Abstract: 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 & gt;6 and/or an estimated creatinine clearance & lt;70 mL/min were randomized 1:1 to receive chlorambucil or venetoclax (216 pts per treatment group) until completion of cycle 12, and in combination with obinutuzumab for the first 6 cycles. The primary endpoint was progression-free survival (PFS), MRD was a secondary endpoint. Peripheral blood (PB) samples for MRD were taken at cycle 7, 9, and 12, and then serially every 3 months. In pts with a treatment response, MRD in bone marrow (BM) was assessed at cycle 9 and 3 months after end of treatment (EOT). MRD was analyzed by quantitative immunoglobulin allele-specific real-time (IGH-ASO)-PCR (cut-off: 10-2 and 10-4) and additionally by next-generation sequencing (NGS, Adaptive Clonoseq assay, cut-off: 10-4, 10-5 and 10-6). Outcome was analyzed according to known MRD risk groups i.e. detectable (≥10-4) and undetectable ( & lt;10-4) as well as to known clinical and biological risk factors. Landmark PFS and time to MRD re-detection from EOT were analyzed using Kaplan-Meier methodology. Apart from re-detection to MRD level ≥10-4, pts with a competing event (including progression of disease, relapse, new CLL therapy, and death) also counted towards the MRD re-detection events total. Results On the basis of the intention-to-treat population (i.e. for the full trial population and irrespective of sample availability), VenG achieved higher rates of undetectable MRD at EOT compared with chlorambucil and obinutuzumab (ClbG) (PB: 75.5% vs. 35.2%, BM: 56.9% vs. 17.1%). In contrast, detectable MRD in PB was found in 19 (8.8%) VenG pts and 103 (47.7%) ClbG pts. Of these, 11 (5.1%) VenG vs. 47 (21.8%) ClbG pts had intermediate MRD at ≥10-4- & lt;10-2 and 8 (3.7%) vs. 56 (25.9%) pts had high positive MRD at cut-off 10-2. Of the 19 VenG pts with detectable MRD, 64.3% had unmutated IGHV, 22.2% had a TP53 disruption and 17.6% had a complex karyotype. In pts with undetectable MRD in PB, the rate of complete response at EOT was higher with VenG than with ClbG (55.8% vs. 40.8%, Table 1). Achieving undetectable MRD in PB with VenG was associated with a high proportion of patients with corresponding BM clearance of 74.8% with only 4.9% of pts being BM MRD-detectable. In addition, depth of MRD response measured by NGS was more profound in VenG compared to ClbG ( & lt;10-5: 67.6% vs. 19.9%, & lt;10-6: 42.1% vs. 6.5%) with undetectable MRD according to both NGS and IGH-ASO-PCR at cut-off 10-4 in 74.5% of pts treated with VenG and an overall concordance between both methods of 95.4%. Considering pts with undetectable MRD in PB at EOT, the time to MRD re-detection was longer with VenG than with ClbG (median 17.7 months and 34 (20.9%) re-detection events with VenG vs. median 7.5 months and 55 (72.4%) re-detection events with ClbG, HR 0.192, 95% CI 0.124-0.296). In landmark analysis from EOT, undetectable MRD correlated with favourable PFS rates at 24 months as compared with detectable MRD: 89.1% vs. 61.9% in VenG and 93.9% vs. 32.6% in ClbG, respectively. Median PFS was not reached in undetectable MRD groups (Figure 1a). Further landmark analysis of PFS by MRD status showed that undetectable MRD translated into improved PFS regardless of the clinical response status at EOT (Figure 1b). Conclusion Fixed-duration treatment with VenG achieves unprecedentedly high and sustainable rates of undetectable MRD in patients with previously untreated CLL and coexisting conditions. Findings confirm the prognostic value of MRD assessment at EOT for this chemotherapy-free treatment regimen. Due to high concordance of undetectable MRD in PB and BM in the context of VenG, BM assessments may not be required for these patients. Disclosures Fischer: Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. 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. Tandon:Roche: Equity Ownership; Roche Products Ltd: Employment. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: travel grants. Stübig:Hexal: Speakers Bureau. Brüggemann:Amgen, Celgene, Janssen: Honoraria, Speakers Bureau; Amgen, Janssen: Membership on an entity's Board of Directors or advisory committees; affimed, Amgen, Celgene, Regeneron: Research Funding; Amgen, Incyte, PRMA: Consultancy. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Schary:Abbvie: Employment, Equity Ownership. Eichhorst:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; 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; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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. Wendtner:MorphoSys: Consultancy, Honoraria, Research Funding; GILEAD Science: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kreuzer:Roche and Abbvie: Honoraria, Other: Expert testimony. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genentech, Inc.: Research Funding. Goede:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, Speakers Bureau; janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; Janssen-CILAG: Honoraria, Other: Travel grants, Research Funding; Roche: Honoraria, Research Funding; Genentech: Research Funding; Becton Dickinson: Research Funding; Novartis: Research Funding. Stilgenbauer:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.

Abstract: 7502 Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score 〉 6 and/or an estimated creatinine clearance 〈 70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles (C) of standard Clb or Ven 400 mg daily in combination with G for first 6 C. Primary endpoint was PFS. MRD− in peripheral blood (PB) or bone marrow (BM) 3 months (mo) after treatment completion was a key secondary endpoint. MRD was analyzed serially from C4 every 3 mo by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10 -4 ) and by next generation sequencing (NGS; cut-offs, 10 -4 , 10 -5 ,10 -6 ). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P 〈 0.0001). MRD− by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P 〈 0.0001]) and BM (57% vs 17% [P 〈 0.0001]) 3 mo after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD− was associated with longer PFS. Higher MRD− rates were achieved early and were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 mo after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off-treatment: 19 mo). MRD− rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD− at 〈 10 -4 , 31% vs 4% at 〈 10 -6 and 35% vs 15% at ≥10 -6 – 〈 10 -5 , respectively. Conclusions: Fixed-duration VenG induced deep ( 〈 10 -6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.

Abstract: Introduction CLL11 is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities, i.e. patients typically treated in daily practice. Here, we present: (i) The final stage 2 analysis with efficacy and safety results of the head-to-head comparison between GA101 plus Clb (GClb) and rituximab plus Clb (RClb); at the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board. (ii) An update on the stage I analysis (GClb vs. Clb and RClb vs. Clb comparisons) with longer observation time; the final stage 1 analysis recently showed that GClb or RClb has superior efficacy to chemotherapy with Clb alone. Methods Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score 〉 6 and/or an estimated creatinine clearance (CrCl) 〈 70 mL/min were eligible. Patients received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progression-free survival (PFS). Response rates, minimal residual disease (MRD), and overall survival (OS) were key secondary efficacy endpoints. Results Final results of the stage 2 analysis: Median observation time was 19 months. The GClb and RClb treatment arms were well balanced for baseline characteristics. Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 63 mL/min respectively. Key efficacy and safety results are shown in the table. The PFS benefit of GClb over RClb was supported by all pre-planned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with MRD negative blood samples at end-of-treatment was more than 10-fold higher with GClb compared with RClb (63/214 [29.4%] vs. 6/243 [2.5%] ). Grade 3-4 infusion-related reactions with GClb occurred at first infusion only. Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p 〈 .0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p 〈 .0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached. Conclusions GA101, a novel, glycoengineered, type II CD20 antibody, in combination with Clb (GClb regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with RClb in previously untreated CLL patients with comorbidities. Infusion-related reactions and neutropenia were more common with GClb without an increase in infections. Furthermore, GClb vs. Clb alone demonstrated a prolongation of OS. Overall, GClb is superior to RClb and a highly active treatment in this typical CLL patient population. Disclosures: Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Fischer:Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Engelke:F. Hoffmann-La Roche: Travel grants Other. Eichhorst:Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Wendtner:F. Hoffmann-La Roche: Consultancy, Research Funding. Dilhuydy:F. Hoffmann-La Roche: Consultancy. Opat:F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Owen:F. Hoffmann-La Roche: Honoraria. Kreuzer:F. Hoffmann-La Roche: Consultancy, Honoraria. Langerak:F. Hoffmann-La Roche: Research Funding. Ritgen:F. Hoffmann-La Roche: Research Funding. Stilgenbauer:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Asikanius:F. Hoffmann-La Roche: Employment. Humphrey:F. Hoffmann-La Roche: Employment. Wenger:F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Abstract: We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL). Patients and Methods In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m 2 on days 1 and 2 combined with 375 mg/m 2 rituximab on day 0 of the first course and 500 mg/m 2 on day 1 during subsequent courses for up to six courses. Results Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.