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Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

PURPOSE Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS ALPINE (ClinicalTrials.gov identifier: NCT03734016 ) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/ TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, aIn patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).

We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies.This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437.Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6).Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib.BeiGene.

7044 Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine (Aza) or decitabine (Dec) is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients (pts) who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated Ven + HMA in an inpatient setting due to concerns of tumor lysis syndrome (TLS). This Phase 3b, single-arm, multicenter, open-label study (NCT03941964) evaluated the efficacy and safety of Ven + HMA in a US community-based outpatient setting. Methods: Pts with ND AML who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Pts received Ven (400 mg) in combination with Aza (75 mg/m2) or Dec (20 mg/m2) for up to 6 cycles during the study period. Pts could continue receiving commercially acquired Ven after the study period. All pts received TLS prophylaxis. The primary endpoint was the composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) per modified International Working Group criteria. Secondary endpoints included CR or CRi rates and transfusion independence (TI). TLS was assessed per Howard criteria (Howard. N Engl J Med. 2011;364:1844). Results: At the 19 Oct 2021 cutoff date, 60 pts were enrolled and treated (Ven + Aza, n=30; Ven + Dec, n=30). Efficacy outcomes are shown in the Table. The composite CR rate was 58%. CR and CRi rates were 13% and 45%, respectively. Most pts (>50%) maintained TI, and 41% and 57% of pts dependent on red blood cells or platelets, respectively, converted to TI. Bone marrow blast clearance was achieved in 42 pts (70%) at a median 26 days after treatment initiation. The most common (≥50%) AEs were anemia (75%), neutrophil count decrease (55%), white blood cell count decrease (52%), and nausea (50%). Serious AEs occurred in 67% of pts, most commonly (≥15%) febrile neutropenia (28%) and sepsis (15%). Two pts (3%) had TLS; neither event led to treatment discontinuation. Of pts who achieved blast clearance, 12/42 (29%) had a new event of myelosuppression post-blast clearance and prior to the next cycle. Conclusions: The results of this US community-based study indicate that Ven + HMA is an effective treatment option for pts with ND AML and, with appropriate TLS prophylaxis and monitoring, can safely be initiated in an outpatient setting. Clinical trial information: NCT03941964. [Table: see text]