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CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

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

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 Conclusions : With up to 5 years of follow-up, IR showed ongoing superiority across clinical outcomes in pts with WM regardless of genotype, prior treatment, and key pt characteristics. Patterns of response with IR were similar for both TN and previously treated pts. IR maintained a manageable safety profile, with no new safety signals identified and minimal increases in common AEs after an additional 24 months of follow-up. Disclosures Buske: Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, Bayer, MSD: Research Funding; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. 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; Sunesis: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trotman:BeiGene: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Celgene: Research Funding. García-Sanz:Amgen: Honoraria; Novartis: Consultancy; Janssen: Honoraria, Other: Travel/accommodations/expenses; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses; IVS (Biomed 2-Euroclonality): Patents & Royalties: and other intellectual property; Gilead: Other: Research grants, Research Funding. MacDonald:AstraZeneca: Honoraria; Janssen: Honoraria; Roche Canada: Consultancy, Honoraria. Leblond:AbbVie: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Amgen: Honoraria; Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding, Speakers Bureau; Lilly: Consultancy. Herbaux:Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Janssen-Cilag: Honoraria. Matous:Pharmacyclics LLC, an AbbVie Company: Consultancy; Celgene: Consultancy, Honoraria. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Heffner:Amgen: Research Funding; Pfizer: Research Funding; Kite: Research Funding, Speakers Bureau; Gilead: Research Funding; Biotest: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Palomba:Novartis: Honoraria; Evelo: Honoraria; Jazz Pharmaceuticals: Honoraria; Therakos: Honoraria; Amgen: Honoraria; Kite: Honoraria; Seres Therapeutics: Current equity holder in publicly-traded company, Honoraria, Patents & Royalties: and other intellectual property; Flagship Ventures: Honoraria; Merck: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria; Juno: Patents & Royalties: and other intellectual property. Shustik:Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Kastritis:Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Pfizer: Consultancy; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Treon:Pharmacyclics LLC, an AbbVie Company, Janssen, and BeiGene: Consultancy, Other: Travel/accomodations/expenses, Research Funding; Bristol-Myers Squibb: Research Funding; Janssen: Consultancy, Other: Travel/accomodations/expenses; Biogene: Consultancy, Other: Travel/accomodations/expenses. Ping:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Hauns:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie: Current equity holder in publicly-traded company. Arango-Hisijara:AbbVie: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

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.

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.

Individuals with bleeding disorder diagnoses require developmentally sensitive care across the lifespan, particularly as they gain knowledge and skills necessary to successfully tackle their illness-specific needs as independent adults (Breakey et al., 2010). The current study describes one phase of a larger quality improvement (QI) initiative aimed at improving transition from pediatric to adult care (TAC) at one US Hemophilia and Thrombosis Center (HTC). Our aim was to assess the feasibility of delivering transition specific education to youth-caregiver dyads during youth annual multidisciplinary clinic appointments. Youth-caregiver dyads were selected given previous research revealing that both patients and their parents express worries about related to TAC (Geerts et al., 2008). Education included discussion of the knowledge and skills necessary for autonomous management of one's bleeding disorder (e.g., illness basics, treatment, communication, and healthy living). During an 8-month period, 101 youth-caregiver dyads were approached. Patients were between the ages of 12 and 25 (M age = 17.66, SD = 3.45). Approximately half of patients were diagnosed with hemophilia A (53.5%) and 16.8% were female. Of the 101 patients approached, 90 completed the transition education discussion. On average, these discussions took 12.80 minutes (SD = 8.49) and ranged from 5 to 50 minutes. Social work delivered the bulk of these discussions (78.7%) and spent an average of 10.61 minutes (SD = 5.76) with youth and caregivers. While the intention was to deliver transition education to youth-caregiver dyads, this only occurred in 37 discussions. Other discussions included the patient only (n = 31), caregiver only (n = 20), or had missing data (n = 1). In instances when a youth-caregiver dyad was approached, but a discussion did not take place, barriers to completing the discussion were identified. "Provider" was listed most frequently (n = 5) as a barrier (e.g., youth sent home by medical team prior to transition discussion occurring; miscommunication between members of multidisciplinary team; low staffing of those trained to deliver transition discussion). Even in instances when a transition discussion did take place, barriers to having the discussion were identified. "Patient" barriers were the most frequently listed (n = 13), followed by barriers related to "Time" (n = 11), and barriers related to "Clinic" (n = 3). At the end of the transition discussion, youth and/or caregivers were encouraged to identify a goal for improving their skills or knowledge in one of the four areas discussed during their appointment. Of those having transition discussions, 72 created a transition goal. The majority of participants reported goals related to Treatment (e.g., infusion skills; n = 36) followed by goals related to Communication (n = 18), Healthy Living (n = 11), and Bleeding Disorder Basics (n = 7). There was a statistically significant difference in the type of goal of expressed by youth and/or caregivers when the patient was 17 years old or younger vs those older than 18, X 2 (3, N = 72) = 9.49, p = 0.024. Generally, more youth reported goals related to Treatment (e.g., infusion skills) than predicted by chance in both age groups. Patients or patient caregivers were contacted via phone between 5 and 14 months following their transition discussion. Approximately 1/3 of the patients who completed transition discussion, responded and provided ratings on progress toward meeting their transition goal. Ratings (M = 4.24, SD = 2.63) were made on a Likert-type scale ranging from 1 (no progress made) to 10 (maximum progress made). The information gleaned from this QI initiative revealed that delivery of transition-specific education within the CU-HTC annual multidisciplinary appointments is feasible and in some cases, served as the impetus necessary for accomplishing transition-specific goals. The results from this initiative have been instrumental in subsequent transition-related efforts related to: (a) fostering full engagement across the multidisciplinary team in TAC efforts utilizing HEMO-Milestones Tool (Croteau et al., 2016); (b) adopting specific materials developed to assess TAC in individuals with bleeding disorder diagnoses (i.e., American Society of Hematology Hemophilia Transition Readiness Assessment); and (c) reducing time between patient goal-setting and follow-up from the HTC. Disclosures Wang: Novo Nordisk: Consultancy, Other: Clinical trial investigator; Bioverativ: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy, Other: Clinical trial investigator; Octapharma: Other; uniQure: Consultancy, Other: Clinical trial investigator; Pfizer/Spark: Other: clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; BioMarin: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial investigator. Buckner: CSL Behring: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; Genetech: Honoraria; Bayer: Honoraria; Spark: Honoraria; Sanofi: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; BioMarin: Consultancy, Honoraria; Takeda: Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; uniQure: Consultancy, Honoraria.