Abstract: INTRODUCTION Chronic lymphocytic leukemia (CLL) is frequently associated with an impaired humoral and cellular immunity. On a global scale chemoimmunotherapy (CIT) has remained one of the most frequently used treatment option. Thus, patients (pts) may experience further cytopenia, particularly treatment-related neutropenia, increasing the risk of infections. In order to better characterize incidence, characteristics and outcomes of infections during and after therapy, a pooled analysis of phase II and III German CLL Study Group trials was performed. METHODS Data of first line pts from 5 clinical trials (CLL7, pts treated with fludarabine, cyclophosphamide, rituximab [FCR]; CLL8, FC vs FCR; CLL10, FCR vs bendamustine-rituximab [BR] ; CLL11, chlorambucil [CLB] vs CLB-R vs CLB-Obinutuzumab [CLB-Ob] and CLL2M, BR) were analyzed. Clinical, laboratory, genetic and event-related data were pooled. Infections defined as severe (CTC grade 3-5) from initiation of therapy until 4 weeks after completion of study treatment were considered related. Due to varying reporting periods for infections of the respective trials later events of infections were not included. Kaplan-Meier curves for landmark overall survival (OS) from completion of study treatment plus 4 weeks were plotted and compared by non-stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard regression modelling. RESULTS Data from 2,291 pts receiving at least one dose of CIT were pooled. Median observation time was 71.7 months, ranging between 43.7 months (CLL2M) and 81.0 months (CLL10). Seven-hundred and twenty-seven pts received FCR, 396 pts FC, 395 pts BR, 116 pts CLB, 326 pts CLB-R and 331 pts CLB-Ob. Overall, 274 severe grad 3/4/5 infections were reported in 229 pts (10.0% of 2,291 pts). Of those 189 pts (82.5%) had max. grade 3 infections, 22 (9.6%) pts had grade 4 infections and 18 (7.9%) pts died due to infectious complications. Median time to severe infection from start of treatment was 1.8 months (IQR 0.9-3.6), with a median number of infectious episodes per patient of 1 (range 1-4). Thirty-one (13.5%) of 229 pts had bacterial infections, 35 (15.3%) viral infections, 5 (2.2%) fungal infections and 172 (75.1%) unspecified infections. Higher grade (i.e. ≥ CTC grade 3) leukopenia and/or neutropenia was reported in 121 (52.8%) pts with severe infections. Eighty-eight (12.1%) of FCR treated pts had severe infections, followed by BR 45 (11.4%), CLB 12 (10.3%), FC 35 (8.8%), CLB-Ob 25 (7.6%) and CLB-R 24 (7.4%). Median age was 64 years in the entire cohort; no differences between pts with and without infections were observed with regards to age, sex, ECOG or creatinine clearance. Molecular and cytogenetic characteristics (deletion 17p, deletion 11q, trisomy 12) and IGHV status were similarly distributed between both groups. Median neutrophil count at enrolment was 4.4x10-9/l in both groups, respectively. Prior to therapy, levels of immunoglobulin were comparable between pts with and without infections (median IgG 7.0 vs 7.5 g/L, IgM 0.3 g/L vs 0.3 g/L). Also, pts with at least one episode of ≥ CTC grade 3 leukopenia/neutropenia had comparable rates of severe infections to pts without higher grade leukopenia/neutropenia (147 [53.6%] vs 127 [46.4%] pts). No differences were observed between pts with or without infections regarding the response to first line treatment (183 pts [79.9%] with complete response or partial response to treatment vs 1715 pts [83.2%] ) as well as the rate of undetectable minimal residual disease levels (50 [21.8%] vs 477 [23.1%] ). Overall survival from 4 weeks after completion of study treatment was significantly shorter in pts with severe infections compared to pts without severe infections (median 73.7 months vs 97.3 months, HR 1.503, 95% CI 1.217-1.856, p & lt; 0.001). CONCLUSION This analysis confirms that prognosis of CLL pts who received first line treatment with (immuno)chemotherapy is influenced by severe infections. This risk does not correlate with the explored cyto- or molecular genetic risk factors, nor with response to treatment, pre-therapeutic levels of immunoglobulins or occurrence of higher grade neutropenia. Pts who experience severe infections have a significantly shorter overall survival compared to pts without severe infections. Due to their vulnerability, careful management of infectious complications in CLL pts is warranted. Figure 1 Disclosures Al-Sawaf: AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: personal fees; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees. Fink:Janssen: Honoraria; Celgene: Research Funding; AbbVie: Other: travel grants. Cramer:F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Beigene: Research Funding; Novartis: Consultancy, Research Funding; Gilead: Other: travel support, Research Funding; AbbVie: Honoraria, Other: travel support. Herling:Roche: Other: Travel support, Research Funding. Von Tresckow:Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Celgene: Other: travel grants; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; AbbVie: Honoraria. Böttcher:Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Dreyling:Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Infinity: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; True North: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Gregor:Roche: Honoraria; Mundipharma: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria. Ritgen:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; Gilead: Other: travel grants. Dürig:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Tausch:AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria. Goede:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Eichhorst:Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding. Langerbeins:AbbVie: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; Mundipharma: Honoraria, Other: travel grants, Research Funding.

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: 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.

Abstract: Introduction The BCL-2 inhibitor venetoclax has yielded promising results in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), both as monotherapy and in combination with rituximab. The CLL14 trial is a prospective, open-label, multicenter randomized phase III trial to compare the efficacy and safety of obinutuzumab and venetoclax with obinutuzumab and chlorambucil in patients with previously untreated CLL and coexisting medical conditions. Prior to opening the randomized phase, a run-in phase was performed to assess the tolerability of obinutuzumab and venetoclax in this particular patient population. Here, we report the final results on safety and efficacy of this run-in phase. Method The protocol specified to enroll 12 previously untreated patients with confirmed CLL and with coexisting medical conditions assessed by cumulative illness rating scale (CIRS) total score 〉 6 and/or estimated creatinine clearance (CrCl) 〈 70 mL/min requiring treatment according to iwCLL criteria into the run-in phase. All patients received 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously with 100 mg on day 1, 900 mg on day 2 (option to deliver 1000 mg on day 1), 1000 mg on day 8 and day 15 of cycle 1 and 1000 mg on day1 for cycles 2-6. A gradual weekly dose ramp-up of venetoclax with 20 mg, 50 mg, 100 mg, 200 mg up to 400 mg was administered starting at day 22 of cycle 1. Risk assessment for tumor lysis syndrome (TLS) based on absolute lymphocyte count and tumor burden was performed before treatment in order to direct prophylactic measures. Study defined stopping criteria for all 12 patients included: one treatment-related death or one grade 4 adverse event related to a clinical tumor lysis syndrome (TLS) despite protocol-specified prophylaxis. Adverse events were graded per the NCI CTCAE v.4 criteria. Final response to treatment including assessment for minimal residual disease (MRD) in peripheral blood by ASO-PCR was assessed per the iwCLL guidelines 3 months after the end of treatment, at month 15. Results Between December 2014 and April 2015, 13 previously untreated patients from Australia, Canada, Germany, New Zealand, United States and Spain were enrolled into the trial. Baseline patient characteristics are summarized in Table 1. The median age was 75 years (range 59 - 88) and 62% of the patients were classified as Binet stage C; 38% of the patients were assessed at medium risk and 62% at high risk for TLS. One patient developed a grade-4 infusion related reaction (IRR) during the first dose of obinutuzumab and was therefore withdrawn from the trial according to the protocol requirements. Eleven of 12 patients completed treatment. One patient discontinued treatment after 6 cycles of obinutuzumab and venetoclax and 2 additional cycles of venetoclax due to patient´s wish. All patients experienced at least one adverse event. The commonest adverse events are summarized in Table 2. No clinical TLS was reported. At month 15, 11 of 12 patients were evaluable for final response assessment. All patients responded to therapy. Complete remissions occurred in 7 of the 12 patients including one complete remission with incomplete bone marrow recovery. Ten of 12 patients had no detectable ( 〈 10-4) minimal residual disease (MRD) in peripheral blood and one patient was assessed intermediate (≥10-4 〈 10-2). At month 15, there were no events of disease progression or deaths, translating into an estimated progression-free survival of of 100%. Conclusions The treatment regimen developed for the experimental arm of the CLL14 trial comprising obinutuzumab monotherapy for one cycle followed by venetoclax and obinutuzumab in previously untreated, elderly patients with CLL and coexisting medical conditions appears well tolerated and effective. The target population in this trial consists of elderly patients with clinically meaningful comorbidities in addition to CLL. None of the protocol defined stopping safety criteria for the run-in phase of the trial were met. The treatment induced substantial responses with an unprecedentedly high number of MRD negative responses seen in all but one evaluable patients including those with poor prognostic features. The main phase of the CLL14 trial was opened in August 2015 and completed recruitment in August 2016 after 432 patients had been randomized. Disclosures Fischer: Hoffmann-LaRoche: Other: Travel grants. Al-Sawaf:Gilead: Other: Travel grants. Fink:AbbVie: Other: Travel grants; Mundipharma: Other: Travel grants; Celgene: Other: Travel grants, Research Funding; Hoffmann-LaRoche: Other: Travel grants. Dixon:Roche Products Limited: Employment, Equity Ownership. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Warburton:Roche UK: Employment. Kipps:Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria. Weinkove:Avalia Immunotherapies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants; Janssen: Honoraria; Capital & Coast District Health Board: Employment; Malaghan Institute of Medical Research: Employment; Health Research Council of New Zealand: Research Funding; Australasian Leukaemia & Lymphoma Group: Membership on an entity's Board of Directors or advisory committees. Robinson:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Consultancy; Lundbeck: Consultancy; Gilead: Consultancy. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Owen:Pharmacyclics: Research Funding; Janssen: Honoraria; Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria. López:Novartis: Consultancy; Abbvie: Consultancy; Merck Sharp & Dohme: Consultancy; Janssen: Consultancy; Roche: Consultancy; Gilead: Consultancy. Humphrey:Genentech, Inc.: Employment. Humerickhouse:AbbVie: Employment. Tausch:Amgen: Other: Travel support; Gilead: Other: Travel support, Speakers Bureau; Celgene: Other: Travel support. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Wendtner:Genetech: Consultancy, Honoraria, Research Funding; Hoffmann‐La Roche: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Munipharma: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen‐Cilag: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding. Langerak:F. Hofmann-LaRoche, Genentech: Research Funding; InVivoScribe Technologies: Patents & Royalties: Royalties are provided to European Network (EuroClonality). Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Boettcher:Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding. Goede:Roche: Consultancy, Honoraria, Other: Travel grant, Research Funding; GlaxoSmithKline: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mobasher:Genentech, Inc.: Employment. Hallek:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: 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; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract: Introduction: The GCLLSG has demonstrated the efficacy of a sequential therapy with bendamustine followed by obinutuzumab (or GA101; G) and ibrutinib (I) according to a "sequential triple-T" concept [Hallek M., Blood 2013] using a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD) in CLL [von Tresckow J, Leukemia 2019] . Here we present the results of the final analysis of the CLL2-BIG trial after the end of maintenance therapy. Methods: This phase-II trial investigated 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 (1L) and relapse/refractory (RR) treatment. Six cycles of induction therapy with G and I were administered followed by maintenance therapy with continuous I and G 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 were scheduled to receive two cycles of bendamustine before start of induction. The primary endpoint was the overall response rate 3 months after the start of last induction cycle administered; secondary endpoints included the best response rate, MRD evaluations as well as survival and safety parameters (graded per the NCI CTCAE v.4 criteria). Results: 66 pts were enrolled. Five pts completed less than two cycles of induction therapy and were therefore excluded from the full analysis set as defined by study protocol. Patient characteristics are shown in Table 1. Of note, half of the pts had received prior therapies and two thirds had a high/very-high CLL-IPI. At the end of induction, ORR was 100% and 29 pts (47.5%) achieved MRD-negativity ( 〈 10-4 by 4-color-flow cytometry) in peripheral blood (PB), as previously published. 59 of 61 pts (96.7%) started maintenance therapy. Response is shown in Figure 1 and was improved in 16 pts, with 6 pts (9.8%) achieving a complete remission (CR) or CR with incomplete recovery of the bone marrow (CRi) and 55 pts (90.2%) a PR by iwCLL criteria, including 54.1% patients who were lacking a bone marrow biopsy or CT scan but fulfilled all other criteria for CR/CRi (clinical CR). 42 pts (71.2%) were MRD negative in PB at the last staging during maintenance therapy. 11 pts discontinued maintenance therapy early due to AE (6 pts (10.2%)), progressive disease (PD), refusal of further treatment (2 pts (3.4%) each) or physician´s decision (1 pt (1.7%)). 15 pts (25.4%) completed 24 months and 33 pts (55.9%) stopped due to MRD negativity after a median time of 15.6 months on study. PFS and OS are shown in Figures 2 and 3. In 1L pts 4 PD (13.3%) and no deaths occurred while among RR pts 8 PD (25.8%) and 7 deaths were reported (3 due to infections, 2 due to progression of CLL, 1 due to comorbidity and 1 due to infection and unknown cause). Among pts who stopped treatment due to MRD negativity, 5 pts relapsed after a median duration of 16.4 months off treatment and 1 pt died after 8.7 months, respectively. During maintenance therapy, no grade 5 AE occurred. 151 (45.5%) of 332 CTC grades 1 - 4 AE were deemed as related to study drugs. Due to AE, I was dose modified in 26 pts (44.1%), G in 1 pt (1.7%). All grade 3-4 toxicities observed are shown in Table 2. Conclusion: The depth of response of the BIG regimen can be improved by maintenance therapy with I and G, leading to a rate of undetectable MRD in the PB in 71.2% of pts. Among 33 pts who discontinued treatment due to MRD negativity only 5 pts relapsed and 1 pt died so far. The data demonstrate that the BIG protocol using an MRD guided concept for treatment discontinuation yields very good results, in particular in 1L CLL pts. Disclosures Von Tresckow: Celgene: Other: Travel support; AbbVie: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding. Cramer:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Other: travel support, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Roche: Honoraria, Other: travel support, Research Funding; mundipharma: Other: travel support. Langerbeins:Mundipharma: Other: travel support; Roche: Honoraria, Other: travel support; Janssen: Honoraria, Other: travel support, Research Funding; AbbVie: Honoraria, Other: travel support; Sunesis: Honoraria. Fink:Celgene: Research Funding; Roche: Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees. 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. Illmer:Roche: Other: travel support. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. 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. Fischer:Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wendtner:Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kreuzer: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; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: travel support; Becton Dickinson: Honoraria; Celgene: Other: tavel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Eichhorst:Novartis: Consultancy, 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; 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hallek:AbbVie: Honoraria, 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; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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. OffLabel Disclosure: Obinutuzumab (GA101) is not registered for Treatment of relapsed/rferactory CLL