Search

BACKGROUND: Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk. METHODS: We conducted an Australian population-based family case-control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression. RESULTS: We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42-0.76; Ptrend < 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52-0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50-0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53-0.96). CONCLUSIONS: High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma. IMPACT: Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy.

OBJECTIVES: We aimed to examine the relationship between occupational exposure to extremely low-frequency magnetic fields (ELF-MFs) and follicular lymphoma (FL) risk. METHODS: We conducted a family case-control study between 2011 and 2016 in Australia and included 681 cases. Controls were either a family member of cases (related (n=294), unrelated (n=179)) or were unrelated recruited for a similarly designed Australian multiple myeloma study (n=711). We obtained detailed job histories using lifetime work calendars. We assigned exposure to ELF-MFs using an enhanced job exposure matrix, with a lag period of 10 years. We examined associations with FL risk using logistic regression accounting for relatedness between cases and controls. We performed sensitivity analyses including by control type, by sex, complete case analyses, ELF-MF exposure percentiles in addition to quartiles, ELF-MF exposure in the maximum exposed job, a shorter lag period (1 year) and the cumulative exposure in the most recent time period (1-9 years). RESULTS: We observed no association with the average intensity, duration or lifetime cumulative exposure to occupational ELF-MF exposure in the primary or sensitivity analyses. CONCLUSIONS: Our findings do not support an association between occupational ELF-MF exposure and FL risk. Although the inclusion of family members as part of the larger control group may have biased our risk estimates towards the null, findings were similar in sensitivity analyses restricted to cases and unrelated controls. Further research incorporating enhanced exposure assessment to ELF-MF is warranted to inform occupational safety regulations and any potential role in lymphomagenesis.

BACKGROUND: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. METHODS: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases. RESULTS: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality. CONCLUSION: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.

Sorafenib maintenance improves outcome after hematopoietic cell transplant (HCT) for patients with FLT3-ITD acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients 18-65 years (2:1) to sorafenib vs placebo (days 4-10) combined with intensive induction; idarubicin 12mg/m2 days 1-3 plus cytarabine 1.5g/m2 twice daily on days 1,3,5,7 (18-55 years) or 100mg/m2 days 1-7 (56-65 years), consolidation therapy, followed by maintenance treatment for 12 months (post-HCT excluded) in newly diagnosed FLT3-ITD AML. Four patients were excluded from modified intention-to-treat final analysis (3 not dosed and 1 later found to be FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery (CR/CRi) were high in both arms (sorafenib 78%/9%, placebo 70%/24%). With 49.1 months median follow-up, the primary endpoint of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%)(hazard ratio [HR] 0.87;95% confidence interval [CI] 0.51-1.51, p=0.61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR 0.76; 95% CI 0.42-1.39). For patients transplanted in first remission, 2-year OS was 84% and 67% in the sorafenib and placebo arms, respectively (HR 0.45;95% CI 0.18-1.12, p=0.08). In exploratory analyses, FLT3-ITD measurable residual disease negative status (<0.001%) post-induction was associated with improved 2-year OS (83% vs 60%) (HR 0.4;95% CI 0.17-0.93, p=0.028). In conclusion, routine use of pre-transplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

Zanubrutinib (zanu) is a selective nextgeneration Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimal off-target effects. SEQUOIA (NCT03336333) is an open-label, global phase 3 study that randomised treatment naive (TN) patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m2 on day 1 and 2 and rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-6 for 6 x 28-day cycles (BR). Adult patients who met International Workshop on CLL (iwCLL) criteria for treatment were eligible if they were >= 65 years or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridisation was required. Patients were stratified by age (<65 years vs. >=65 years), Binet Stage (C vs. A/B), immunoglobulin heavy chain gene (IGHV) mutational status and geographical region. The primary end-point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end-points included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS) and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria and Lugano criteria respectively. Adverse events (AEs) were recorded until disease progression. From 31 Oct 2017-22 Jul 2019, 479 patients without del(17p) were randomised to zanu ( n = 241) and BR ( n = 238). Treatment groups were well balanced for demographical and disease characteristics (zanu vs. BR): median age, 70.0 years vs. 70.0 years; unmutated IGHV, 53.4% (125/234) vs. 52.4% (121/231); and del(11q), 17.8% vs. 19.3%. At median followup (26.2 months), PFS was significantly prolonged with zanu versus BR as assessed by IRC (hazard ratio [HR] 0.42, 95% CI 0.28-0.63, 2-sided p < 0.0001), and INV (HR 0.42, 95% CI 0.27-0.66, 2-sided p = 0

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: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. Method(s): We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13.1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13.1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided alpha of 0.05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. Finding(s): Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13.1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26.2 months (IQR 23.7

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHOD(S): We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13.1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13.1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided alpha of 0.05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13.1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26.2 months (IQR 23.7-2

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08−1.74), former smoking (OR = 1.36, 95%CI = 1.05−1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06−2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04−2.01), smoking duration (OR = 1.53, 95%CI = 1.07−2.18) and pack-years (OR = 1.56, 95%CI = 1.10−2.22). For never smokers, FL risk increased for those exposed indoors to >2 smokers during childhood (OR = 1.84, 95%CI = 1.11−3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91−9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Context: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. Design: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. Main Outcome Measures: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. Results: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

The phase I/II AU-003 study in patients with treatment-naive (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47.2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95.9% (TN, 100%; R/R, 95%) with 18.7% achieving complete response (CR). Ongoing response at 3 years was reported in 85.7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87.5% (CR 16.7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade >=3 adverse events were neutropenia (15.4%), pneumonia (9.8%), hypertension (8.9%) and anaemia (6.5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade >=3 neutropenia and Grade >=3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.Copyright © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

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

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase III SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42-86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0-26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI: 79.0-94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI: 88.4-98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered as clinicaltrials.gov Identifier: NCT03336333.Copyright ©2021 Ferrata Storti Foundation

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naive (TN) and relapsed/refractory (R/R) patients with WM. Method(s): Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusion(s): Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients w

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

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

The phase I/II AU-003 study in patients with treatment-naive (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47.2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95.9% (TN, 100%; R/R, 95%) with 18.7% achieving complete response (CR). Ongoing response at 3 years was reported in 85.7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87.5% (CR 16.7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade >=3 adverse events were neutropenia (15.4%), pneumonia (9.8%), hypertension (8.9%) and anaemia (6.5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade >=3 neutropenia and Grade >=3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.Copyright © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase III SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42-86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0-26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI: 79.0-94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI: 88.4-98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered as clinicaltrials.gov Identifier: NCT03336333.Copyright ©2021 Ferrata Storti Foundation

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: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naive (TN) and relapsed/refractory (R/R) patients with WM. Method(s): Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusion(s): Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients w

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

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase III SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42–86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0–26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI: 79.0–94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI: 88.4–98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered as clinicaltrials.gov Identifier: NCT03336333.

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment- naive (TN) and relapsed/refractory (R/R) patients with WM. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in patients with TN or R/R WM. Method(s): Patients had TN or R/R WM and required treatment as per IWWM criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the efficacy evaluable patients. Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (54% were aged > 65 and 21% > 75 years). A total of 73 out of 77 patients were considered efficacy evaluable. At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AEs) in 13% of patients (only one treatment-related), disease progression (10.4%) and other (3.9%). Five grade 5 AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, (patient with prior history of scedosporium abscess) bronchiectasis, and gastric adenocarcinoma (none related). Results are presented for TN and R/R patients combined. The overall response rate was 96% and the VGPR/CR rate was 45% (Table). The rates of VGPR/CR increased over time; 22% at 6 months, 33% at 12 months and 45% at 24 months. The VGPR/CR rate was the highest among patients with the MYD88L265P/CXCR4WT genotype (59%). Of the patients with known MYD88WT, 62.5% had a major response. The rate of progression-free and overall survival at 3 years were 81% and 85%, respectively. The most c

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment- naive (TN) and relapsed/refractory (R/R) patients with WM. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in patients with TN or R/R WM. Method(s): Patients had TN or R/R WM and required treatment as per IWWM criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the efficacy evaluable patients. Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (54% were aged > 65 and 21% > 75 years). A total of 73 out of 77 patients were considered efficacy evaluable. At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AEs) in 13% of patients (only one treatment-related), disease progression (10.4%) and other (3.9%). Five grade 5 AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, (patient with prior history of scedosporium abscess) bronchiectasis, and gastric adenocarcinoma (none related). Results are presented for TN and R/R patients combined. The overall response rate was 96% and the VGPR/CR rate was 45% (Table). The rates of VGPR/CR increased over time; 22% at 6 months, 33% at 12 months and 45% at 24 months. The VGPR/CR rate was the highest among patients with the MYD88L265P/CXCR4WT genotype (59%). Of the patients with known MYD88WT, 62.5% had a major response. The rate of progression-free and overall survival at 3 years were 81% and 85%, respectively. The most c

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

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

Background: Zanubrutinib, an investigational BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/ pharmacodynamic properties in preclinical studies. Aim(s): To present updated zanubrutinib safety and efficacy data in patients (pts) with WM. Method(s): This is a global, open-label, multicenter, phase 1/2 study in pts with B-cell malignancies with indication-specific expansion cohorts. Pts received doses of zanubrutinib ranging from 40 mg once daily to the final recommended phase 2 dose of 160 mg twice daily or 320 mg once daily until disease progression (PD) or unacceptable toxicity. We report here on the 77 WM pts from the cohorts who had no prior BTK therapy. The primary endpoint is safety/tolerability. Secondary endpoints include response rate and PFS assessed by IRC. Result(s): As of September 16th, 2018, 77 pts with WM received zanubrutinib (Table). The most common (>15%) adverse events (AEs) of any grade were upper respiratory tract infection (46%), contusion (30%), cough (20%), headache (18%), back pain (17%), diarrhea (17%), urinary tract infection (16%), and constipation (16%). Grade >=3 AEs in >=5% of pts were neutropenia (10%) anemia (8%), hypertension (5%), and basal cell carcinoma (5%). The most common serious AEs were cellulitis (5%), pneumonia (4%), pyrexia (3%), febrile neutropenia (3%), and atrial fibrillation (3%). Sixteen pts discontinued treatment, 8 due to AE, 4 due to PD, 1 due to investigator decision, and 3 others (radiation therapy [n = 1], not compliant with taking drug [n = 2]). Five fatal AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, bronchiectasis, and gastric adenocarcinoma, of which one was considered related to treatment (septic arthritis) Regarding AEs of special interest with BTK inhibitor therapy, 2 pts (3%) had major haemo

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

Background: Zanubrutinib, an investigational BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/ pharmacodynamic properties in preclinical studies. Aim(s): To present updated zanubrutinib safety and efficacy data in patients (pts) with WM. Method(s): This is a global, open-label, multicenter, phase 1/2 study in pts with B-cell malignancies with indication-specific expansion cohorts. Pts received doses of zanubrutinib ranging from 40 mg once daily to the final recommended phase 2 dose of 160 mg twice daily or 320 mg once daily until disease progression (PD) or unacceptable toxicity. We report here on the 77 WM pts from the cohorts who had no prior BTK therapy. The primary endpoint is safety/tolerability. Secondary endpoints include response rate and PFS assessed by IRC. Result(s): As of September 16th, 2018, 77 pts with WM received zanubrutinib (Table). The most common (>15%) adverse events (AEs) of any grade were upper respiratory tract infection (46%), contusion (30%), cough (20%), headache (18%), back pain (17%), diarrhea (17%), urinary tract infection (16%), and constipation (16%). Grade >=3 AEs in >=5% of pts were neutropenia (10%) anemia (8%), hypertension (5%), and basal cell carcinoma (5%). The most common serious AEs were cellulitis (5%), pneumonia (4%), pyrexia (3%), febrile neutropenia (3%), and atrial fibrillation (3%). Sixteen pts discontinued treatment, 8 due to AE, 4 due to PD, 1 due to investigator decision, and 3 others (radiation therapy [n = 1], not compliant with taking drug [n = 2]). Five fatal AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, bronchiectasis, and gastric adenocarcinoma, of which one was considered related to treatment (septic arthritis) Regarding AEs of special interest with BTK inhibitor therapy, 2 pts (3%) had major haemo

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: 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

The very massive star, Eta Carinae, is enshrouded in an unusual complex of stellar ejecta, which is highly depleted in C and O, and enriched in He and N. This circumstellar gas gives rise to distinct absorption components corresponding to at least 20 different velocities along the line-of-sight. The velocity component at -513 kms-1 exhibits very low ionization with predominantly neutral species of iron-peak elements. Our statistical equilibrium/photoionization modeling indicates that the low temperature (T = 760 K) and high density (n_H=10^7 cm^-3) of the -513 kms-1 component is conducive to molecule formation including those with the elements C and O. Examination of echelle spectra obtained with the Space Telescope Imaging Spectrograph (STIS) aboard the confirms the model's predictions. The molecules, H_2, CH, and most likely OH, have been identified in the -513 kms-1 absorption spectrum. This paper presents the analysis of the HST/STIS spectra with the deduced column densities for CH, OH and C I, and upper limit for CO. It is quite extraordinary to see molecular species in a cool environment at such a high velocity. The sharp molecular and ionic absorptions in this extensively CNO- processed material offers us a unique environment for studying the chemistry, dust formation processes, and nucleosynthesis in the ejected layers of a highly evolved massive star., Comment: tentatively scheduled for the ApJ 1 September 2005, v630, 1 issue

We focus on two Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS) spectra of the Weigelt Blobs B&D, extending from 1640 to 10400A; one recorded during the 1998 minimum (March 1998) and the other recorded in February 1999, early in the following broad maximum. The spatially-resolved spectra suggest two distinct ionization regions. One structure is the permanently low ionization cores of the Weigelt Blobs, B&D, located several hundred AU from the ionizing source. Their spectra are dominated by emission from H I, [N II], Fe II, [Fe II], Ni II, [Ni II], Cr II and Ti II. The second region, relatively diffuse in character and located between the ionizing source and the Weigelt Blobs, is more highly ionized with emission from [FeIII], [Fe IV], N III], [Ne III], [Ar III], [Si III], [S III] and He I. Through photoionization modeling, we find that the radiation field from the more massive B-star companion supports the low ionization structure throughout the 5.54 year period. The radiation field of an evolved O-star is required to produce the higher ionization emission seen across the broad maximum. This emission region is identified with slow-moving condensations photoionized by the O star and located in the extended mass flow emanating from the B star primary. Comparison between the models and observations reveals that the high ionization region is physically distinct (n_H ~ 10^7 cm^(-3) and T_e ~ 10^4K) from the BD Blobs (n_H ~ 10^6 cm^(-3), T_e ~ 7000K)., Comment: 35 Pages, 5 figures. Accepted for the Astrophysical Journal

The very massive star, Eta Carinae, is enshrouded in an unusual complex of stellar ejecta, which is highly depleted in C and O, and enriched in He and N. This circumstellar gas gives rise to distinct absorption components corresponding to at least 20 different velocities along the line-of-sight. The velocity component at -513 kms-1 exhibits very low ionization with predominantly neutral species of iron-peak elements. Our statistical equilibrium/photoionization modeling indicates that the low temperature (T = 760 K) and high density (n_H=10^7 cm^-3) of the -513 kms-1 component is conducive to molecule formation including those with the elements C and O. Examination of echelle spectra obtained with the Space Telescope Imaging Spectrograph (STIS) aboard the confirms the model's predictions. The molecules, H_2, CH, and most likely OH, have been identified in the -513 kms-1 absorption spectrum. This paper presents the analysis of the HST/STIS spectra with the deduced column densities for CH, OH and C I, and upper limit for CO. It is quite extraordinary to see molecular species in a cool environment at such a high velocity. The sharp molecular and ionic absorptions in this extensively CNO- processed material offers us a unique environment for studying the chemistry, dust formation processes, and nucleosynthesis in the ejected layers of a highly evolved massive star., Comment: tentatively scheduled for the ApJ 1 September 2005, v630, 1 issue

We focus on two Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS) spectra of the Weigelt Blobs B&D, extending from 1640 to 10400A; one recorded during the 1998 minimum (March 1998) and the other recorded in February 1999, early in the following broad maximum. The spatially-resolved spectra suggest two distinct ionization regions. One structure is the permanently low ionization cores of the Weigelt Blobs, B&D, located several hundred AU from the ionizing source. Their spectra are dominated by emission from H I, [N II], Fe II, [Fe II], Ni II, [Ni II], Cr II and Ti II. The second region, relatively diffuse in character and located between the ionizing source and the Weigelt Blobs, is more highly ionized with emission from [FeIII], [Fe IV], N III], [Ne III], [Ar III], [Si III], [S III] and He I. Through photoionization modeling, we find that the radiation field from the more massive B-star companion supports the low ionization structure throughout the 5.54 year period. The radiation field of an evolved O-star is required to produce the higher ionization emission seen across the broad maximum. This emission region is identified with slow-moving condensations photoionized by the O star and located in the extended mass flow emanating from the B star primary. Comparison between the models and observations reveals that the high ionization region is physically distinct (n_H ~ 10^7 cm^(-3) and T_e ~ 10^4K) from the BD Blobs (n_H ~ 10^6 cm^(-3), T_e ~ 7000K)., Comment: 35 Pages, 5 figures. Accepted for the Astrophysical Journal

The enrichment of Fe relative to α-elements such as O and Mgrepresents a potential means to determine the age of quasars and probethe galaxy formation epoch. To explore how Fe II emission in quasars islinked to physical conditions and abundance, we have constructed an 830level Fe II model atom and investigated through photoionizationcalculations how Fe II emission strengths depend on nonabundancefactors. We have split Fe II emission into three major wavelength bands,Fe II (UV), Fe II (Opt1), and Fe II (Opt2), and explore how the Fe II(UV)/Mg II, Fe II (UV)/Fe II (Opt1), and Fe II (UV)/Fe II (Opt2)emission ratios depend on hydrogen density and ionizing flux in thebroad-line regions (BLRs) of quasars. Our calculations show that (1)similar Fe II (UV)/Mg II ratios can exist over a wide range of physicalconditions, (2) the Fe II (UV)/Fe II (Opt1) and Fe II (UV)/Fe II (Opt2)ratios serve to constrain ionizing luminosity and hydrogen density, and(3) flux measurements of Fe II bands and knowledge of the ionizing fluxprovide tools to derive distances to BLRs in quasars. To derive all BLRphysical parameters with uncertainties, comparisons of our model withobservations of a large quasar sample at low redshift (z<1) aredesirable. The STIS and NICMOS instruments aboard the Hubble SpaceTelescope offer the best means to provide such observations.

The enrichment of Fe, relative to alpha-elements such as O and Mg, represents a potential means to determine the age of quasars and probe the galaxy formation epoch. To explore how \ion{Fe}{2} emission in quasars is linked to physical conditions and abundance, we have constructed a 830-level \ion{Fe}{2} model atom and investigated through photoionization calculations how \ion{Fe}{2} emission strengths depend on non-abundance factors. We have split \ion{Fe}{2} emission into three major wavelength bands, \ion{Fe}{2} (UV), \ion{Fe}{2}(Opt1), and \ion{Fe}{2}(Opt2), and explore how the \ion{Fe}{2}(UV)/\ion{Mg}{2}, \ion{Fe}{2}(UV)/\ion{Fe}{2}(Opt1) and \ion{Fe}{2}(UV)/\ion{Fe}{2}(Opt2) emission ratios depend upon hydrogen density and ionizing flux in broad-line regions (BLR's) of quasars. Our calculations show that: 1) similar \ion{Fe}{2}(UV)/\ion{Mg}{2} ratios can exist over a wide range of physical conditions; 2) the \ion{Fe}{2}(UV)/\ion{Fe}{2}(Opt1) and \ion{Fe}{2}(UV)/\ion{Fe}{2}(Opt2) ratios serve to constrain ionizing luminosity and hydrogen density; and 3) flux measurements of \ion{Fe}{2} bands and knowledge of ionizing flux provide tools to derive distances to BLR's in quasars. To derive all BLR physical parameters with uncertainties, comparisons of our model with observations of a large quasar sample at low redshift ($z<1$) is desirable. The STIS and NICMOS spectrographs aboard the Hubble Space Telescope (HST) offer the best means to provide such observations., Comment: ApJ accepted

Interpretation of the \ion{Fe}{2}(UV)/\ion{Mg}{2} emission ratios from quasars has a major cosmological motivation. Both Fe and Mg are produced by short-lived massive stars. In addition, Fe is produced by accreting white dwarf supernovae somewhat after star formation begins. Therefore, we expect that the Fe/Mg ratio will gradually decrease with redshift. We have used data from the Sloan Digital Sky Survey to explore the dependence of the \ion{Fe}{2}(UV)/\ion{Mg}{2} ratio on redshift and on luminosity in the redshift range of $0.75< z< 2.20$, and we have used predictions from our 830-level model for the \ion{Fe}{2} atom in photoionization calculations to interpret our findings. We have split the quasars into several groups based upon the value of their \ion{Fe}{2}(UV)/\ion{Mg}{2} emission ratios, and then checked to see how the fraction of quasars in each group varies with the increase of redshift. We next examined the luminosity dependence of the \ion{Fe}{2}(UV)/\ion{Mg}{2} ratio, and we found that beyond a threshold of \ion{Fe}{2}(UV)/\ion{Mg}{2} =~ 5, and $M_{2500} < -25\rm mag$, the \ion{Fe}{2}(UV)/\ion{Mg}{2} ratio increases with luminosity, as predicted by our model. We interpret our observed variation of the \ion{Fe}{2}(UV)/\ion{Mg}{2} ratio with redshift as a result of the correlation of redshift with luminosity in a magnitude limited quasar sample., Comment: ApJL accepted

Using the high dispersion NUV mode of the Space Telescope Imaging Spectrograph (STIS) aboard the Hubble Space Telescope (HST) to observe Eta Carinae, we have resolved and identified over 500 sharp, circumstellar absorption lines of iron-group singly-ionized and neutral elements with ~20 velocity components ranging from -146 km/s to -585 km/s. These lines are from transitions originating from ground and metastable levels as high as 40,000 cm-1 above ground. The absorbing material is located either in dense inhomogeneities in the stellar wind, the warm circumstellar gas immediately in the vicinity of Eta Carinae, or within the cooler foreground lobe of the Homunculus. We have used classical curve-of-growth analysis to derive atomic level populations for FeII at -146 km/s and for TiII at -513 km/s. These populations, plus photoionization and statistical equilibrium modeling, provide electron temperatures, Te, densities, n, and constraints on distances from the stellar source, r. For the -146 km/s component, we derive Te = 6400 K, n(H)>10e7 - 10e8 cm-3, and d ~1300 AU. For the -513 km/s component, we find a much cooler temperature, Te= 760 K, with n(H)> 10e7cm-3, we estimate d~10,000 AU. The large distances for these two components place the absorptions in the vicinity of identifiable ejecta from historical events, not near or in the dense wind of Eta Carinae. Further analysis, in parallel with obtaining improved experimental and theoretical atomic data, is underway to determine what physical mechanisms and elemental abundances can explain the large number of strong circumstellar absorption features in the spectrum of Eta Carinae., Comment: 22 pages, Accepted ApJ Feb 10, 2005 issue

We report the first detection of X-ray emission associated with the Homunculus Nebula which surrounds the supermassive star Eta Carinae. The emission is characterized by a temperature in excess of 100 MK, and is consistent with scattering of the time-delayed X-ray flux associated with the star. The nebular emission is bright in the northwestern lobe and near the central regions of the Homunculus, and fainter in the southeastern lobe. We also report the detection of an unusually broad Fe K fluorescent line, which may indicate fluorescent scattering off the wind of a companion star or some other high velocity outflow. The X-ray Homunculus is the nearest member of the small class of Galactic X-ray reflection nebulae, and the only one in which both the emitting and reflecting sources are distinguishable., Comment: 17 pages, 5 figures, accepted by ApJ