ALBERT

Description: Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or CLL/SLL suggests that zanubrutinib has been generally well tolerated amongst pts with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data in pts with treatment-naïve (TN; n=22) or relapsed/refractory (R/R; n=56) CLL/SLL showed that zanubrutinib was highly active: 96.2% overall response rate (ORR), including 4.5% and 1.8% with complete response in TN and R/R CLL/SLL, respectively (Tam et al. Blood 2019). Study Design and Methods: This ongoing phase 3, randomized, global study (ALPINE; NCT03734016) is designed to compare the efficacy of zanubrutinib to ibrutinib based on ORR in pts with R/R CLL/SLL (Figure). This open-label study randomizes approximately 400 pts 1:1 to each arm, stratified by age (〈 65 vs ≥ 65 years), refractory status (yes vs no), geographic region (China vs other), and del(17p)/TP53 mutation status (present vs absent). The study population includes adult pts who have had prior treatment for their CLL/SLL and were either refractory to or relapsed from prior CLL/SLL treatment. Major inclusion criteria include R/R CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) criteria, disease measurable by computed tomography/magnetic resonance imaging, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematologic function. Major exclusion criteria include prior treatment with a BTK inhibitor, current or past history of Richter transformation, clinically significant cardiovascular disease, or history of severe bleeding disorder. Zanubrutinib is dosed at 160 mg twice daily, and ibrutinib is dosed per label at 420 mg daily; treatment in both arms may continue until progression. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for pts with CLL and per 2014 Lugano Classification for pts with SLL. The study is powered to test the non-inferiority, and subsequently the superiority, of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, ORR as determined by investigator, safety, duration of response, overall survival, and pt-reported outcomes. Exploratory endpoints include the correlation between clinical outcomes and prognostic and predictive biomarkers. Recruitment began in November 2018 and is ongoing in 14 countries. Disclosures Hillmen: Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S. Eichhorst:BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lamanna:Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Ming: Research Funding; Infinity/ Verastem: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Regeneron: Research Funding; Eisai: Consultancy; Celgene: Consultancy; Aptose Biosciences, Inc: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy. Salmi:BeiGene: Employment. Hilger:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Description: Abstract 205 Introduction: Bendamustine has shown considerable activity in monotherapy for lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging results have also been obtained using the BR combination treatment in previously treated CLL. This multicenter phase II trial (CLL2M) is the first study assessing the efficacy and toxicity of bendamustine in combination with rituximab in previously untreated CLL patients (pts). Patients and Methods: Between March 2007 and September 2008 117 pts with untreated CLL requiring therapy were enrolled into the protocol. Bendamustine was given at a dose of 90 mg/m2 on day 1 and 2, combined with 375 mg/m2 rituximab for the first cycle and 500 mg/m2 for subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for analysis by fluorescence in situ hybridization (FISH), the IgVH mutational status and expression of ZAP70/CD38. Minimal residual disease (MRD) was evaluated in peripheral blood and bone marrow by 4-color flow cytometry. Results: Data on the entire study population of 117 pts (median age 64 years) with a total of 583 treatment cycles are available. As of June 2009 the median observation time was 15.4 months (mo). 11.1% of the pts presented with stage Binet A, 41.0% with Binet B and 47.9% with Binet C disease. A mean number of 5.0 courses were delivered. 114 pts were evaluable for toxicity, 110 for response and 113 for progression free survival (PFS). The most frequent adverse events based on 583 treatment cycles were myelosuppression and infections: grade 3/4 anemia occurred in 4.9%, grade 3/4 leukopenia in 14.6%, grade 3/4 neutropenia and thrombocytopenia in 6.5% and 6.1% of all given courses, respectively. 29 episodes of CTC grade 〉3 infections were documented (5.1% of all courses). Treatment related mortality occurred in 2.6% of the pts: one liver failure after attempt of suicide with antihistamines, one fatal pneumonia and one sepsis in neutropenia. The overall response rate was 90.9% with 32.7% (36 pts) clinical complete remissions (CR). A nodular partial remission (nPR) was achieved in 2.7% (3 pts) and a partial response (PR) in 55.5% of the pts (61 pts), respectively. 9.1% of the pts (10 pts) had stable disease (SD) whereas none of the pts was progressive (PD). After 18 mo 75.8% of the pts were still in remission, median PFS has not been reached. An MRD level below 10E-4 was observed after completion of therapy in 29 of 50 evaluable pts in peripheral blood, while 7 of 25 pts achieved MRD negativity in bone marrow. Differences in response were observed among the genetic subgroups: 19 of 21 pts with 11q- achieved a remission with 10 PR and 9 CR (ORR: 90.5%). Accordingly, 17 of 19 patients with +12 responded (14 PR, 3 CR, ORR: 89.5%). In the high-risk group with 17p-, 3 of 7 pts showed a partial response (ORR: 42.9%). 56 of 63 pts (ORR: 88.9%) with unmutated IgVH status responded to BR. Conclusion: Bendamustine plus rituximab (BR) is effective and safe in the first-line treatment of CLL. Major side effects (myelosuppression and infections) were infrequent. Based on these encouraging phase II data the German CLL Study group is presently investigating the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) in the first-line treatment of CLL within a randomized phase III trial (CLL10 protocol). Disclosures: Fischer: Roche: travel expenses. Cramer:Roche: travel grants. Stilgenbauer:Bayer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Fink:Roche: . Boettcher:Roche: Research Funding. Ritgen:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Döhner:Roche: Research Funding. Eichhorst:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Hospira: Honoraria. Hallek:Roche: Consultancy, Honoraria, Research Funding. Wendtner:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Schering: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Key Points Prognostic tool for CLL patients with high discriminatory power compared with conventional clinical staging systems. Prognostication on the individual patient level independent of clinical stage.

Description: The CLL4 trial evaluated 1st line treatment with F or FC among 375 CLL patients up to 65 years (Eichhorst et al., Blood, 2006). Updated follow-up (median 52.8 months (mo) for alive patients) revealed 50.4% events for progression-free survival (PFS) and 24.5% for overall survival (OS). Comparing the treatment arms, significant differences were observed in favor of FC for CR (19.9% vs 5.9%, p7% in 47.9%. β2-MG and TK (both n=261) were 〉5 mg/L in 13.8% and 〉 10U/L in 73.0%, respectively. The distributions of these biologic markers and the major clinical characteristics (age: median 59 (42–65) years, sex: 73.1% male, stage: Binet A 9.2%, B 55.4%, C 35.4%, LDH 〉 250U/L: 39.2%, lymphocytes 〉 50/nl: 57.1%, comorbidities 〉1: 21.4%, and creatinine clearance were not significantly different between treatment arms. Outcome was analyzed for subgroups defined by the clinical and biologic parameters in univariate analyses for the entire population (i.e. both treatment arms combined). PFS was significantly shorter for 11q-, 17p- (Fig.1), TP53 mutation, elevated TK and LDH. OS was significantly shorter for the same parameters and unmutated VH, elevated β2-MG, and 〉1 comorbidities. All except 2 patients with 17p- had TP53 mutations. There were 13 additional cases with TP53 mutation without 17p-. OS was similarly poor for TP53 mutation without 17p- as compared to 17p- and all other cases (OS at 48 mo: 25.9%, 21.4%, and 84.6%, respectively, p7% (p=.011), and β2MG

Description: Purpose Although minimal residual disease (MRD) is an established surrogate marker for outcomes following treatment with chemoimmunotherapy, less is known about the value of MRD in chemotherapy-free treatments in the first-line setting. We investigated the prognostic value of MRD detection after a fixed-duration treatment of venetoclax plus obinutuzumab (VenG) with respect to clinical and genetic risk factors and source of material in previously untreated patients (pts) with CLL and coexisting conditions. Methods In this multinational, open-label, Phase 3 trial, 432 previously untreated pts with a Cumulative Illness Rating Scale score 〉6 and/or an estimated creatinine clearance

Description: Introduction: Staging of CLL is based on simple methods to estimate the prognosis of CLL at the time point of diagnosis. Both, the Rai and Binet staging systems, are based on physical examination and peripheral blood count. According to the recently updated IWCLL guidelines for CLL (Hallek et al., Blood, 2008) no radiological examinations are needed for staging and response evaluation outside clinical trials. Previously, it was shown that CT scans add no benefit to the response criteria defined by the National Cancer Institute (NCI) (Byrd et al., 2007). However, it is still unclear, how much additional information can be gained by using CT scans by routine at pretherapeutic evaluation and during follow-up phase. Therefore the GCLLSG initiated a metaphase analysis based on the results of three phase III studies (CLL4, CLL5 and CLL8 protocol of the GCLLSG), in order to evaluate the clinical relevance of CT scans on disease outcome. Patients: A total of 1372 patients (pts) receiving first line therapy for CLL within a phase III trial of GCLLSG were included in this analysis. 362 pts younger than 65 years were included in the CLL4 trial, 193 pts older than 64 years in the CLL5 trial and 817 pts with normal renal function and a comorbidity score ≤ 6 were included in the CLL8 trial. 100 pts received chlorambucil, 257 fludarabine (F), 590 F plus cyclophosphamide (FC) and 408 FC plus rituximab. Response as well as progression during later follow-up was assessed according to the NCI-WG criteria (Cheson et al., Blood 1996). CT scan or other radiological examinations were not performed by routine, but were recommended at pretherapeutic staging, interim and final staging and during the follow-up phase, if clinically indicated. Results: The median follow up time for pts alive in the CLL4 trial was 54 months (mo), 40 mo in CLL5 and 27 mo in CLL8 (overall 31 mo). During follow-up a total of 11.103 CT scans, 22.728 ultrasounds as well as 2.350 chest x-rays were performed in 1372 pts. In contrast, 59.742 physical examinations were performed either additionally to radiological examination or alone. In a first step we evaluated the number of pts for whom the radiological examination was crucial in order to reconcile progressive disease (PD) according to the NCI criteria. A total 491 pts were considered as progressive during treatment or follow-up. In 100 pts the definition of PD by the treating physician could not be confirmed by a strict, independent application of the NCI-WG criteria and were therefore excluded from the analysis. In the remaining 391 pts PD was clinical apparent in 326 (83%), while CT scans were relevant for the decision of PD in 39 pts (10%) only and ultrasound in 26 pts (7%). In a next step we assessed the number of pts for whom CT scan or ultrasound had a clinical consequence by initiating relapse treatment because of bulky disease (defined as a lymph node of 〉 5 cm) in the thorax or abdomen. Out of 176 pts receiving relapse treatment due to PD, in only 2 pts (1%) the retreatment decision was based on the result of the CT scan or ultrasound: in these pts a new bulk was detected by radiological examination, while physical examination and blood count were normal. Moreover, an initially detected bulky disease by radiological examination had no prognostic value as well. Pts with initially detected bulky disease showed a higher rate of complete remissions in comparison to pts without bulky disease (29% versus 22%, p = 0.02). Interestingly, no difference in overall response rates (86% versus 89%, p = 0.2), as well as progression free survival (36 versus 39 months, p = 0.2) and overall survival (OS) (median OS not reached vs. 85 months, p = 0.08) was assessed. Conclusion: These data from 1372 patients included in three prospective phase III trials show that the use of CT scans has no apparent clinical benefit for the evaluation of PD or the decision to initiate relapse treatment in the follow-up phase of CLL. In 1% of the relapse treatment receiving pts only the result of the CT scan was crucial for retreatment decision. Moreover, the initial detection of bulky disease by CT scan or ultrasound had no prognostic impact. Our data suggest that physical examination and blood count remain the methods of choice for clinical follow-up of patients with CLL.

Description: Introduction: Alemtuzumab has shown considerable activity in both relapsed/refractory chronic lymphocytic leukemia (CLL) and frontline treatment setting. In a prior randomised phase III trial we have demonstrated that consolidation with alemtuzumab significantly improves progression-free survival and the rate of molecular remissions in CLL patients after fludarabine based chemotherapy. However, significant toxicity including severe infections were observed. This ongoing phase I/II trial investigates the maximum tolerated dose (MTD) of alemtuzumab consolidation in patients with CLL after 2nd line chemotherapy. Methods: 12 patients (pts) in complete or partial remission after induction chemotherapy with either fludarabine plus cyclophosphamide (FC) or fludarabine plus cyclphosphamide plus rituximab (FCR) were eligible to receive alemtuzumab consolidation 90 to 150 days after last chemo infusion. Alemtuzumab was administered in 2 different cohorts either intravenously (iv, cohort A) or subcutaneously (sc, cohort B), once weekly for 8 weeks. Dose escalation was started with 10 mg iv/sc and increased in 10 mg intervals per dose level, each dose level including a minimum of 3 pts. All pts received standard premedication and infection prophylaxis. Blood samples were taken to determine pharmacokinetics in week 4 and 8. MRD was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry at week 8 and 3-monthly thereafter. Results: 10 pts (median age 68 years) in complete or partial remission (1 CR, 1 nPR, 8 PR) after FC/FCR were treated with alemtuzumab in cohort A. Due to 2 dose limiting toxicities (DLT) at dose level 2 (20 mg iv, 1 FUO requiring iv antibiotics, 1 exacerbated erythema exsudativum multiforme) the MTD of alemtuzumab was determined at 10 mg iv. In cohort B, so far 2 patients (1 CR, 1 PR) have been treated with 10 mg alemtuzumab sc and no DLT has been observed. Besides the 2 DLT overall toxicity was tolerable in both cohorts with 8 CTC grade III cytopenias reversible in less then 2 weeks, 1 FUO and 2 subclinical CMV reactivations. All infections were successfully treated. After the last dose of alemtuzumab (week 8) the clinical response status of 4 pts converted from PR to CR. Up to a median follow up of 22 months 3 pts presented with PD, 2 of them died due to disease progression. MRD negativity (〈 1 × 10E-4) was achieved in 3/10 pts in cohort A and 1/2 pts in cohort B. The median PFS of all pts was 19.9 months. For the majority of patients examined alemtuzumab plasma concentrations in week 4 and 8 showed rapid accumulation with stable levels after administration in the range of 100 to 300 ng/ml. Conclusion: Consolidation with alemtuzumab in CLL pts after 2nd line therapy is safe and able to achieve response improvement including MRD negativity. Dose escalation of alemtuzumab has determined a MTD of 10 mg, if administered intravenously. Ongoing trial activity is attempting to determine the MTD, pharmacokinetic and clinical efficacy of subcutaneous alemtuzumab consolidation.

Description: Introduction BCL2 is an anti-apoptotic protein overexpressed in CLL and critical in the pathogenesis of the disease; venetoclax (VEN) is an orally available, selective BCL2 inhibitor. Bendamustine (B) and rituximab (R) combination has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated (frontline, 1L) patients (pts) with CLL. Preclinical data suggest that VEN+BR may provide synergistic activity in pts with CLL. Clinical data from VEN, both as a single-agent and in combination with R, support VEN+BR combination in CLL. We report an ongoing phase 1b study (NCT01671904) that is evaluating as primary objectives the maximum tolerated dose (MTD) of VEN when combined with BR, plus safety, tolerability, and order of administration to reduce toxicities of this combination in R/R or 1L CLL pts. Methods Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts and subsequent safety expansion cohorts, ranging from VEN 100 to 400 mg/day (3+3 dose escalation design). Pts are assigned to one of two dosing schedules (Fig 1) with VEN (Schedule A) or BR (Schedule B) introduced first; both include a gradual VEN dose ramp-up and other prophylactic measures to reduce the risk of tumor lysis syndrome (TLS) and risk stratification for TLS (high, intermediate and low). On completing combination therapy, pts continue single-agent VEN until disease progression (R/R CLL) or up to 18 months (1L CLL). Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by investigators (iwCLL guidelines; Hallek et al. 2008). Results At data cutoff (April 30, 2015), 30 pts have been treated; 20 R/R pts, 12 on Schedule A (3 at 100 mg, 3 at 200 mg, and 6 at 400 mg) and 8 on Schedule B (all at 400 mg), and 10 1L pts, 6 on Schedule A and 4 on Schedule B (all at 400 mg). Baseline characteristics are shown in Fig 2. Of 10 pts with reported cytogenetics, 2 have del(17p). Median time on study is 5.5 (range, 0.03-15.2) months. No safety difference between Schedules A and B was seen in the DLT observation period for R/R CLL pts; neither schedule exhibited any toxicities precluding choice of the highest administered dose of 400 mg daily VEN. Schedule B was chosen for R/R safety expansion due to potential for tumor debulking prior to VEN. Dose finding in 1L Schedule A also selected 400 mg; dose finding for Schedule B is ongoing. Of 30 safety-evaluable, 27 (90%) pts experienced any adverse event (AEs; Fig 3). Most common AEs were neutropenia and nausea. Most G3 AEs were hematological toxicities; common non-hematological included diarrhea and hypertension. No TLS events (laboratory or clinical) were observed. There were 13 serious AEs in 10 (33.3%) pts, 8 (26.7%) due to study treatment. No deaths were reported. Of all 30 pts, 25 received VEN, with 5 still completing the BR only portion of Schedule B. Dose interruptions were seen in 13 pts mainly due to neutropenia for both VEN and BR; 8 pts had a VEN dose reduction. Early drug discontinuations (any reason): VEN, 2pts (gastroenteritis norovirus, progressive disease); BR together, 3 pts; B, 7 pts (commonly for neutropenia or physician decision); R, 1 pt. Across cohorts, 17/20 R/R CLL pts had response assessments; 100% responded, with 3 CRi. Response evaluation for 1L pts is early and evaluation across all cohorts and patients is ongoing. Full MRD data will be presented at the meeting, but early analysis shows pts exhibiting MRD negativity in peripheral blood, many as early as Cycle 4. Conclusion These early results report the first study evaluating the VEN+BR combination in pts with CLL. Daily VEN 400 mg can be safely combined with BR in patients with R/R CLL using both administration schedules (VEN or BR first), with 400 mg also established as safe for 1L pts with CLL under Schedule A. No TLS was observed with either administration schedule, despite many pts at medium (53%) or high (33%) TLS risk. VEN+BR is, as expected, associated with frequent hematologic toxicity, which appears manageable in most pts being treated, although 10 pts discontinued either B or BR prior to completing 6 cycles of administration. Early response and MRD data are promising. Disclosures Salles: Celgene Corporation; Roche: Speakers Bureau; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Boyd:Genentech, Inc.: Research Funding; Celgene: Speakers Bureau; US Oncology: Research Funding. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Wendtner:Roche: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Eichhorst:AbbVie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cartron:Gilead: Honoraria; GSK: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Li:Genentech, Inc.: Employment. Hilger:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Stilgenbauer:Roche: Honoraria, Research Funding.

Description: Introduction: FCR is still the standard frontline regimen for physically fit CLL pts without TP53 alteration. The international phase III CLL10 study demonstrated the inferiority of BR in comparison to FCR in this population. In order to evaluate long-term outcome and toxicity we performed an updated analysis after extended observation time. Methods and Patients: 561 pts were randomized as previously published (Eichhorst B et al., Lancet Oncol 2016). 282 and 279 pts were randomized to receive either 6 courses of FCR or BR respectively. After the end of treatment pts were followed 3-monthly for 2 years (yrs) and 6-monthly for 3 yrs, and afterwards annually until progressive disease (PD). After PD annual visits were documented either within the study or within the registry of the GCLLSG. Health related quality of life (HRQOL) was evaluated by using the EORTC C30 questionnaire, which was completed at baseline, after 3, 6 and 12 months and then annually until year 5. Results: After a median observation time of 58.2 months (mo) (range, 0 - 88 mo), the median progression-free survival (PFS) for FCR was 57.6 mo versus (vs) 42.3 mo for the BR arm [Hazard ratio (HR)=1.593 (95% confidence interval (CI), 1.271-1.996); p 65 yrs] (57.6 vs 42.3; p=0.134). Richter transformation (RT) was assessed as PD and occurred in 5 pts (1.8%) after FCR and 8 pts (2.9%) after BR. 77 (27.3%) pts following FCR and 108 (38.7%) following BR treatment received at least one subsequent therapy. BR was the most common second line therapy after prior FCR (42 pts), while BR re-exposure after frontline BR was performed in 31 pts. 33pts switched to FCR after BR first line therapy. So far, only 3 pts after FCR and 2 pts after BR received kinase inhibitors. 51 pts (18.1%) of the FCR arm and 54 (19.4%) pts of the BR arm deceased so far. Main cause of death in the FCR arm were secondary malignancies (14 pts; 5.0%), followed by CLL including RT (11 pts incl. 2 RT; 3.9%), infections (7 pts; 2.5%) and concomitant diseases (6 pts; 2.1%). In the BR arm CLL was the most common cause of death (15 pts incl. 6 pts with RT; 5.4%) followed by infections (12 pts; 4.3%) and concomitant disease and secondary malignancies (10 pts each; 4.3% each). Other causes of deaths were distributed similarly (incl. adverse events to frontline or relapse treatment or unknown). No differences in overall survival (OS) were observed (OS at 5 yrs, 80.9% for FCR vs 80.1% for BR; HR=1.108, 95% CI 0.755-1.627; p=0.599). The difference in OS for younger pts was statistically not significant (OS at 5-yrs 85.6% for FCR vs 81.1% for BR; p=0.119). Otherwise, 5-yrs OS was 78.8% for pts 〉 65 yrs receiving BR and 70.9% for those receiving FCR (p=0.238). Multivariate analysis identified treatment arm, male sex, high serum thymidine kinase (TK), del(11q) and unmuated IGHV status, but not age as independent prognostic factors for PFS. For OS only high serum TK and unmutated IGHV status were assessed as independent prognostic factors. Secondary neoplasia was documented in 49 (17.6%) of 279 FCR treated pts and 35 (12.5%) of 278 BR treated pts. No difference in the incidence rate of secondary solid tumors was observed between both arms (for FCR 28 (10.0%) and for BR 25 (9.1%)). Secondary MDS and/or AML occurred more frequently after FCR therapy (12 [4.3%] vs 2 [0.7%]), particularly in pts 〉65 yrs (6 [7.0%] vs 1 [0.9%]). 540 of 561 pts (96.3%) were evaluable for HRQOL analysis, 272 pts of the FCR and 268 pts of the BR arm. No differences between both arms were detected with respect to global health status or any functional or symptom scale. As compared to an age- and sex-matched normal population functional scale values were impaired mostly during treatment phase and symptom scales also during follow-up. However, after the end of therapy and during follow-up global health status was improved. Conclusion: Long-term follow-up data of the CLL10 study confirm the superiority of FCR regimen in young (≤ 65 yrs) and fit CLL patients. However, importantly these data support the recommendation of using BR in fit elderly pts. This particular group of pts had both a very good outcome after BR and compared to FCR a decreased risk of secondary MDS and/or AML. Disclosures Eichhorst: Novartis: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Maurer:Mundipharma: Other: Travel grants. Kiehl:Roche: Consultancy, Other: Travel grants, Speakers Bureau. Fischer:Roche: Other: travel grants. Kneba:Amgen: Research Funding; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants. Wendtner:Hoffmann-La Roche, Mundipharma, Janssen, Gilead, Abbvie, Servier, Morphosys: Consultancy, Other: Travle grants, Research Funding. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Kreuzer:Roche Pharma GmbH and Mundipharma GmbH: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Research Funding, Speakers Bureau. Böttcher:Celgene: Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; AbbVie: Honoraria, Research Funding. Stilgenbauer:GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding. Fink:Celgene: Research Funding; Roche: Honoraria, Other: Travel grants; Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants. Hallek:Celgene: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding.

Description: Background Chronic lymphocytic leukemia (CLL) primarily affects elderly patients, who regularly present with clinically relevant coexisting conditions. Improvement and maintenance of health-related quality of life (QoL) is an important objective of effective therapies. In the phase 3 CLL14 trial, elderly patients with CLL and comorbidities were randomized to receive either chlorambucil-obinutuzumab (ClbG) or venetoclax-obinutuzumab (VenG) over 12 cycles. In the primary analysis, treatment with VenG achieved significantly longer progression-free survival compared with ClbG (Fischer et al, 2019). Here, we report data from a longitudinal observation of patient-reported outcomes (PRO) focusing on functioning, symptoms, and QoL in patients treated in CLL14. Methods Paper PRO questionnaires were completed at each treatment cycle and every 3 months during follow-up. Disease- and treatment-related symptoms were assessed using the M.D. Anderson Symptom Inventory (MDASI) with the CLL module. Lower MDASI scores (range 0-10) indicate lower symptom severity or interference. Changes in physical functioning, role functioning, and global health status (GHS)/QoL were assessed using the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Higher scores (range 0-100) for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). All scores are given as mean values for all patients per study arm. Results At baseline, compliance was 100% for both the EORTC and MDASI questionnaires, and completion rates remained above 90% throughout treatment and 85% throughout follow-up until month 18 after completion of study treatment. Median observation time was 28.1 months. At the start of treatment, physical function (mean 75.9 [standard deviation (SD) ±20.1] in the ClbG arm and 76.9 (±19.4) in the VenG arm), role function (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms. Overall, patients reported moderate-to-high functioning and GHS/QoL, and low symptom severity, with dyspnea (21.3 [± 25.6] and 24.8 [±27.76]), fatigue (35.8 [±23.3] and 39.2 [±24.7]) and insomnia (26.9 [±29.0] and 30.8 [±30.5]) being the most severe symptoms at baseline, followed by pain (16.8 [±22.1] and 18.4 [±25.6]), appetite loss (14.7 [±23.6] and 15.6 [±26.7]), and constipation (10.9 [±20.9] and 12.8 [±23.7]). Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with VenG showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least 8 points at cycle 3, whereas less pronounced and consistent improvement was observed with ClbG at cycle 8 (Figure 1). Insomnia and fatigue scales likewise demonstrated improvement starting at cycle 3 in the VenG arm, whereas this was observed later at cycle 4 and 6, respectively, in the ClbG arm (Figures 2 and 3). According to MDASI scoring, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]), and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline. No clinically meaningful improvements or deterioration were observed for either arm during treatment and follow-up (Figure 4). Conclusion Overall, patients treated in CLL14 with either ClbG or VenG experienced no impairment to baseline physical functioning, role functioning, and global health status/QoL during treatment and follow-up, nor increase in symptom burden and interference. This status was maintained after treatment completion and into follow-up. This analysis also shows that patients treated with VenG showed earlier improvement on the GHS/QoL scale by approximately 5 months on average compared with patients treated with ClbG. Earlier relief from insomnia and fatigue was observed with VenG, as well. As elderly patients with CLL typically experience impairment of QoL, particularly when suffering from various other conditions, such improvement should be considered a main therapeutic goal. Our data confirm that rapid and sustained improvement of QoL as measured by PRO can be achieved with a tolerable, fixed-duration treatment with VenG. Disclosures Al-Sawaf: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Gentile:Genentech, Inc.: Employment. Devine:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Tandon:Roche: Equity Ownership; Roche Products Ltd: Employment. Fink:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: travel grants. Kutsch:Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding. Fischer:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: travel grants. Hallek:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, 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, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.