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: 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: Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts 〈 65 yrs and ≥ 65 yrs. While there was a significant difference in pts 〈 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p 〈 0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p 〈 0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p 〈 0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

Abstract: Introduction: In chronic lymphocytic leukemia (CLL), improved anti-CD20 antibodies such as obinutuzumab (GA101) and targeted drugs, such as ibrutinib, show very good efficacy and tolerability. With the CLL2-BIG trial, the German CLL Study Group designed a regimen composed of obinutuzumab and ibrutinib for induction and maintenance therapy. Patients with high tumor burden receive bendamustine as debulking resulting in the proposed "sequential triple-T" concept [Hallek M., Blood 2013] of a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD). Here we present the results of the primary endpoint analysis of the trial. Methods : This prospective, open-label, multicenter phase-II trial investigates the efficacy and safety of a novel regimen for physically fit and unfit CLL patients (pts) requiring treatment, irrespective of high-risk genetics. 62 pts were to be recruited according to a predefined allocation for the two strata of first-line and relapse/refractory treatment. Six cycles of induction treatment with obinutuzumab and ibrutinib were administered followed by maintenance therapy with continuous ibrutinib and obinutuzumab every three months until achievement of an MRD-negative complete remission or up to 24 months. Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5cm received two cycles of bendamustine before start of induction. The primary endpoint is overall response rate (ORR) three month after the start of last induction cycle administered; secondary endpoints include ORR after debulking, MRD evaluations and safety parameters (graded per the NCI CTCAE v.4 criteria). Results: 66 pts were enrolled between January and August 2015. Five pts completed less than two cycles of induction and were therefore excluded from the full analysis set as defined by protocol. The current analysis includes 58 pts; an update including all 61 pts will be available for presentation at the meeting. The median age was 65.5 (range 36-83) years and the median time since initial diagnosis was 56.2 (2.1 - 222.8) months. 27 pts were treatment-naïve and 31 relapsed/refractory with a median of one prior treatment line (1-5). Baseline characteristics are summarized in table 1. 41 pts (71%) received bendamustine debulking, of these 27 pts (66%) responded; five pts (12%) achieved clinical complete remission (CR), 3 pts (7%) clinical CR with incomplete recovery of the bone marrow (CRi) and 19 pts (46%) partial remission (PR). 57 pts completed six cycles of induction treatment. One patient died after the fifth course due to grade 5 duodenitis related to study therapy. The combination showed promising efficacy with an ORR of 100% by investigator assessment at the end of induction. Statistically, the primary endpoint was met and the null hypothesis could be rejected. Response rates are presented in table 2. 27 pts (47%) achieved MRD negativity ( 〈 10-4 by flow cytometry) in peripheral blood (pB) at the end of induction. An intermediate MRD-status (≥ 10-4 and 〈 10-2) was found in 15 pts (26%) whereas 13 pts (22%) were MRD positive (≥ 10-2). In three pts (5%) no MRD sample was available. So far, 38 pts (65%) received at least one dose of maintenance treatment; one patient already stopped treatment due to MRD negativity as defined per protocol. CTC Grade 3-4 adverse events occurred in 19 pts (33%) during induction therapy. The most common toxicities observed are shown in table 3. *The table includes all grade 3-4 AEs regardless of frequency and AEs of any grade observed in at least six patients. Conclusion: With an ORR of 100% and an MRD negativity rate of 47% in the pB the BIG-regimen showed a very good efficacy in a heterogeneous study population. No major toxicity occurred so far. Table 1. Demographics and baseline characteristics Table 1. Demographics and baseline characteristics Table 2. Response rates Table 2. Response rates Table 3 Safety Table 3. Safety Disclosures von Tresckow: Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Celgene: Other: Travel grants; Hoffmann-LaRoche: Other: Travel grants, Research Funding. Cramer:Astellas: Other: Travel grants; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; GlaxoSmithKline/Novartis: Research Funding; Gilead: Other: Travel grants, Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Mundipharma: Other: Travel grants. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Engelke:Hoffmann-LaRoche: Other: Travel grants. Langerbeins:Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: Travel grants, Research Funding; Mundipharma: Honoraria, Other: Travel grants, Research Funding. Fink:Mundipharma: Other: Travel grants; Celgene: Other: Travel grants, Research Funding; AbbVie: Other: Travel grants; Hoffmann-LaRoche: Other: Travel grants. Illmer:Hoffmann-LaRoche: Honoraria, Other: travel grants. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fischer:Hoffmann-LaRoche: Other: Travel grants. Wendtner:Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding. Böttcher:AbbVie: Honoraria, Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Hallek:Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract: Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P & lt; .01]; HR, 2.7 [P & lt; .01], respectively) and VenG (HR, 4.4 [P & lt; .01]; HR, 3.1 [P & lt; .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.

Abstract: BACKGROUND: Minimal residual disease (MRD) negativity is one of the strongest predictors of outcome after first-line treatment with chemoimmunotherapy. Likewise, persisting MRD-positivity defines patients (pts) with chronic lymphocytic leukemia (CLL) at a high risk of short overall survival (OS). A cross‐trial comparison of randomized, phase 3 data allows an OS analysis of high risk pts over time. METHODS: Here we present an analysis of OS for high risk pts enrolled in the CLL8, CLL10 and CLLM1 trials of the German CLL Study Group (GCLLSG). High risk was defined as either MRD positivity (≥ 10-2) in the peripheral blood after at least partial response to first-line treatment with chemoimmunotherapy or intermediate MRD level ( 〈 10-2 and ≥ 10-4) combined with either TP53 alterations or unmutated IGHV gene status. High risk pts meeting the criteria as defined above with previously untreated CLL and without relevant comorbidities enrolled in the FCR-Arm of CLL8 (between 2003 and 2006), CLL10 (between 2008 and 2011) and CLLM1 (between 2012 and 2016) studies of the GCLLSG were eligible for this analysis. Pts enrolled in CLL8 and CLL10 received up to 6 cycles of chemoimmunotherapy with fludarabine, cyclophosphamide plus rituximab (FCR) or bendamustine plus R (BR). Pts enrolled in CLLM1 were randomised (2:1) to receive lenalidomide or placebo after first-line therapy consisting of at least four cycles of FCR or BR. Details on subsequent therapies will be presented at the conference. Overall survival was defined as the time from the start date of first-line therapy to the date of death; censoring was at longest follow-up. Estimation for overall survival was done with Cox regression method and Kaplan-Meier survival curves. FINDINGS: A total of 204 (CLL8, n=40 pts; CLL10, n=79 pts; CLLM1, n=85 pts) high risk pts were included in this analysis. Median observation time for the entire cohort was 59.9 months (interquartile range: 50.6-71.7). Overall, 71% of the pts are still alive, 45% of the pts in CLL8; 68% of the pts in CLL10 and 86% of the pts in CLLM1. Patient characteristics are shown in table 1. Median age was 62 years. 80% of the pts were male. Deletion of 17p was an exclusion criterion for CLL10 and was present in 15.4% of CLL8 and 9.3 % of the CLLM1 pts. TP53 mutation was not analysed for CLL10, and found in 23% (CLL8 and CLLM1) of the pts. Overall, 92.3% of the pts had an unmutated IGHV gene status. 58% of the pts had a high or very high CLL-IPI (Table 1). As per inclusion criterion for this analysis, all pts were MRD-positive, with 34.8% of a high MRD level and 65.2% of an intermediate level. Overall survival was shorter for CLL8 with a median of 63.7 months as compared to not reached in CLLM1 (HR 4.107, 95% CI: 1.983-8.141). Median overall survival for CLL10 was not reached, but shorter than the OS in CLLM1 as well (HR, 2.492, 95% CI: 1.251-4.963). Five-year survival rates were between 56% (CLL8), 68% (CLL10) and 82% (CLLM1) respectively. (Figure 1a). As compared to FCR pts in CLL8, pts in CLLM1 assigned to the lenalidomide (HR: 0.281, 95% CI: 0.129-0.612) and the placebo group (HR: 0.186, 95% CI: 0.056-0.623) had an OS advantage. As compared to CLL10 BR the OS advantage was shown for pts assigned to the lenalidomide group (HR: 0.414, 95% CI: 0.181-0.947) and the placebo group (HR: 0.274, 95% CI: 0.079-0.947) as well. (Figure 1b) INTERPRETATION: This analysis demonstrated an improvement for overall survival in patients with high risk CLL included in the CLLM1 study as compared to pts in the CLL8 and CLL10 trials of the GCLLSG. So far, the results suggest that progress in maintenance therapy or subsequent use of novel agents (BTK or PI3K inhibitors) may improve the outcome of high-risk CLL patients initially treated with chemoimmunotherapy. Disclosures Fink: Roche: Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Kutsch:Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Wendtner:GILEAD Science: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Kreuzer:Roche: 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; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Other: travel grants, Research Funding. Böttcher:Roche: Honoraria, Research Funding; Janssen-CILAG: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Other: Travel grants, Research Funding; Genentech: Research Funding; Becton Dickinson: Research Funding; Novartis: Research Funding. Fischer:Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hallek:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GILEAD Science: 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, Other: Travel grants, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding, Speakers Bureau. Eichhorst: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; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; ArQule: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide is not indicated as a maintenance therapy after immunochemotherapy in patients with CLL.

Abstract: Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle–associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.

Abstract: The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib, and venetoclax (GIVe regimen) in 41 previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of GIVe; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and with detectable minimal residual disease. The primary end point was the complete remission rate at cycle 15, which was achieved at 58.5% (95% CI, 42.1-73.7; P  & lt; .001). The last patient reached the end of the study in January 2022. After a median observation time of 38.4 months (range, 3.7-44.9), the 36-month progression-free survival was 79.9%, and the 36-month overall survival was 92.6%. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8%, grade ≥3) and infections (19.5%, grade ≥3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% between cycles 1 and 12, as well as hypertension (4.9%) between cycles 1 and 6. The incidence of adverse events of any grade and grade ≥3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycles 27 and 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile.