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Introduction: BGB-11417, a potent and highly selective BCL2 inhibitor, had superior antitumor activity vs venetoclax (approved BCL2 inhibitor) in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma xenograft models. BGB-11417 had a favorable PK profile with excellent bioavailability and BCL2 selectivity at <1 nM. Toxicology studies showed a broad therapeutic index and tolerable safety profile. Zanubrutinib (zanu), a next-generation BTK inhibitor with excellent activity and favorable toxicity in pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and MCL, is approved for MCL, R/R marginal zone lymphoma, and Waldenstrom's macroglobulinemia (WM). Combining BCL2+BTK inhibitors is tolerable with synergistic activity in CLL and MCL. Method(s): BGB-11417-101 (NCT04277637), a phase 1, open-label, multicenter, dose-escalation/expansion study, examined BGB-11417 +/- zanu in non-Hodgkin lymphoma (NHL) or CLL/SLL. For dose escalation, pts with R/R B-cell malignancies were enrolled in 1 of 5 BGB- 11417 dose cohorts (40, 80, 160, 320, or 640 mg QD). All pts used a ramp-up to intended target dose that varied by disease. Pts in the combination arm received zanu 320 mg daily starting 8-12 wks before BGB- 11417 introduction. Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT) was assessed from ramp-up through day 21 at intended daily dose; Bayesian logistic regression determined the maximum tolerated dose. Result(s): As of 24 May 2021 (data cutoff) 19 pts were treated; 14 with monotherapy (NHL: n=11; CLL/SLL: n=3) and 5 with combination (all CLL; 3 on zanu pretreatment; 2 started combination). All pts (median age, 72 y) were R/R (median of 2 prior regimens); median follow-up was 1.9 mo. No DLTs were seen in pts with NHL receiving BGB-11417 alone (n=11) up to 160 mg. Reported AEs across all doses are shown in Table 1. Five pts (all NHL) discontinued treatment

Background: BCL2 is aberrantly expressed in many hematologic malignancies and promotes tumorigenesis by enabling cells to evade apoptosis. BCL2 inhibitors have an established role in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. The currently approved BCL2 inhibitor, venetoclax, is associated with mild gastrointestinal toxicities, neutropenia, and the development of BCL2 mutations leading to resistance. BGB-11417 is a highly selective inhibitor of BCL2 with superior potency to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL) cell lines, and xenograft model of diffuse large B-cell lymphoma (DLBCL). BGB-11417 has favorable pharmacokinetics with excellent bioavailability and selectivity for BCL2. Toxicology studies have shown a broad therapeutic index and an improved safety profile. Aim(s): BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation and expansion study (NCT04277637) evaluating the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral BGB-11417 as monotherapy or in combination with the BTK inhibitor ZANU, in pts with B-cell malignancies. Method(s): In separate monotherapy and combination therapy dose-escalation cohorts, pts with relapsed/refractory (R/R) B-cell malignancies received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg once daily [QD]) with a weekly or daily ramp-up to intended target dose. Pts in the combination therapy cohorts received ZANU (320 mg QD or 160 mg twice daily) 8-12 weeks before BGB-11417. Dose-limiting toxicity for each dose cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at intended dose. Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0. Result(s): As of 17 Dec 2021, 58 pts received BGB-11417 (32 monotherapy; 26 combination). Of the pts receiving monotherapy, 26 with R/R non-Hodgkin lymphoma (NHL; 17 D

Background: BCL2, a key regulator of apoptosis, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. BCL2 inhibitors have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. Treatment with the currently approved BCL2 inhibitor, venetoclax, can be limited by common gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2. It has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (Hu, AACR 3077). BGB-11417 also has a favorable pharmacokinetic profile with excellent bioavailability and selectivity for BCL2 at concentration <1nM. Toxicology studies have shown a broad therapeutic index and tolerable safety profile. The combination of a BCL2 inhibitor and a BTK inhibitor is tolerable with synergistic activity in CLL and MCL pts (Hillmen, J Clin Oncol 2019;37(30):2722-9; Jain, N Engl J Med 2019;30;380(22):2095-103; Siddiqi, ASH 2020 S158; Tam, N Engl J Med 2018; 378:1211-23). Zanubrutinib is a next-generation BTK inhibitor that has shown excellent activity and favorable toxicity in pts with CLL/SLL (Hillmen, EHA 2021 LB1900) and MCL (Tam, Blood Adv 2021;5(12):2577-85); with approval for treatment in MCL. Here we report preliminary results of the BGB-11417-101 trial (NCT04277637) in pts with non-Hodgkin lymphoma (NHL) or CLL/SLL treated with BGB-11417 monotherapy or in combination with zanubrutinib. Method(s): BGB-11417-101 is a phase 1, open label, multicenter, dose-escalation and expansion study. Pts with NHL or CLL/SLL are treated with BGB-11417 as monotherapy or in combination with zanubrutinib. For dose esc

Background: BCL2, a key protein regulator of the apoptotic pathway, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. Within the cell there is a delicate balance between BH3-only proteins which activate apoptosis and BCL2 which inhibits it. BH3 mimetics have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. Treatment with currently approved BCL2 inhibitor venetoclax can be limited by common mild gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance after continued use. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2 and has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (preclinical internal data). BGB-11417 also has a favorable pharmacokinetics profile with low plasma clearance in rodents and dogs. Toxicology studies have shown a broad safety window and an excellent safety profile. Aim(s): BGB-11417-101 is an ongoing first-in-human phase 1/1b study (NCT04277637) to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose of BGB-11417 in pts with R/R B-cell malignancies. Method(s): The study has a dose-escalation component, followed by a safety expansion. For dose escalation, pts with R/R B-cell malignancies were enrolled in 1 of 5 oral BGB-11417 dose cohorts (40, 80, 160, 320, or 640 mg once daily). All pts received a weekly or daily ramp-up to intended target dose; pts with non-Hodgkin lymphomas (NHLs) received a 2-day dose ramp-up (day 1, 25% of intended dose; day 2, 50%) before reaching the intended daily dose (day 3+, 100%). Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0. A Bayesian logistic regre

Background: Investigational Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity vs other TEC and EGFR family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642). A recent update of clinical data suggested that complete and sustained 24-hour BTK occupancy is associated with durable responses in patients with non-Hodgkin lymphomas (Tam et al. Blood 2017;130:152). Here, we present updated safety and efficacy data from patients with mantle cell lymphoma (MCL). Method(s): Study AU-003 is a global, open-label, multicenter, phase 1b trial investigating zanubrutinib in patients with B-cell malignancies. After dose escalation, the expansion phase enrolled disease specific cohorts at the recommended phase 2 dose of zanubrutinib (320 mg/day once daily or 160 mg bid). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and response was assessed per International Conference on Malignant Lymphoma criteria (Cheson et al. J Clin Oncol 2014;32:3059). Positron-emission tomographic (PET) scan was not required for response assessment. Result(s): As of 28 Feb 2018, 43 patients were enrolled: 38 relapsed/refractory and 5 treatment-naive (Table). Median follow-up was 10.3 months (range, 0.1-39.2). Twenty patients have discontinued treatment (12 due to progressive disease; 8 due to TEAEs). Most common TEAEs of any cause (>=15% of patients) included diarrhea (30.2%), petechiae/purpura/contusion (30.2%), upper respiratory tract infection (27.9%), constipation (18.6%), fatigue (18.6%), and rash (16.3%). Two cases of atrial fibrillation/flutter (4.7%) and 3 cases of major hemorrhage (7.0%; renal hematoma, gastrointestinal hemorrhage, and tumor

Background: Zanubrutinib (zanu) is a potent, specific and irreversible oral BTK inhibitor. In Phase 1 testing, we have demonstrated that high plasma concentrations can be safely achieved, resulting in complete and sustained BTK inhibition in blood and lymph nodes. Early clinical data from an ongoing Phase 1 trial has shown single-agent zanu to be safe and efficacious for the treatment of pts with chronic lymphocytic leukemia (Seymour 2017), WM (Trotman 2017), and other non-Hodgkin lymphomas (Tam 2017). Aim(s): Report updated safety and efficacy data from WM pts with a median follow-up of >1 year in this Phase 1 trial. Method(s): This is an open-label, multi-center, dose-finding Phase I study of zanu in pts with B-cell malignancies, with indication-specific expansion cohorts: reported here are data from 67 WM pts enrolled as of 3 Nov 2017. Pts received doses of zanu ranging from 40 mg once daily to the final RP2D of 160 mg twice daily until disease progression (PD) or unacceptable toxicity. Pts were assessed by IgM monthly with full assessment of extramedullary disease every 3 months. Result(s): 67 pts with WM were enrolled and evaluable for safety; 51 pts were evaluable for efficacy, excluding those with <12 weeks follow-up (n=13) or IgM <5 g/L at baseline (n=3). The 67 pts included 21 treatmentnative (TN) and 46 relapsed/refractory (R/R; 1-8 prior therapies) and median follow-up 15.5 months (range, 0.1-37.6). The most frequent AEs (>=15%, all Gr 1-2 but 1) were petechia/purpura/contusion (37%), upper respiratory tract infection (34%), constipation (18%) and diarrhea (18%). Gr 3-4 AEs included anemia (8%), headache (2%), and diarrhea (2%). Serious AEs (SAEs) were seen in 22 pts (33%) with 5 individual pts (8%) considered related to zanu; febrile neutropenia, colitis, atrial fibrillation, hemothorax (spontaneous), and headache. There was 1 fatal event from worsening preexisting bronchiectasis in a pt with VGPR. Atrial fibrillation/flutter was experienced by 4 pts (6%

Background: Bruton's tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration and adhesion. Zanubrutinib is a potent, selective and irreversible BTK inhibitor. It has demonstrated profound BTK inhibition with minimal inhibition of offtarget kinases such as EGFR, ITK, JAK3, HER2, and TEC, providing a good scientific rationale for a reduced toxicity profile. Aim(s): To demonstrate the safety profile of zanubrutinib. Method(s): Safety data from patients (pts) in 6 ongoing zanubrutinib monotherapy studies were analyzed. All pts have been treated with >=1 dose of oral (po) zanubrutinib at 40 mg once-daily to 160 mg twice-daily (bid). The analysis included frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation. Result(s): A total of 424 pts were included in the pooled analysis, with a data cutoff date of September 15, 2017. The median age was 64 years (range 20- 87) and 71.9% were males. The median follow-up duration was 4.8 months (range 0.03-36.0). The most common (occurring in >=10% of pts) AEs were upper respiratory tract infection (23.8%), contusion (17.5%), diarrhea (14.2%), cough (13.0%), rash (12.7%), anemia (11.8%), and neutrophil count decreased (11.6%). Serious AEs (SAEs) were reported in 24.3%, including 7.5% that were assessed as related to zanubrutinib. The most common SAEs included pneumonia (3.5%), lung infection (1.7%) and febrile neutropenia (1.2%). AEs of special interest are shown in the Table 1. The most common bleeding events included contusion (17.5%) and hematuria (8.3%). Major hemorrhage, defined as serious or Grade >=3 bleeding of any site, or central nervous system bleeding of any grade included gastrointestinal hemorrhage, purpura (0.5% each), melena, hemorrhagic cystitis, hematuria, renal hematoma, cerebral hemorrhage and hemothorax (0.2% each). The median time to first major hemorrhage was 23 days (range 3-262). The f

Introduction Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion (Rickert, 2013; Aalipour, 2013; Choe, 2016). The BCR pathway is an established therapeutic target in multiple subtypes of non-Hodgkin's lymphoma (NHL). BGB-3111 is a potent, highly specific, and irreversible BTK inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and demonstrates favorable pharmacokinetic and pharmacodynamic properties. We have previously shown complete and sustained BTK occupancy in both peripheral blood mononuclear cells (PBMCs) and lymph nodes (LN) in patients (pts) treated at the 160 mg BID dose in a phase 1 trial (Tam et al. ASH 2016). A recent update of clinical data suggests that complete and sustained BTK occupancy is associated with durable responses in pts with CLL/SLL and Waldenstrom's macroglobulinemia (Seymour et al. ICML 2017; Trotman et al. ICML 2017). Here, we present early safety and efficacy data in pts with other NHL subtypes: relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Methods This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Dose escalation included pts with R/R B-cell malignancies, while the expansion phase enrolled disease-specific cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as 160 mg twice-daily [BID]). Response was assessed per ICML criteria (Cheson 2014). Results As of 18 May 2017, 75 pts with NHL were enrolled, including 23 DLBCL, 31 MCL, 14 FL, and 7 MZL pts. Patient characteristics are shown in the Table. With the exception of 1 pt with treatment-naive MCL, all pts had R/R disease. Safety: Median follow - up was 7 months (range, 0.3-31.9). The most frequent adverse events (AEs) of any cause were contusion (22.7%), upper respiratory tract infe

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC-and EGFR-family kinases, and demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317. Method(s): This is an open-label multicenter, phase study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenstrom's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W. Result(s): As of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table. Safety: Median follow-up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associ

Introduction: BTK inhibitors have been shown to be highly active in WM, particularly WM harboring a MYD88 mutation (MYD88MUT). BGB-3111 is a potent, specific, and irreversible BTK inhibitor. In primary patient (pt) samples, BGB-3111 demonstrated profound BTK inhibition with minimal inhibition of off-target kinases such as EGFR, ITK, JAK3, HER2, and TEC. In phase 1 testing, high plasma concentrations were safely achieved, resulting in complete, sustained BTK inhibition in blood and lymph nodes. Method(s): This was an open-label, multicenter, dose-finding phase 1 study of BGB-3111 in pts with B-cell malignancies, with indicationspecific expansion cohorts. Here, updated safety and efficacy in WM are reported. Result(s): As of 31 Dec 2016, 46 pts with WM were enrolled: median 2 prior therapies (range 0-8), median follow-up 8.2 months (1.4-28), 46 evaluable for safety, 41 for efficacy; 5 non-evaluable pts had either baseline IgM <500 mg/dL (n = 3) recent plasmapheresis (n = 1) or <12 weeks' follow-up (n = 1). The most frequent adverse events (>=20%, all grade [Gr] 1 or 2) were upper respiratory infection (33%), contusion (28%), and constipation (22%). There were 3 treatment-related serious adverse events (Gr 2 atrial fibrillation [AF], Gr 2 headache, Gr 3 cryptococcal meningitis); in all 3 cases, BGB-3111 was withheld and safely resumed. 3 pts developed AF (one Gr 1, two Gr 2), and 1 developed Gr 3 diarrhea. No serious hemorrhage was reported. The objective response rate was 93% (38/41), with a major response rate of 78% (32/41): VGPR in 39% (16/41) and PR in 39% (16/41). Median time to response was 28 days. Response by MYD88 and CXCR4 mutational status, in pts with known status (n = 32) is shown in Table 1. In pts with hemoglobin <10 g/dL at baseline, hemoglobin increased from a median of 8.8 g/dL (7.1-9.8) to 13.8 g/dL (10.7-16.1). IgM decreased from a median of 32.5 g/ L (6-88.5) at baseline to 5.4 g/L (0.4-47.8).16 pts with baseline lymphadenopathy had a median reduc

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and favorable pharmacokinetic and pharmacodynamic properties. BGB-3111 was shown to achieve complete, continuous BTK occupancy in peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL and Waldenstrom macroglobulinemia. Here, updated preliminary safety and activity data in relapsed/refractory (R/R) and treatment-naive (TN) pts with CLL/ SLL are reported. Method(s): This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Pts with R/R CLL/SLL were included in dose escalation, and both TN and R/R CLL/SLL pts were included in expansion cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as a twice-daily [BID] dose). Adverse events (AEs) are reported per Common Terminology Criteria for AEs version 4.03, and response per the modified iwCLL criteria (Hallek 2008, Cheson 2012 clarification for novel therapies). Result(s): As of 15 Dec 2016, 68 pts with CLL/SLL (50 R/R and 18 TN) were enrolled: 4 pts in dose escalation and 64 in cohort expansion at doses of 160 mg QD (n = 3), 160 mg BID (n = 25), and 320 mg QD (n = 40). Patient characteristics are shown in Table 1. Safety: Median follow-up was 7.2 (range, 0-23.3) months. The most frequent AEs of any cause were bruising (35%) and petechiae (11%), upper respiratory tract infection (28%), fatigue (25%), cough (22%), and diarrhea (21%). Four serious AEs related to BGB-3111 were seen in 3 pts: grade (Gr) 2 cardiac failure, Gr 2 pleural effusion, Gr 3 purpura, and Gr 3 pneumonia. The case of Gr 3 purpura (subcutaneous hemorrhage) was the only major bleeding event reported. Atrial fibrillation (Gr 3) occurred in 1 pt. One pt discontinued BGB-3111 for an AE (pleural effusion). Activity: of the 54 pts evaluable

PURPOSE: This paper visualizes the available data on vitamin D status on a global map, examines the existing heterogeneities in vitamin D status and identifies research gaps. METHODS: A graphical illustration of global vitamin D status was developed based on a systematic review of the worldwide literature published between 1990 and 2011. Studies were eligible if they included samples of randomly selected males and females from the general population and assessed circulating 25-hydroxyvitamin D [25(OH)D] levels. Two different age categories were selected: children and adolescents (1-18 years) and adults (>18 years). Studies were chosen to represent a country based on a hierarchical set of criteria. RESULTS: In total, 200 studies from 46 countries met the inclusion criteria, most coming from Europe. Forty-two of these studies (21 %) were classified as representative. In children, gaps in data were identified in large parts of Africa, Central and South America, Europe, and most of the Asia/Pacific region. In adults, there was lack of information in Central America, much of South America and Africa. Large regions were identified for which the mean 25(OH)D levels were below 50 nmol/L. CONCLUSIONS: This study provides an overview of 25(OH)D levels around the globe. It reveals large gaps in information in children and adolescents and smaller but important gaps in adults. In view of the importance of vitamin D to musculoskeletal growth, development, and preservation, and of its potential importance in other tissues, we strongly encourage new research to clearly define 25(OH)D status around the world.