ALBERT

Description: Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Description: Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

Description: Background The provision of effective and tolerable therapy in elderly and unfit patients is a clear priority in CLL. The BCL2 inhibitor venetoclax has shown remarkable efficacy in relapsed/refractory population and recently, in unfit untreated patients receiving a fixed duration schedule combined with obinutuzumab. Large retrospective real word experiences confirmed the efficacy and survival outcomes previously seen in trials. Although toxicity analysis including rates of tumor lysis syndrome (TLS), dose interruptions and discontinuations have been assessed in a recent cohort (Eyre et al. BJH 2020), the question of whether age and fitness may affect efficacy and survival on venetoclax treatment is still open. Methods This is a multicenter retrospective analysis evaluating 158 patiens in 14 Italian centers treated with venetoclax from February 2017 to May 2020. For each patient we analyzed the impact of age (6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG-PS (0-1 versus 〉1) and CCI ( 6 significantly influenced PDR (p 0.012) but not tox-DTD. In younger patients CIRS 〉6 did not show effect on treatment management; CIRS3+ instead, led to higher rate of tox-DTD (p 0.044). Progression free survival, EFS and OS were not affected by CIRS3+ and CIRS〉6 even when patients were stratified according to age. Patients with an ECOG 〉1 experienced more tox-DTD (P 0.003) and a significantly shorter PFS (p

Description: Background: Marginal zone lymphoma (MZL) is rare and heterogeneous and it has been difficult to define optimal therapeutic strategies. Like other indolent non-Hodgkin lymphomas, advanced stage disease is considered incurable, with most patients experiencing a continuing pattern of relapse and remission. MZL is typically dependent on B-cell receptor (BCR) signaling suggesting a role for BCR pathway targeting via inhibition of Bruton's tyrosine kinase (BTK). The utility of this approach was confirmed by the pivotal phase 2 study demonstrating a 48% objective response rate (ORR) to ibrutinib in patients with relapsed/refractory (R/R) MZL (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib (BGB-3111) is a potent, highly specific, and irreversible next-generation BTK inhibitor. It was specifically designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are thought to be related to atrial fibrillation, thrombocytopenia, and bleeding events. In an early-phase study (BGB-3111-AU-003) of 20 patients with R/R MZL treated with zanubrutinib, at a median follow-up of 27.1 months, the ORR was 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Presented here are initial efficacy and safety data in patients with R/R MZL enrolled in the MAGNOLIA trial (BGB-3111-214). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adult patients requiring systemic treatment for R/R MZL who had previously received one or more lines of therapy including at least one CD20-directed regimen. All patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR as determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: In total, 68 patients were enrolled and treated. The median age was 70 years (range, 37-95), with 28% aged ≥75 years. MZL subtypes included extranodal (mucosa-associated lymphoid tissue) in 38%, nodal in 38%, splenic in 18%, and unknown in 6% of patients. The median number of prior therapies was 2 (range, 1-6), and 35% of patients had disease refractory to last therapy. At a median follow-up of 6.8 months (range, 1.6-12.8), 67 patients were evaluable for efficacy. Investigator-assessed ORR (CR + PR) was 60% (CR 15%, PR 45%, stable disease 27%). Responses were observed in all MZL subtypes, with an ORR of 58%, 64%, 58%, and 50% in extranodal, nodal, splenic, and unknown subtypes, respectively. CR rate was 23% for extranodal MZL, 12% for nodal, and 50% for unknown subtype. CR was not observed in patients with splenic MZL. The median DOR and median PFS were not reached. Twenty-one (30.9%) patients discontinued study treatment. Treatment discontinuation was mainly due to disease progression (16 patients; 23.5%); 1 withdrew consent, 2 required prohibited medications, and 2 due to adverse events (AEs) - 1 from pyrexia (later attributed to disease transformation) and 1 from myocardial infarction. The most common treatment-emergent AEs reported in ≥10% of patients were diarrhea (19.1%), bruising (17.6%), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%). Most AEs were low grade. Neutropenia was the most common grade ≥3 AE (7.3%). Treatment-related serious AEs included atrial flutter, pyrexia, pneumonia, and thrombocytopenia (1 patient each). One patient with pre-existing coronary artery disease died from myocardial infarction, which was assessed as unrelated to zanubrutinib. All-grade AEs of interest included neutropenia (10.3%), thrombocytopenia (10.3%), and atrial flutter (1.5%). To date, no major hemorrhage, serious opportunistic infection, or tumor lysis syndrome have been reported. Conclusion: Preliminary results of this phase 2 study suggest that zanubrutinib is active in R/R MZL, with a favorable safety profile. (NCT03846427) Disclosures Opat: Beigene: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Epizyme: Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tedeschi:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy. Linton:The Christie NHS Foundation Trust and The University of Manchester: Current Employment; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria. McKay:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Beatson West of Scotland Cancer Centre: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Gilead, Takeda, and Janssen: Other: For lectures etc. Hu:Kite: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectar: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Beigene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chan:Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Browett:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; University of Auckland: Current Employment; BeiGene: Research Funding. Coleman:BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding. Sobieraj-Teague:Flinders Medical Centre: Current Employment; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ke:Peking University Third Hospital: Current Employment. Sun:Institute of Hematology and Blood Disease Hospital,Chinese Academy of Medical Sciences and Peking Union of Medical College: Current Employment. Marcus:Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding. Zhou:Henan Cancer Hospital: Current Employment. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Co:BeiGene: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Wang:BeiGene: Current Employment. Tankersley:Clovis Oncology, Inc: Ended employment in the past 24 months; BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zhou:BeiGene: Current Employment, Current equity holder in publicly-traded company; Beth Israel Deaconess Medical Center: Ended employment in the past 24 months. Cappellini:BeiGene Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; BeiGene Aus Pty. Ltd.: Current Employment. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Trotman:BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for MZL in the US

Description: Background Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Advancing age is associated with greater vulnerability, increasing treatment side effects and reduced survival with chemoimmunotherapy (CIT). Comorbidities burden, Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS) scores emerged as reliable tools in trials with patients (pts) receiving CIT. Ibrutinib changed CLL treatment paradigm. Nevertheless, adverse events leading to dose reductions and discontinuations are frequent in everyday practice. Finally, it is still unclear whether age, ECOG and comorbidities retain a predictive value with ibrutinib and if number and types of concomitant medications may interfere with treatment outcome. Methods This multicenter retrospective analysis evaluated 712 pts in 15 Italian centers treated with ibrutinib from March 2014 to May 2020. We analyzed the impact of age (6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG (0-1 vs 〉1) and CCI (6, CIRS3+, ECOG 〉1 and CCI ≥2, showed to be significant for tox-DTD. All parameters except age ≥ 65y had an impact on PDR. ECOG 〉1 was the only parameter affecting PFS, EFS and OS (p6 negatively influenced PFS and EFS but not OS. In pts stratification according to age, only in the elderly CIRS 〉6 was significant for tox-DTD (p 0.009), PDR (p1 and CIRS〉6 were the only fitness-related parameters affecting both PFS and EFS; the influence of ECOG was significant for tox-DTD and OS also (Table 2). CCI ≥2 had an impact on PDR only. Baseline neutropenia also influenced pts tox-DTD and all survival outcomes. Treatment with CYP3A4 inhibitors/inducers was independently associated with higher PDR. Pts outcome in terms of EFS, PFS and OS was also significantly dependent on number of previous lines of treatment (0 vs 1-2 vs ≥3) and presence of del17p/TP53 mutation (not shown in table 2). Ibrutinib PDR did not affect PFS and OS, while OS was significantly reduced in pts definitively discontinuing treatment due to toxicity (p 6. ECOG〉1 significantly affected pts outcome. Furthermore, CIRS〉6 was associated with shorter EFS and PFS in elderly. In the Cox regression hazards model ECOG and CIRS〉6 were the only fitness-related factors influencing outcome. Baseline neutropenia also emerged as a parameter significantly affecting both treatment management and survival outcomes. Disclosures Tedeschi: Abbvie: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ciolli:Abbvie: Research Funding; Janssen: Honoraria. Reda:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses. Murru:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Vitale:Janssen: Honoraria. Di Raimondo:Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen, Takeda, Novartis: Honoraria; GILEAD, Incyte: Research Funding. Montillo:F. Hoffmann-La Roche: Honoraria, Research Funding; AbbVie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria.

Description: Background : Ibr is an established standard of care in CLL and is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit in randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). The synergistic combination of Ibr + Ven (oral inhibitor of BCL2) has been shown to mobilize and clear CLL cells from multiple disease compartments leading to deep responses, providing a rationale to evaluate time-limited treatment (Jain et al. NEJM 2019). CAPTIVATE (PCYC-1142) is a multicenter phase 2 study (NCT02910583) of first-line Ibr + Ven with 2 cohorts: Minimal Residual Disease (MRD) and Fixed-Duration (FD). For both cohorts, patients (pts) received 3 cycles of Ibr lead-in followed by 12 cycles of combined Ibr + Ven. Pts in the MRD cohort were randomized by MRD status to placebo or further treatment. In the pre-randomization phase of the MRD cohort, Ibr + Ven resulted in high rates of undetectable MRD (uMRD) in both peripheral blood (PB; 75%) and bone marrow (BM; 72%), with concordant uMRD results in 93% of pts with matched samples (Tam, ASH 2019). We present primary results from the MRD-guided randomization phase of the MRD cohort, evaluating whether this regimen allows for treatment-free remission in the setting of uMRD. Methods : Pts

Description: Background: Zanubrutinib is a highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. Zanubrutinib has been associated with improved specificity and durable clinical responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; Tam, Blood 2019;134:851-9). Early clinical data from Arm C of the SEQUOIA trial suggested that zanubrutinib was active and well-tolerated in treatment-naïve (TN) CLL/SLL patients with the high-risk characteristic deletion of chromosome 17p13.1 [del(17p)] (Tam ASH 2019 #499). In that cohort, an overall response rate (ORR) of 92.7% was reported, and the most common adverse events (AEs; 20.1% contusion, 15.6% upper respiratory tract infection, 13.8% rash) and most common grade ≥3 AEs (10.1% neutropenia, 3.7% pneumonia, 2.8% hypertension) were consistent with those in previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Venetoclax is a B-cell lymphoma 2 protein (BCL-2) inhibitor approved for the treatment of adult patients with CLL or SLL. Results of several phase 2 CLL trials of BCL-2 inhibitor and BTK inhibitor combinations have suggested that combination treatment is tolerable and may have synergistic activity (Hillmen JCO 2019;37:2722-9. Jain, NEJM 2019;380:2095-103. Siddiqi, EHA 2020 #S158.). Combination treatment given for a finite duration as determined by undetectable minimal residual disease (uMRD) is of significant interest and has the potential to alter the CLL/SLL treatment landscape if shown to induce deeper responses with a fixed duration of therapy. In the BOVen study, zanubrutinib was given in combination with venetoclax and obinutuzumab to TN CLL patients, and uMRD in the peripheral blood and bone marrow was used to determine treatment discontinuation (Soumerai, ASCO 2020 #8006.) Preliminary data showed that 62% of patients met the uMRD endpoint and successfully discontinued treatment after a median of 8 months (6 months of triplet therapy), and 100% of patients had a best response of partial response or higher (43% complete response/complete response with incomplete marrow recovery). The most common grade ≥3 AEs (15.4% neutropenia, 5.1% thrombocytopenia, 5.1% lung infection, 2.6% infusion-related reaction, 2.6% rash, 2.6% bleeding) were consistent with those previously reported in combination treatment studies, and no events of tumor lysis syndrome (TLS) were reported. Study Design and Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of up to 50 TN patients with del(17p) CLL/SLL. Arm D is designed to provide combination treatment of zanubrutinib and venetoclax and use serial monitoring of uMRD to determine treatment discontinuation. Patients are treated with zanubrutinib (160 mg twice daily) for 3 months followed by the combination of zanubrutinib (same dosing) and venetoclax (ramp-up cycle followed by 400 mg once daily). Combination treatment is given for 12-24 cycles until disease progression, unacceptable toxicity, or requirements for uMRD at 7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib and venetoclax combination therapy will be assessed, including the risk of TLS at baseline and before initiation of venetoclax. Responses will be assessed by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56. Cheson, JCO 2012;30:2820-2) and for SLL per Lugano criteria (Cheson, JCO 2014;32:3059-68). Secondary endpoints include ORR, progression-free survival, duration of response, rate of uMRD4 at various time points, safety, and pharmacokinetics of zanubrutinib and venetoclax. Exploratory endpoints include overall survival, patient-reported outcomes, and time to recurrence of detectable MRD after discontinuation of zanubrutinib and/or venetoclax. Recruitment began in November 2019 and is ongoing in 8 countries. Figure 1 Disclosures Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Flinn:Novartis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Research Funding; Forty Seven: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Curis: Research Funding; Calithera Biosciences: Research Funding; Karyopharm Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Loxo: Research Funding; Celgene: Research Funding; MorphoSys: Consultancy, Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Forma Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; ArQule: Research Funding; Agios: Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Tedeschi:Department of Hematology Niguarda Hospital Milano: Current Employment; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy. Ferrant:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Research Funding; Acerta: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AstraZeneca: Honoraria, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BioGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; UCB: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Momenta: Consultancy; Takeda: Consultancy; Octapharma: Honoraria; Morphosys: Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; Pfizer: Research Funding. Ghia:Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Kuwahara:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Hua:BeiGene USA Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Agios Pharmaceuticals Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vertex: Current equity holder in publicly-traded company. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Description: Background : Ibrutinib is a once-daily Bruton's tyrosine kinase inhibitor approved in the US and EU as either a single-agent therapy or in combination with rituximab (R) for treatment of patients (pts) with Waldenström's macroglobulinemia (WM) across all lines of therapy. In the phase 3 iNNOVATE study (PCYC-1127; NCT02165397), ibrutinib demonstrated superior progression-free survival (PFS) in combination with R (IR) vs placebo plus R in pts with WM after a 26.5 mo median follow-up in the primary analysis (Dimopoulos, N Engl J Med 2018). After a 30.4 mo median follow-up, IR continued to show superiority over R in treatment-naive (TN) and previously treated pts with WM, regardless of genomic factors (Buske, ASH 2018). Here, we present results from the final analysis of the randomized arms of iNNOVATE. Methods : Pts with confirmed symptomatic WM requiring treatment were randomized to once-daily ibrutinib 420 mg or placebo plus R (375 mg/m2/week IV at weeks 1-4 and 17-20). Pts could be TN or previously treated; pts with prior R therapy had to have achieved at least a minor response (MR) to their last R-based regimen. Endpoints included PFS and response rates per Independent Review Committee (IRC), overall survival (OS), hemoglobin (Hgb) improvement, time to next treatment (TTNT), and safety. Results : Of the 150 pts randomized (75 per arm), baseline characteristics were well balanced between arms. Median follow-up was 50 mo (range 0.5+ to 63). Median PFS was not reached (NR; 95% CI 57.7 mo to not estimable) with IR vs 20.3 mo (95% CI 13.0-27.6) with R (hazard ratio [HR] 0.25 [0.15-0.42]; P

Description: We performed gene expression profiling (GEP) of 36 patients with Waldenström's Macroglobulinemia (WM), 13 subjects with Monoclonal Gammopathy of Uncertain Significance (IgMMGUS), and 7 healthy subjects (CTRLs) by Affymetrix GeneChip Human Genome U133 Plus 2.0. GEP was performed on 36 WM bone marrow (BM) CD19+ cells vs. 10 IgMMGUS BM CD19+cells vs. 7 CTRLs BM CD19+ cells. We analyzed 32 WM BM CD138+ cells vs. 10 IgMMGUS BM CD138+ cells vs. 7 CTRLs BM CD138+ cells by microarray. Data was preprocessed and normalized using RMA and ComBat and analyzed using Statistical Analysis for Microarrays (SAM) on 3 groups and a false discovery rate threshold of 5%, followed by a pair-wise SAM test. We found 2038 and 29 unique genes in the comparison between WM, IgMMGUS and CRTLs in CD19+ and CD138+ cells, respectively. There were 16 differently expressed (DE) genes in common between the CD19+ and the CD138+ cells. Genes were grouped accordingly to the following patterns of differential expression: 1) WM〉MGUS〉CTRL, 2) WM

Description: Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL per modified iwCLL criteria (Blood 2008;112:5259; J Clin Oncol. 2012;30:2820) and for SLL per Lugano criteria (J Clin Oncol. 2014;32:3059). Results : As of 15 Apr 2020 (data cutoff), median follow-up was 18.2 mo (range, 5.0-26.3) for the 109 pts enrolled; 97 pts (89.0%) remained on treatment with zanubrutinib. The best overall response rate (ORR) was 94.5% (3.7% complete response [CR] or CR with incomplete bone marrow recovery, 87.2% partial response [PR], 3.7% PR with lymphocytosis, 4.6% stable disease, 0.9% progressive disease). Five pts (4.6%) met clinical CR criteria but did not undergo bone marrow biopsy. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not reached. Estimated 18-mo PFS (Figure), 18-mo DoR, and 18-mo OS were 88.6% (95% CI, 79.0-94.0), 84.0% (95% CI, 67.5-92.6), and 95.1% (95% CI, 88.4-97.9), respectively. Investigator-reported transformation occurred in 5 pts (4.6%), of whom 4 had histologic confirmation. Median time to transformation was 13.6 mo (time to transformation for each pt: 3.9, 7.0, 13.6, 13.8, and 15.7 mo). In an exploratory analysis, 37.2% and 26.7% of pts with evaluable karyotypes had at least 3 or 5 distinct karyotypic abnormalities, respectively; no differences in ORR or PFS were observed between pts with or without complex karyotype. With extended follow-up, adverse events (AEs) reported in ≥10% of treated pts included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%). Grade ≥3 AEs occurring in 〉2% of pts included neutropenia/neutrophil count decreased (12.9%) and pneumonia (3.7%). AEs of interest (pooled terms) included infections (64.2%), bleeding (47.7%; 5.5% grade ≥3 or serious), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Skin tumors were reported in 9.2%, and non-skin second malignancies were reported in 4.6% of pts. Three pts (2.8%) reported an AE of atrial fibrillation or flutter of which 2 events occurred in the setting of sepsis. Four pts (3.7%) discontinued zanubrutinib due to AEs (including pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury [in the context of disease progression]), of which 2 pts have died. Three additional pts died, 2 due to disease progression and 1 from sepsis after progression. No sudden or unknown deaths were reported. Conclusions : Extended follow-up of zanubrutinib monotherapy in TN CLL/SLL pts with del(17p) showed the durability of responses in this high-risk cohort, with an estimated 18-mo PFS of 88.6% and estimated 18-mo OS of 95.1%. Zanubrutinib was generally well tolerated, with low rates of discontinuation due to AEs. These data support the potential utility of zanubrutinib in the frontline management of pts with high-risk disease. Disclosures Brown: TG Therapeutics: Consultancy; Sunesis: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Verastem: Consultancy, Research Funding; Kite: Consultancy; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Sun: Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy; Juno/Celgene: Consultancy. Robak:Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Pfizer: Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; GSK: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; UTX-TGR: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Ghia:Novartis: Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Walker:Alfred health: Current Employment; Peninsula Health: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Janowski:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Chan:Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Shadman:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta Pharma: Ended employment in the past 24 months; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding. Laurenti:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opat:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Ciepluch:Copernicus Wojewodzkie centrum Onkologii: Current Employment. Verner:Cilag Pty Ltd: Research Funding; Concord Repatriation General Hospital: Current Employment; Janssen: Research Funding. Šimkovič:University Hospital Hradec Kralove: Current Employment; Acerta Pharma: Consultancy; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Österborg:Sanofi: Consultancy; Kancera: Current equity holder in publicly-traded company, Research Funding; BeiGene: Research Funding; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Trněný:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Blombery:Invivoscribe: Honoraria; Janssen: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Yin:BeiGene: Current Employment, Current equity holder in publicly-traded company; Arcus Biosciences: Current equity holder in publicly-traded company; Cornell University: Patents & Royalties: A genetically modified mouse model, licensed to pharmaceutical companies. Feng:BeiGene: Current Employment, Current equity holder in publicly-traded company. Ramakrishnan:BeiGene: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US