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Introduction: Venetoclax (VEN) is a BCL-2 inhibitor FDA approved in combination with azacitidine (AZA), decitabine (DEC), or low-dose cytarabine (LDAC) for newly diagnosed (ND) acute myeloid leukemia (AML) in adults aged ≥75 or those with comorbidities precluding intensive chemotherapy. We explored real-world practices and clinical outcomes of patients (pts) treated with VEN-based vs. non-VEN-based regimens in the AML Real world evidenCe (ARC) Initiative. Methods: This multicenter chart review study includes adult pts with ND AML treated with VEN (VEN cohort) after 11 April 2016 matched to pts with non-VEN-based regimens (control cohort) after 15 May 2015 from 10 academic sites in the US and 4 in Israel. Pts were randomly selected and matched on age ( Results: Select results are shown in Table 1. 133 VEN and 133 control ND AML pts were included. Median age was 73 years (Range: 34-89) in the VEN cohort and 71 years (Range: 40-89) in the control cohort; 60.9% of matched pts were The mean duration of follow-up was 9.2 months in the VEN cohort and 14.6 months in the control cohort and the mean duration of treatment was 6.9 months and 4.3 months. Composite complete remission (CCR: CR+CRi) rate was 60.4% in the VEN cohort and 50.0% in the control cohort and rate of MLFS was 7.2% and 3.4%, respectively; among the pts who achieved a response (CR, CRi, CRh, or MLFS; 81 VEN and 68 control pts), median time to best response was 1.7 months and 1.3 months, respectively. The 1-year KM DOR for patients who achieved CCR was 57.7% in the VEN cohort and 53.1% in the control cohort. After initial therapy, 5.3% of pts in the VEN cohort and 15.0% of pts in the control cohort were referred to HCT. The 1-year KM OS was 62.6% in the VEN cohort and 49.8% in the control cohort and the 1-year KM EFS was 41.4% and 31.5%. In the Conclusions: The current analyses support real-world treatment effectiveness of VEN combinations and are consistent with data reported from clinical trials, despite the relatively short follow-up at the time of interim analyses. The outcomes, including OS at 1 year, for VEN combinations in ND AML pts appear similar to matched control pts, including the subgroup of pts Figure 1 Figure 1. Disclosures Garcia: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Research Funding; Prelude: Research Funding; AstraZeneca: Research Funding. Wolach: Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Vachhani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talati: Jazz: Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria; AbbVie: Honoraria; Astellas: Speakers Bureau. Pollyea: Karyopharm: Consultancy; Syndax: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Glycomimetics: Other. Lai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moshe: Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Abedin: Astellas Pharma Inc.: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Actinium: Research Funding; AltruBio: Research Funding; Agios: Honoraria; Helsinn: Research Funding. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures. Zuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; BioSight Ltd: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Xavier: ADC Therapeutics: Speakers Bureau; Epizyme: Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Speakers Bureau; Morphosys/Incyte: Speakers Bureau; Beigene: Speakers Bureau; Acrotec: Consultancy; Genentech: Honoraria; Kite/Gilead: Honoraria; Jansen/Pharmacyclics: Honoraria; AstraZeneca: Honoraria, Speakers Bureau; Verastem: Honoraria; AbbVie: Consultancy, Speakers Bureau. Lee: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bui: Abbvie: Current Employment, Other: May hold equity. Svensson: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Burne: Analysis Group Inc: Current Employment, Other: Analysis Group Inc received consulting funds from AbbVie. Kye: AbbVie: Current Employment, Other: May hold equity. Maitland: Analysis Group Inc: Current Employment, Other: Analysis Group Inc received consulting funds from AbbVie. Ma: Genentech, Inc.: Current Employment, Other: May hold equity. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Grunspan: AbbVie: Current Employment, Other: May hold equity. Goldberg: Aptose: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aprea: Research Funding; Celularity: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Venetoclax-based combinations were recently approved to treat patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Limited prospective 'real-world' data is available on treatment patterns of venetoclax-based therapy in routine clinical practice. We investigated patterns of patient selection, efficacy, toxicity, patient related outcome and post-remission management in a nationwide multicenter prospective observational trial. Methods: Newly diagnosed pts with AML were enrolled at the time of venetoclax-based therapy initiation from 10 medical centers in Israel. Demographic, clinical and patient-related baseline characteristics were documented. Treatment patterns, safety and efficacy outcomes are reported. Results: Between August 12, 2019, and June 17, 2021(data cut) ,127 AML pts were enrolled to receive venetoclax based therapy. Baseline patient and disease characteristics are reported in Table 1. The main reasons for physician's choice of venetoclax-based therapy were age ≥75, comorbidities and ECOG ≥2 (patient related factors) in 76% of cases and adverse disease biology predicting poor response to intensive chemotherapy (disease related factors) in 24% of cases. Most pts started therapy in an inpatient setting, 82 (64.6%) with a median hospitalization duration of 14 days, while 44 pts (34.6%) started therapy as out pts. Pts received a median of 3.8 cycles of therapy (range 1-21). Most pts (97%) received venetoclax in combination with hypomethylating agents. The full dose of 400mg QD after a median ramp-up duration of 3 days was achieved in 88% of the pts. Dose interruptions and dose modifications during follow-up occurred in 59 (46%) and 30 (24%) of pts, respectively. To allow for adequate follow up for response assessment, efficacy analysis was limited to pts enrolled prior to December 31, 2020, and included 108 pts with a median follow-up of 8 months (range 1-20). As of data cut, 93 pts completed cycle 1 of therapy, 66 pts completed cycle 3 and 39 pts completed cycle 6. 29 pts (27%) are still active on treatment. Best composite complete remission [CCR = complete remission (CR) plus CR with incomplete count recovery (CRi)] was achieved in 62 (57%) pts. CCR rates were assessed in different pre-defined subgroups. Best CCR in pts selected for therapy based on disease-related and patient-related factors were 70% and 54% respectively. Best CCR in pts with AML arising from MPN and pts with other AML were 45% and 58% respectively. Estimated median overall survival (OS) of all pts was 9.6 months (range 7.4-10.6) (Figure 1). Achieving CCR was associated with a superior probability for survival. Estimated median OS was 13.6 months (range 10.6 - not reached) in pts achieving CCR and 4.2 months (range 1.2-10.3) in non-CCR (p Allogeneic transplantation following venetoclax based treatment was offered to 16 (26%) pts with a median age of 71 years (range 43-77). Last documented response prior to transplant was CR in 5 (32%) pts, CRi 9 (56%), MLFS 1 (6%) and PR in 1 (6%) patient. Among grade ≥3 AEs were febrile neutropenia in 28% and infections in 21% of pts. Clinical and laboratory tumor lysis syndrome (TLS) was documented in 2 and 4 pts, respectively. Antifungal prophylaxis was administered in 20% of pts and granulocyte colony-stimulating factor (GCSF) support was used in 17% of pts in response. Early death rate at 30 and 60 days were 7% and 13%, respectively. Conclusion: This prospective real-world analysis reveals unique patterns of patient selection and venetoclax treatment utilization in a medical system with wide access for this indication. Venetoclax-based therapies are effective and associated with manageable toxicity, including in AML patient populations that were excluded from previous registration trials with comparable CCR and early death rates. Factors associated with patient selection in the 'real-world' setting and immature follow up data most probably led to a shorter estimated median OS in this analysis as compared to controlled trials. The REVIVE study continues to expand and is expected to provide additional insights on treatment patterns, management as well as clinical and patient related outcomes. Figure 1 Figure 1. Disclosures Wolach: Janssen: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Astellas: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Neopharm: Consultancy. Levi: AbbVie: Consultancy, Research Funding. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures. Tavor: AbbVie: Consultancy. Hellmann: AbbVie: Consultancy. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Zuckerman: Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; Cellect Biotechnology: Honoraria; BioSight Ltd: Honoraria; AbbVie: Honoraria; Orgenesis Inc.: Honoraria. Stemer: AbbVie: Consultancy. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Ofran: Medison Israel: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Moshe: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

Introduction: Venetoclax (VEN) is a novel BCL-2 inhibitor indicated in the US for treatment of newly-diagnosed (ND) acute myeloid leukemia (AML) in adults ≥75 years or with comorbidities precluding use of intensive chemotherapy, in combination with azacitidine (AZA), decitabine (DEC), or low-dose cytarabine (LDAC). Despite widespread clinical use of VEN combinations in ND AML, real-world practice patterns are largely unknown. We set out to explore real-world outcomes and treatment paradigms in ND AML patients treated with VEN-based regimens. Methods: The AML Real world evidenCe (ARC) Initiative is a multicenter chart review study of adult pts with ND AML treated with VEN-based regimens and matched control pts (by age and ELN risk) from different academic sites in the US (10 sites) and Israel (4 sites), assessing real-world outcomes as well as VEN treatment practices. Interim descriptive results with data cutoff of 17 May 2021 are presented; data collection is ongoing, with a targeted sample size of over 250 VEN pts and further global expansion planned. Descriptive results are presented here on VEN-related treatment practices overall, and separately in the US and Israel. Results: At data cutoff, 133 VEN ND AML pts were included. The majority of pts were treated at US sites (102 pts, 76.7%). Regimens administered were VEN+AZA (106 pts, 79.7%), VEN+DEC (24 pts, 18.0%), and VEN+LDAC (3 pts, 2.3%). In Israel, all pts were treated with VEN+AZA (31 pts, 100.0%). Median age was 73.2 years, and the majority of pts (64.7%) had adverse ELN risk. Common genetic mutations observed included TP53 (30 pts, 22.7%), RUNX1 (21 pts,15.9%), IDH1/IDH2 (22 pts, 16.5%), NPM1 (15 pts, 11.4%), and FLT3 ITD (12 pts, 9.1%). Mean [median] duration of follow-up was 9.2 months [7.1] and duration of VEN-based treatment was 6.9 months [4.1]. 27.8% of pts had discontinued VEN. Among those who discontinued (37 pts), reasons for discontinuation included intolerance (13/37 pts, 35.1%), relapse (8/37 pts, 21.6%), and insufficient response (7/37 pts, 18.9%; results not shown). Unplanned dose interruptions during therapy were observed for 40 pts (30.1%) with common reasons including severe febrile neutropenia (13/40 pts, 32.5%), neutropenia (severe: 10/40 pts, 25.0%; non-severe: 5/40 pts, 12.5%), and patient request (6/40 pts, 15.0%). Venetoclax ramp-up was performed for 74.4% of pts overall and was more common in Israel (29 pts, 93.5%) than US sites (70 pts 68.6%). Among pts with venetoclax ramp-up performed, the majority received initial VEN treatment in the inpatient setting (US: 47/70 pts, 67.1%; Israel: 25/29 pts 86.2%), median starting and ending doses were 100mg and 400mg respectively, and median ramp-up duration was 3 days; which was similar in the US and Israel. Antifungal use during the first cycle, either prophylactically or in response to an infection, was observed in two-thirds of pts (88 pts, 66.2%) and was more common in the US (72 pts, 70.6%). Among pts with prophylactic antifungal use of a strong CYP3A4 inhibitor (33 pts, 24.8%), 42.4% of pts did not ramp-up and started and maintained a venetoclax dose of 100mg. At data cutoff, 120 pts had laboratory testing and bone marrow assessment results available in the full sample. Of these pts, timing of first bone marrow biopsy assessments varied, with 44.5% of pts having an assessment in their first cycle of venetoclax and 11.8% of pts having an assessment after the first two cycles. In Israel, a higher proportion of pts had a bone marrow assessment during their first cycle of venetoclax (18 pts, 58.1%). Out of those with response assessed (111 pts, 90.2%), 65.8% of pts achieved a response of CR, CRh, or CRi (US: 54/86 pts, 62.8%; Israel: 19/25 pts, 76.0%). Conclusions: The ongoing ARC Initiative provides insights on real-world treatment practices and management of ND AML pts treated with VEN-based regimens from academic sites. The ramp-up and dosing patterns appear consistent with label, with some variation. Delay in timing of bone marrow assessments may affect the assessment of time to response and post-response management in the real-world. Additional data collection in the ARC Initiative will provide more robust and valuable insights into VEN-based treatment practices and management in the real world. Figure 1 Figure 1. Disclosures Vachhani: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wolach: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Garcia: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Research Funding; Prelude: Research Funding; AstraZeneca: Research Funding. Talati: Pfizer: Honoraria; AbbVie: Honoraria; BMS: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau. Pollyea: Takeda: Consultancy; Daiichi Sankyo: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy; Glycomimetics: Other; Amgen: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy. Lai: Genentech: Consultancy, 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; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Jazz Pharma: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moshe: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Abedin: Agios: Honoraria; Actinium: Research Funding; AltruBio: Research Funding; Helsinn: Research Funding; Pfizer: Research Funding; Amgen: Honoraria; Astellas Pharma Inc.: Research Funding. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Xavier: AbbVie: Consultancy, Speakers Bureau; Morphosys/Incyte: Speakers Bureau; Jansen/Pharmacyclics: Honoraria; ADC Therapeutics: Speakers Bureau; Epizyme: Speakers Bureau; Genentech: Honoraria; Kite/Gilead: Honoraria; Beigene: Speakers Bureau; Acrotec: Consultancy; Seattle Genetics: Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Verastem: Honoraria; Celgene/BMS: Speakers Bureau. Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bui: Abbvie: Current Employment, Other: May hold equity. Svensson: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kye: AbbVie: Current Employment, Other: May hold equity. Burne: Analysis Group Inc: Current Employment, Other: Analysis Group Inc received consulting funds from AbbVie. Maitland: Analysis Group Inc: Current Employment, Other: Analysis Group Inc received consulting funds from AbbVie. Ma: Genentech, Inc.: Current Employment, Other: May hold equity. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Grunspan: AbbVie: Current Employment, Other: May hold equity. Goldberg: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arog: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aptose: Consultancy, Research Funding; Aprea: Research Funding; DAVA Oncology: Honoraria; Celularity: Research Funding; Prelude Therapeutics: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL). Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry. Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%). Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS. Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD ( Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient). Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals. Figure 1 Figure 1. Disclosures Herishanu: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

Background: The outcome of elderly patients with Acute Myeloid Leukemia (AML) is poor and treatment options in these high-risk groups are limited. Recently, venetoclax combinations with hypomethylating agents or low dose cytarabine were approved to treat patients with AML ineligible for intensive chemotherapy. However limited prospective data is available on the safety and efficacy of venetoclax treatment in routine clinical practice. Israel is among the first countries to have approved venetoclax-based combinations as first line therapy for AML and this treatment is fully reimbursed via the national health system. Here we present the initial results of a prospective, multicenter, nationwide trial that sought to assess the use of venetoclax-based therapy in a real-world setting. Methods: A prospective observational nationwide multicenter trial. Newly diagnosed patients with AML were enrolled at the time of venetoclax-based therapy initiation. Demographic, clinical and patient-related baseline characteristics were documented. Treatment patterns, safety and efficacy outcomes are reported. Patient related outcomes were assessed at baseline and after cycle 3 using the EQ-5D-5L and EORTC QLQ-C30 questionnaires. Results: A total of 70 patients were enrolled between August 2019 and June 2020 (data cut off) with a median age of 75 years (range 45-88) and a median follow-up of 74 days (8-232). Two-thirds of patients were males (62.9%). Over one-quarter (28.6%) of patients had an ECOG performance status of 2 or higher; the median modified Charlson Comorbidity Index (CCI) was 0 (range 1-4) with 27.1% with a CCI ≥2. De-novo AML was documented in 44.3%, secondary AML was diagnosed in 52.8% (secondary to MDS (27.1%), MPNs (11.4%) and therapy related AML (14.3%)). European LeukemiaNet (ELN) risk category was favorable, intermediate and adverse in 8.6%, 30% and 42.9%, respectively (Table 1). Time from diagnosis to initiation of therapy was 8 days (median, range 1-38). The main reasons for choosing venetoclax-based low intensity therapy as reported by treating physicians were patient related factors (mainly age>75 years, performance status) in the majority of cases and adverse disease biology predicting poor response to intensive chemotherapy in 17.1%. Of the 57 patients with available data, 38 (67%) initiated therapy in an inpatient setting with a median hospitalization duration of 12 days (range 1-62 days) and 19 (33%) patients started therapy as outpatients. By data cutoff, of 63 patients that initiated therapy 45, 23 and 7 patients completed cycle 1, cycle 3 and cycle 6 assessments, respectively. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 23/44 (52.3%) patients that were assessed for best response. Of responding patients, 6 (23%, 5 CRi and 1 Partial Remission (PR)) went on to receive an allogeneic transplantation (median age 70.5 years). Ninety percent of patients received venetoclax in combination with hypomethylating agents (azacytidine n=56, decitabine n=1). The full dose of 400mg was administered in 87% of cases with a median ramp-up duration of 3 days. Dose interruptions, dose modifications and dose discontinuations during follow-up were frequent and occurred in 41%, 35% and 27%, respectively. During therapy 63.5% of patients experienced adverse events (AE) of any grade; severe AE's were recorded in 41.3% of patients. Febrile neutropenia was documented in 22.2% and Tumor Lysis Syndrome (TLS) was documented in 2 patients (grade 2; 3.2%). Early death rates at 30 and 60 days were 6.3% and 11.1%, respectively. Conclusion: In the real-world setting venetoclax-based therapies are effective and associated with manageable toxicity including in the outpatient setting. In routine practice patient-related factors and disease-related factors (disease-risk) both seem to play a role in choice of therapy. Venetoclax treatment in real-life practice in Israel appears to follow general recommendations, is tolerable with approximately 90% of patients achieving target dose. These observational data are expected to provide information on patient selection patterns, efficacy and safety and patient related outcomes in patients not in clinical trial. Table Disclosures Wolach: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy. Levi:Abbvie Inc: Consultancy, Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Tavor:Abbvie: Consultancy, Honoraria, Research Funding. Hellmann:Abbvie: Research Funding. Stemer:Abbvie: Research Funding. Cohen:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Afik:Abbvie Inc: Current equity holder in publicly-traded company. Ofek:Abbvie Inc: Current Employment. Banayan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Kan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Grunspan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Moshe:Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.

The brain is a large and complex network of neurons. Specific neuronal connectivity is thought to be based on the combinatorial expression of the 52 protocadherins (Pcdh) membrane adhesion proteins, whereby each neuron expresses only a specific subset. Pcdh genes are arranged in tandem, in a cluster of three families: Pcdhα, Pcdhβ and Pcdhγ. The expression of each Pcdh gene is regulated by a promoter that has a regulatory conserved sequence element (CSE), common to all 52 genes. The mechanism and factors controlling individual Pcdh gene expression are currently unknown. Here we show that the promoter of each Pcdh gene contains a gene-specific conserved control region, termed specific sequence element (SSE), located adjacent and upstream to the CSE and activates transcription together with the CSE. We purified the complex that specifically binds the SSE-CSE region and identified the CCTC binding-factor (CTCF) as a key molecule that binds and activates Pcdh promoters. Our findings point to CTCF as a factor essential for Pcdh expression and probably governing neuronal connectivity.

Objectives: Colorectal carcinoma, a common adult malignancy, has an estimated childhood incidence of 0.3 to 1.5/million in Western countries and 0.2/million in Israel. Diagnosis is difficult because adult screening measures are unfeasible in children. The tumor is frequently associated with predisposing genetic factors, aggressive biological behavior, and poor prognosis. The aim of this multicenter study was to document the clinical profile, treatment and prognosis of colorectal carcinoma in children in Israel. Patients and Methods: The clinical, laboratory, therapeutic, and prognostic parameters of all 7 children from 4 medical centers in Israel who were diagnosed with colorectal carcinoma over a 25-y period were reviewed. Results: Patients presented with rectal bleeding (4 of 7), abdominal pain (2 of 7), and abdominal distension (2 of 7). Average time to diagnosis was 6 months. Six patients underwent surgery (1 refused), and 5 received chemotherapy. Histopathological studies showed poorly differentiated mucinous adenocarcinoma, signet-ring type, in 4 cases, moderately differentiated adenocarcinoma in 2, and well-differentiated carcinoma in 1. Three patients died of the disease, 2 shortly after diagnosis. One patient with recurrent metastatic disease was lost to follow-up. Conclusion: Colorectal carcinoma in children is characterized by aggressive tumor behavior and delayed diagnosis, resulting in a worse prognosis than in adults. Heightened physician awareness of the possibility of this disease in children, with special attention to adolescents with predisposing factors and rectal bleeding, could help to improve outcome.