ALBERT

Description: Introduction Recently, progress has been made in the treatment of patients with higher risk myelodysplastic syndromes (HR MDS) and acute myeloid leukemia (AML). Nevertheless, patients failing hypomethylating agents (HMA) have a dismal prognosis and very limited treatment options. Targeting CD123 on leukemic stem cells (LSC) is one promising approach in MDS and AML. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells (NKs). Aim The SAMBA trial, a phase II study of the German and French MDS study groups within the EMSCO network assessed the overall hematological response rate after 3 months of single agent TAL treatment in AML or HR MDS patients failing hypomethylating agents (HMAs). Methods TAL was given IV at a dose of 9 mg/kg once every two weeks for a total of 6 infusions, responders received up to 20 additional infusions. After the first 3 months, overall hematological response rate (either CR, PR, marrow-CR, HI, SD) was evaluated by bone marrow biopsy. The study was accompanied by an immune monitoring via flow cytometric analysis to investigate the distribution of T- and NK cells in peripheral blood (PB) and bone marrow (BM) at the time of screening and during therapy in comparison with healthy, age-matched controls. Results 24 patients (19 AML and 5 HR MDS) with a median age of 77 (range 71-90) years, who either failed to achieve complete- (CR), partial response (PR), hematological improvement (HI) or relapsed after HMA therapy were included in the study. After TAL administration, 14 patients could be assessed for response after 4 infusions and 10 patients after 6 infusions. The overall response rate (ORR) was 20.8% including 1 complete remission (CRi), 1 patient with hematologic improvement (HI-E) and additionally 3 patients with disease stabilization. The median duration of response in these patients was 3 months (range 3-14 months). Two patients are still on treatment, one patient despite losing objective response (14 months) and one patient with disease stabilization (13 months). The median overall survival for the entire cohort of patients was 3.2 months (range 0.4-11.2 months). In 10 patients (41.6%), therapy with TAL resulted in grade 3/4 infusion related side effects (pneumonia, n=1; infusion-related reaction, n=8; septic shock, n=1). Before treatment initiation, patients had lower levels of CD56dim NK-cells in PB (82% vs. 89% of NK-cells; p=0.069) expressing significantly more inhibiting NK-cell receptors like KIR2DL2 (8.8% vs. 3.2% of NK-cells; p

Description: Introduction: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and peripheral cytopenia. In about half of patients with lower-risk (LR) MDS, thrombocytopenia is present at the time of diagnosis and associated with shortened survival and an increased risk of progression to acute myeloid leukemia (AML). The thrombopoietin receptor agonist (TPO-RA) romiplostim has shown safety and marked efficacy in a still poorly-defined subset of LR-MDS patients with thrombocytopenia. Methods: The EUROPE multicenter phase 2 trial within the EMSCO network investigated the impact of biomarkers like endogenous thrombopoietin (TPO) level and platelet transfusion events (PTE) on the efficacy of romiplostim (750µg SC qw) treatment in patients with LR-MDS (IPSS low/int-1). Patients were eligible if baseline bone marrow blast count was

Description: Background The current standard of therapy in superficial vein thrombosis (SVT) comprises subcutaneous injections of the indirect factorXainhibitorfondaparinuxfor up to 45 days, which was highlyeffectivecompared to placebo in the CALISTO trial. However,fondaparinuxis expensive, requires daily injections and cost-effectiveness in SVT therapy has been questioned. Rivaroxaban is a direct oral factorXainhibitor which has been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). We hypothesizedthat SVT patientsat high risk for VTE complications may be treated as efficacious and safe with rivaroxaban as withfondaparinux. Methods The SURPRISE trial, a randomized, open-label blinded outcome event adjudication trial, compared rivaroxaban 10 mg once daily withfondaparinux2.5 mg once daily in patients with SVT at high risk of VTE complications (defined assupragenualSVT + age 〉 65 years, male sex, previous VTE, cancer, autoimmune disease or SVT of non-varicose veins). Treatment duration for both treatments was 45+5 days with an observational period until day 90+10. The primary efficacy outcome was a composite endpoint of deep vein thrombosis, pulmonary embolism, SVT progression towards thesaphenofemoraljunction, SVT recurrence or all cause death in the per-protocol analysis at day 45. A predefined sensitivity analysis was performed in all randomized patients (full analysis set). The primary safety outcome was the rate of ISTH major bleeding during treatment. Further outcome measures included the composite efficacy outcome up to day 90, each component of the primary efficacy outcome, rates of surgical treatment of SVT and rates of major VTE (composite of symptomatic PE or symptomatic proximal DVT or VTE-related death) at days 45 and 90. The trial was designed to test for non-inferiority of rivaroxaban compared tofondaparinuxwith respect to the primary efficacy outcome and to the rates of ISTH major bleeding. Results A total of 472 patients were randomized (mean age 60.3 years; 60.4% female) and treated with rivaroxaban (n=236) orfondaparinux(n=236). Mean treatment duration was 44.0 days for rivaroxaban and 44.8 days forfondaparinux. Until day 45+5, the primary efficacy outcome (n=435 in per-protocol analysis set) occurred in 3.3% (95%-CI 0.90; 5.73) of patients treated with rivaroxaban and 1.8% (95%-CI 0.05; 3.52) of patients receivingfondaparinux(absolute difference between rivaroxaban andfondaparinuxwas 1.53%; one-sided upper CI limit 4.03%; p-value for non-inferiority 0.025; table 1 and figure 1). Until day 90+10, the respective rates were 7.1% for rivaroxaban and 6.7% forfondaparinux(absolute difference 0.41;one-sided upper CI limit 4.41%;p-value for non-inferiority 0.047). Non-inferiority of rivaroxaban vs.fondaparinuxwas preserved in the full analysis set. No major bleeding occurred and rates of non-major, clinically relevant bleeding were 2.5 vs. 0.4% for day 45+5 and 2.5 vs. 0.9% for day 90+10 in safety set for rivaroxaban andfondaparinux, respectively (table 1).Mean±SDadherence (pill/syringe count at day 45) was 98.9±13.4% for rivaroxaban and 99.3±6.2% forfondaparinux(full analysis set). Conclusions In high-risk SVT patients, rivaroxaban was non-inferior tofondaparinuxin preventing thromboembolic complications with comparable safety. VTE events were predominantly SVT recurrence. Few cases of DVT and PE occurred, which indicates that a 45 days course of rivaroxaban 10 mg orfondaparinux2.5 mg is sufficient to prevent serious complications in this specific subset of SVT patients. As to whether oral rivaroxaban offers a better quality of life compared to 45 days of injections, this has to be investigated in future studies. We found higher SVT complications rates in both treatment arms compared to thefondaparinuxarm in the CALISTO trial. Therefore, patients at higher VTE risk can be identified by use of a simple risk factor assessment, which may help to improve cost-effectiveness of SVT therapy. However, the concept of SVT risk stratification needs to be further investigated, since patients without additional risk factors may not need anticoagulant therapy at all. (Funded by Bayer Vital GmbH, Germany, ClinicalTrials.gov NCT01499953) In response to a pre-submission enquiry, the New England Journal of Medicine indicated potential interest in the study results and a simultaneous publication/presentation is targeted. Disclosures Beyer-Westendorf: Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding. Schellong:Bayer: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Daichii Sankyo: Honoraria; LeoPharma: Honoraria. Gerlach:ASPEN: Honoraria; Bayer: Honoraria; Boehringer-Ingelheim: Honoraria; LeoPharma.: Honoraria. Rabe:Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daichii-Sankyo: Honoraria; LeoPharma: Honoraria; Pfizer: Honoraria. Bauersachs:Bayer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; BristolMyers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; ASPEN: Honoraria, Research Funding.

Description: *AK, PP shared first-, UP, HM, LA shared senior authors Introduction: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (HR-MDS) or acute myeloid leukemia (AML), not eligible for intensive chemotherapy or allogeneic stem cell transplantation. However, the majority of patients do not respond to these agents. Patients failing HMA therapy still have a dismal outcome with very limited treatment options available. Bemcentinib (BEM) is a selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor mediating resistance to chemotherapeutic agents and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents a potential novel target in patients with MDS and AML. Methods: The multicenter phase 2 BERGAMO trial evaluated the safety and efficacy of BEM in patients with HR-MDS or AML, refractory to or relapsing after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively. Patients received an initial loading dose of 400mg BEM orally administered on d1-3 of cycle 1 and a maintenance dose of 200mg BEM on d4-28 of cycle 1 as well as on d1-28 in subsequent 28-day cycles. The primary endpoint was overall response rate (CR, CRi, PR or SD) assessed after 4 treatment cycles. All patients who achieved CR, CRi, PR or SD after 4 cycles of BEM were considered as responders and allowed to continue treatment for a total of up to 9 cycles. Non-responding patients stopped treatment after 4 cycles. Secondary endpoints of the trial included a translational project evaluating the role of biomarkers and response. Results: Between 2018 and 2020, 58 patients in 10 European centers were screened (MDS=27/AML=31) with a median age of 78 years (range, 62-86 years). 45 patients (MDS=21, AML=24) received at least one cycle of BEM and were eligible for safety and efficacy analysis after the first 4 months of treatment. Thirty six (80%) out of 45 patients were considered relapsed after a response to HMA, 8 (18%) had primary resistance and 1 patient (2%) had HMA intolerance. The median number of prior AZA or DAC cycles was 13. In addition, 18 patients (40%) (MDS=9/AML=9) were red blood cell transfusion-dependent. Treatment with BEM was generally well tolerated with only low rates of grade 3-4 hematologic toxicities (n=7). Forty-seven serious adverse events (SAE) occurred in 22 patients (MDS=9/AML=13), mostly due to infectious complications (n=12), hematological toxicity (n=4) or gastrointestinal disturbance (n=6). Until the first 4 months of BEM treatment, the median number of BEM treatment cycles received was 1.5 (range, 0.5-4). During study, 9 patients (20%) died due to infection (MDS=1/AML=3), deterioration of general condition (MDS=1/AML=2) and progressive disease (MDS=0/AML=2). BEM treatment is currently ongoing in four patients (MDS=3/AML=1). The primary endpoint was met in 9 of 45 patients (20.0%). Within the MDS cohort 33.3% achieved a response (n=7/21; CR=1, CRi= 3, SD=3), while 8.3% of patients (n=2/24) with AML achieved stable disease(SD). The 4 MDS patients achieving CR/CRi had a normal karyotype and a median baseline IPSS-R score of 4 (range 3-5). Among the MDS non-responders 4 patients had a complex karyotype, median IPSS-R score was 5 (range 3-5). Median baseline bone marrow blast count was 15% vs. 13% and median pretreatment hemoglobin-, platelet- and WBC levels were 9.2 g/dl (range 7.9-11.8 g/dl), 51 G/L(range 26-120 G/L) and 1.9x109/l (range 1.18-8.9 x109/l) vs. 9.6 g/dl (range 7.9-11.3 g/dl), 35 G/L (range 0-167 G/L) and 1.45x109/l (range 0.82-6.97 x109/l) comparing MDS responders (CR/CRi) vs MDS non-responders, respectively. Preliminary data evaluating soluble AXL (sAXL) in blood plasma at baseline showed that 66.6 % (n=2/3) of MDS patients achieving CR/CRi displayed sAXL levels below a defined threshold, while this was only seen in 20% (n=2/10) of MDS non-responders. Conclusion: These results of the prospective phase II BERGAMO trial confirm, that single agent BEM is generally safe and well tolerated in this patient population with an unmet medical need. Importantly, BEM showed clinical efficacy in a subgroup of MDS patients. These encouraging clinical results are being further explored by an in depth translational research program aiming to identify additional molecular and biological prognostic factors associated with response. Disclosures Kubasch: Celgene: Research Funding; Shire: Research Funding; Novartis: Research Funding. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Teipel:janssen: Honoraria. Jentzsch:Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Giagounidis:Novartis: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees. McPherson:BerGenBio ASA: Current Employment. van de Loosdrecht:novartis: Honoraria; celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Platzbecker:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding. Medyouf:Bergenbio: Consultancy, Research Funding. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Bemcentinib is currently undergoing Phase II clinical trials for non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), acute myeloid leukemia /myelodysplastic syndrome (AML/MDS), melanoma and metastatic pancreatic cancer. In 2019, FDA have granted fast track designation to bemcentinib for the treatment of elderly patients with acute myeloid leukemia (AML) whose disease has relapsed.

Description: *UP, LA contributed equally Introduction A significant proportion of lower risk (LR)-MDS patients present with thrombocytopenia, being associated with shortened survival and higher risk of progression to acute myeloid leukemia (AML). Treatment options for patients with LR-MDS and severe thrombocytopenia remain limited apart from transfusion support. Romiplostim (ROM), a thrombopoietin receptor agonist (TPO-RA) has shown safety and efficacy dependent on endogenous TPO levels as well as platelet transfusion history in a poorly defined subset of LR-MDS patients (Giagounidis et al. Cancer 2014, Sekeres et al. BJH 2014). Methods The multicenter phase 2 EUROPE trial investigated potential biomarkers of response (e.g. TPO levels, molecular markers) to single agent ROM in LR-MDS patients with severe thrombocytopenia. Patients were eligible if platelet counts were ≤30 G/L or ≤50 G/L in case of bleeding history. The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P, according to IWG 2006 criteria) lasting for at least 8 weeks after 16 weeks of ROM (750µg SC qw) treatment. At the time of screening, patients were assigned into 3 different cohorts based on their previous platelet transfusion events (PTE) as well as centrally assessed TPO serum levels (A: TPO