primary endpoint was progression-free survival (PFS) by independent review committee (IRC). Results: A total of 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Median age was 66 (range, 36 - 87); 53% had ISS II/III disease; 54% received 2 or 3 prior lines of therapy; 59% had prior stem cell transplant; 70% had prior PI, 68% had prior immunomodulatory drug, 41% had both. Among pts with evaluable results, 18% had high-risk cytogenetics, 13% had MM positive for t(11;14), and 79% had high levels of BCL-2 protein by immunohistochemistry (IHC). In the primary endpoint analysis per IRC, the median PFS was 22.4 months (m) in Ven vs 11.5 m in Pbo (HR=0.630, p=0.01), with a median follow-up of 18.7 m (as of 26 Nov 2018). As of updated analysis based on a data cut-off of 18 March 2019, the median PFS (per investigator [INV]) was 22.9 m in Ven vs 11.4 m in Pbo (HR=0.587, p=0.001; Table 1), with a median follow-up of 22.7 m. Per INV, higher overall response (ORR, 84% vs 70%, p=0.009) and very good partial or better response (≥VGPR, 61% vs 40%, p<0.001; Table 2) rates were observed in Ven vs Pbo. Minimal residual disease negativity rate (by next-generation sequencing) was also higher in the Ven arm vs Pbo (MRD- [10-5], 13% vs 1%). Median duration of response was 23.4 m for Ven and 12.8 m for Pbo. In the overall population, median overall survival (OS) was not reached in either arm but continued to favor Pbo (HR 1.474, 95% CI=0.870-2.498). A total of 70 deaths have been reported, 51 (26%) in the Ven arm and 19 (20%) in the Pbo arm. In the safety population (N=289), the most common treatment-emergent adverse events (TEAEs; Ven/Pbo) were diarrhea (59%/48%), nausea (37%/22%), constipation (35%/31%), and fatigue (31%/32%). The most common Grade 3/4 TEAEs were neutropenia (18%/8%), pneumonia (17%/12%), anemia (16%/15%), thrombocytopenia (15%/30%), and diarrhea (15%/12%); 23%/12% discontinued Ven due to a TEAE. The rates of serious AEs (51%/51%) and serious infections (30%/28%) were comparable between arms. There were 69 deaths in the safety population: in the Ven arm, 14 were treatment-emergent (TE; treatment start to 30 days after discontinuation) and 36 were non-TE (>30 days after treatment discontinuation); in the Pbo arm, 1 was TE and 18 were non-TE. In the t(11;14) subgroup, median PFS has not been reached for pts receiving Ven, but was 9.3 m for Pbo (HR=0.095; per INV). In the t(11;14)-negative (neg) subgroup, median PFS was 22.4 m and 10.7 m for Ven and Pbo, respectively (HR=0.627; per INV). Median OS has not been reached in either arm for the t(11;14) and t(11;14)-neg subgroups, although the HR favored Ven in t(11;14) pts, and Pbo in t(11;14)-neg pts. Analyses indicate that low BCL-2 expression by IHC and high-risk cytogenetics (defined as t(4;14, t(14;16), or del(17p)) were associated with decreased PFS and OS in the Ven arm (Table 1). In the high-risk cytogenetics pts, median PFS was 11.4 m in both arms (HR=0.99), and median OS has not been reached in either arm but favors Pbo (HR=10.6). In the subgroup with low BCL-2 expression by IHC, median PFS was 11.7 m and 17.0 m for Ven and Pbo, respectively (HR=1.42), and median OS was 21.3 m in the Ven arm and not reached in Pbo (HR=4.58). Conclusions: Updated analysis of BELLINI continue to reflect a favorable benefit-risk profile in t(11;14) pts, with meaningful clinical responses and improvement in PFS, as well as a positive trend in OS in this subgroup when treated with Ven + Bd. Disclosures Moreau: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Harrison:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, 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; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. De La Rubia:Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria:Celgene: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Amgen: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Janssen Cilag: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Gay:Janssen: 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; Amgen: 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; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: 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: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Celgene: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mikala:Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Punnoose:Genentech, Inc.: Employment; Roche: Other: Stock/stock options. Hong:Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Sood:AbbVie: Employment, Other: Stock/stock options. Jalaluddin:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Ward:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

AbstractMyeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG‐MRT), and AIRC‐Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN‐SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN‐SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient‐years. Vitamin K‐antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN‐SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN‐SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN‐U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to‐date largest, contemporary cohort of MPN‐SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.

Abstract INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.