Abstract: Background: In early studies of venetoclax (ven) in CLL, severe tumor lysis syndromes (TLS) were observed leading to the implementation of multiple safety measures including a 5-week ramp up schedule. Since then, studies have consistently reported low rates of TLS in ven-treated patients (pts), most likely as a result of strict prophylactic and laboratory monitoring measures. Various lead-in regimens prior to the administration of ven were shown to be feasible and effective in reducing the risk of TLS in pts with CLL. However, no comparison of different pretreatment regimens has been performed so far in a prospective randomized trial. Using the set-up of the GAIA trial, we compared TLS incidence and formal TLS risk reduction between 3 different ven-based combinations. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against standard chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT (FCR in pts ≤65 years; BR in pts & gt;65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe). In RVe, GVe and GIVe, ven was added at cycle 1 day 22 (ramp up day 1) after a 21-day pretreatment with rituximab (1 dose), obinutuzumab (3 doses) or obinutuzumab (3 doses) plus ibrutinib (continuous) (Figure 1A). The safety population (i.e. all pts who received study treatment) of the ven-containing arms was used for this analysis. TLS was reported according to Cairo-Bishop criteria (Cairo M, Bishop M. Br J Haematol. 2004). For TLS risk evaluation, the most recent available CT/MRI and absolute lymphocyte count (ALC) were used. TLS risk was evaluated at baseline and at ramp up day 1, before the first dose of ven. The patients were categorized retrospectively according to the following TLS risk categories: high (any lymph node [LN] with largest diameter ≥10 cm or any LN with largest diameter ≥5 cm and ALC ≥25 G/L), intermediate (any LN ≥5 cm to & lt;10 cm or ALC ≥25 G/L), low (all LN & lt;5 cm and ALC & lt;25 G/L). Results: The safety population of all ven-containing arms comprised of 696 pts (RVe: 237, GVe: 228, GIVe: 231). Baseline TLS risk was high in 22%, 23% and 19% of pts in the RVe, GVe and GIVe arm, intermediate in 62%, 65%, 67% and low in 10.5%, 14.7% and 12.4% of pts, respectively. After the first 21 days of treatment (i.e. at ramp up day 1), the fraction of pts with a reduction in TLS risk varied between the treatment arms with 31.7% (RVe), 71.4% (GVe) and 47.3% (GIVe) of pts decreasing by at least one TLS risk category (Figure 1B). With regard to TLS risk reduction, GVe was superior to RVe (p & lt;0.001) and GIVe (p & lt;0.001) while GIVe was superior to RVe (p=0.001)). At ramp up day 1, 2 patients (1.0%) in the GVe arm versus 60 patients (29.6%) in the GIVe arm had an ALC ≥25 G/L, likely as a correlate of ibrutinib-associated redistribution of lymphocytes to the peripheral blood, readily explaining part of the difference in TLS risk reduction between GVe and GIVe. In total, 36, 30 and 19 cases of TLS occurred in 29 (12.2%), 26 (11.4%) and 19 (8.2%) pts in the RVe, GVe and GIVe arm. The majority of TLS cases were categorized as CTC grade 3 (28 [RVe], 19 [GVe] , 12 [GIVe]), only few CT C grade 4 TLS were reported (1 [RVe], 2 [GVe] , 3 [GIVe]). There were no cases of fatal TLS and no pts requiring dialysis due to TLS. In the obinutuzumab arms the majority of TLS cases occurred before ramp up day 1 (GVe: 76.7%, GIVe: 68.4%), i.e. before any venetoclax intake, in contrast 80.6% of TLS cases in the RVe arm were reported during ven ramp up (Figure 2). While there was no significant difference in the cumulative TLS incidence between the treatment arms (p=0.334), there was an increase in TLS occurring after ramp up day 1 in the RVe arm compared to GVe (p & lt;0.001) and GIVe (p=0.002). Conclusions: This analysis represents the first comparison of the formal TLS risk reduction and actual TLS incidence of different ven-based combinations in a randomized trial. GVe led to the highest TLS risk reduction, while the lowest number of TLS cases occurred in the GIVe arm. Most TLS cases in the GVe and GIVe arms occurred before the start of ven. RVe was least effective in reducing TLS risk and in contrast to the obinutuzumab-containing arms, the vast majority of TLS cases was reported during the ven ramp up. The relatively high incidence of TLS in comparison to other trials might partly be a consequence of using different reporting criteria (Cairo-Bishop vs Howard criteria). No fatal TLS occurred in any of the treatment arms. Figure 1 Figure 1. Disclosures Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: AbbVie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Jansen: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Eichhorst: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for the treatment of CLL

Abstract: Background: Venetoclax (ven)-based time-limited combination treatments have yielded high rates of undetectable MRD (uMRD) in patients (pts) with CLL. In correlative analyses, attainment of uMRD status was associated with longer progression-free survival (PFS), making uMRD a robust surrogate parameter for remission duration particularly after time-limited therapy. While MRD is usually assessed by conventional 4-color flow cytometry (FCM) defining uMRD as less than 1 CLL cell in 10 000 leukocytes ( & lt;10 -4, uMRD4), a better prognostic discrimination by more sensitive methods appears feasible. In addition to conventional 4-color FCM, we assessed uMRD5 ( & lt;10 -5) and uMRD6 ( & lt;10 -6) with high-sensitivity FCM (hsFCM) and next-generation sequencing (NGS) of immunoglobulin genes in the GAIA (CLL13) trial. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT for 6 cycles of 28 days each (FCR for pts ≤65 years; BR for pts & gt;65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe), all for 12 cycles with the option for ibrutinib continuation until cycle 36 for pts not obtaining uMRD4. The co-primary endpoints were the rate of uMRD4 at month (MO) 15 (GVe vs CIT) and PFS (GIVe vs CIT). MRD was centrally assessed by FCM at MO2, MO9, MO12 and MO15 in peripheral blood (PB) and at final restaging (RE, two months after the end of treatment) in bone marrow (BM). The following categories were used: high (≥10 -2), intermediate (≥10 -4 to & lt;10 -2), uMRD4 ( & lt;10 -4). Exploratory post hoc MRD analyses were performed by hsFCM and/or an amplicon-based one-step NGS protocol by the EuroClonalityNGS group. HsFCM data was generated by reevaluation of FCM data files and reducing the cut off for CLL events to at least 10 events in 2 of 3 MRD tubes. MRD data were evaluated with regard to categories of uMRD5 and uMRD6. Results: In total, 926 pts were randomized (CIT: 229, RVe: 237, GVe: 229, GIVe: 231). Based on the intention-to-treat (ITT) population, rates of uMRD4 in PB by FCM were 62.0% (CIT), 73.0% (RVe), 88.6% (GVe) and 88.3% (GIVe) at MO9 and 52.0% (CIT), 57.0 (RVe), 86.5% (GVe) and 92.2% (GIVe) at MO15. BM uMRD4 results at RE were 37.1% (CIT), 43.0 (RVe), 72.5% (GVe) and 77.9% (GIVe). HsFCM samples were available for 844 (MO9 PB), 863 (MO15 PB) and 744 (RE BM) pts with median limits of detection (LOD) of 1.6x10 -5 (MO9 PB), 1.4x10 -5 (MO15 PB) and 9.9x10 -6 (RE BM) that were similar between the treatment arms. With hsFCM a lower limit of detection (LOD) of ≤10 -5 was achieved in 364 (MO9) and 477 (MO15) PB samples and in 580 BM samples at RE. 480 (MO9 PB), 386 (MO15 PB) and 164 (RE BM) samples did not reach a LOD of ≤10 -5 and were thus not included in the MRD5-evaluable populations (Figure 1). Among pts with samples evaluable for MRD5 in PB at MO15, 26 of 82 (31.7%, CIT), 45 of 132 (34.1%, RVe), 81 of 131 (61.8%, GVe) and 93 of 132 (70.5%, GIVe) achieved uMRD5. BM uMRD5 rates at RE were 24.2% (23 of 95 pts), 16.1% (27 of 168 pts), 41.7% (65 of 156 pts) and 53.4% (86 of 161 pts), respectively (Figure 2A). The median MRD level at MO9 was lower in CIT, GVe, GIVe (all 1x 10 -5) compared with RVe (2x 10 -5) by hsFCM (Figure 2B). While the obinutuzumab-containing arms stayed at this low level between MO9 and MO15, median MRD levels in CIT and RVe increased to 8.9x 10 -5 (CIT) and 3.1x 10 -5 (RVe) in the same period. The different treatment arms showed distinct patterns of differential clearance of CLL in BM and PB. While the fraction of concordant MRD results between PB and BM at RE was lower in the CIT arm with 14/34 (41.2%), the ven-containing arms showed a similar compartment effect with a proportion of concordant results of 67/108 (62.0%, RVe), 70/101 (69.3%, GVe) and 71/104 (68.3%, GIVe). In 9/16 (56.3%, CIT), 23/36 (63.9%, RVe), 22/63 (34.9%, GVe) and 23/73 (31.5%,GIVe) pts who achieved uMRD5 in PB (RE) MRD was still measurable in BM. More sensitive NGS analyses and detailed correlative analyses are pending and will be presented at the conference. Conclusions: HsFCM improves MRD detection in CLL below 10 -4 in PB and BM by capturing low levels of MRD (≥10 -5 to & lt;10 -4) in samples that were assessed as uMRD4 by FCM. HsFCM was able to show differences in uMRD rates between the treatment arms more clearly than FCM. Obinutuzumab-containing arms and in particular the GIVe arm showed the highest uMRD5 rates in PB and BM. Figure 1 Figure 1. Disclosures Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for treatment of CLL

Abstract: Independent prognostic impact of biological markers, notably TP53 and SF3B1 mutations, in CLL patients requiring therapy. NOTCH1 mutation as a predictive factor for reduced benefit from the addition of rituximab to FC chemotherapy.

Abstract: Background: For fit CLL patients (pts), continuous BTK inhibitor treatment is replacing CIT as standard of care in frontline setting, particularly in pts with unfavorable prognostic factors. The time limited combinations venetoclax plus obinutuzumab (GVe) and venetoclax plus rituximab (RVe) have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed setting. For frontline therapy GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort are not yet available. The GAIA (CLL13) trial evaluated the efficacy and safety of three Ven+CD20 antibody-based regimens in comparison to CIT as a frontline treatment for fit pts with CLL and without TP53 mutation/deletion. Methods: Treatment-naïve fit (CIRS ≤6, normal creatinine clearance with ≥ 70ml/min) CLL pts requiring therapy were eligible. Based on known poor response to CIT, pts with TP53 aberrations were excluded. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pt ≤65 years: fludarabine 25 mg/m² d1-3, cyclophosphamide 250 mg/m² d1-3, rituximab 375 mg/m² d1 cycle 1 and 500 mg/m² d1 cycle 2-6; BR for pt & gt;65 years: bendamustine 90mg/m² d1-2, rituximab) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RVe], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GVe] , or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIVe] . Pts were stratified according to country, Binet stage and age (≤ 65/ & gt; 65 years). The co-primary endpoints of the trial are (1) the rate of uMRD ( & lt;10-4) by flow in peripheral blood (PB) at month 15 (MO15, GVe vs CIT) and (2) PFS (GIVe vs CIT), each with a significance level of 2.5%. The co-primary endpoint PFS will be analyzed within a pre-planned interim analysis as soon as 138 (65%) PFS events will have been reported in the GIVe and CIT arm. The co-primary endpoint analysis of uMRD per protocol was performed after the last MO15 MRD sample had been collected. In addition, comparisons regarding uMRD for all study arms were performed using a pre-specified hierarchical test sequence. Bone marrow (BM) was evaluated 3 months after end of treatment (MO9 for CIT, MO15 for all others arms) in pts with clinical CR. Key secondary endpoints as investigator-assessed responses according to iwCLL 2008 guidelines and safety were analyzed. Trial is registered at ClinicalTrials.gov (NCT02950051). Results: A total of 926 pts (CIT: 229 (150 FCR, 79 BR), RVe: 237, GVe: 229, GIVe: 231) with a median age of 61 years (range 27-84) were accrued between 12/2016 and 09/2019. The majority of pts were in advanced Binet stage (B: 37.8%, C: 35.6%) and unmutated IGHV status was present in 56%. Fourteen pts did not receive study treatment (13 FCR, 1 GVe) and were not included in the safety population. The data cut for the first co-primary endpoint analysis was February 28, 2021. The median observation time was 27.9 months. The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in ITT population was significantly higher in GVe compared to CIT: 86.5% (97.5% CI 80.6-91.1) vs 52.0% (CI 44.4-59.5; p & lt;0.0001), respectively. GIVe also showed a superior uMRD rate of 92.2% (CI 87.3-95.7) compared to CIT (p & lt;0.0001), while RVe (57.0%, CI 49.5-64.2) did not (p=0.317) (Figure 1A). Corresponding BM uMRD rates in ITT population were 37.1% (CIT), 43.0% (RVe), 72.5% (GVe) and 77.9% (GIVe), respectively. MO15 overall response rates and complete response rates (CRR) are shown in Figure 1B. The most common grade 3-5 treatment-emergent AE were neutropenia (50.5% of all pts), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%) and pneumonia (5.3%)). Atrial fibrillation and bleeding events occurred more frequently in GIVe while infusion-related reactions were most common in the GVe arm (Table 1). The absolute numbers of second malignancies were 33, 19, 22 and 21 for CIT, RVe, GVe and GIVe. Fatal AEs occurred in 5, 7, 6 and 9 of the patients. Conclusions: The time-limited therapies of GVe and GIVe provided superior uMRD rates in PB at MO 15 compared to CIT. In addition, uMRD rates in BM and CRR were higher in GVe and GIVe in particular than in CIT. All arms showed a good safety profile in this fit pt population. Figure 1 Figure 1. Disclosures Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.

Abstract: Abstract 1267 Poster Board I-289 The international multicenter randomized CLL8 trial evaluated 1st line treatment with FC or FCR in 817 CLL patients. Analysis of TP53 mutation status by a re-sequencing chip (Amplichip, Roche Molecular Systems) and confirmatory direct DNA sequencing were performed in a central reference laboratory. Samples were available for 628 (76.9%) patients and this cohort was representative of the full trial population regarding other baseline prognostic factors and demographics. Outcome was analyzed for subgroups defined by genetic parameters in univariate and multivariate analyses. The incidence of the TP53 mutations was 11.9% (71/628; 41 in FC arm, 30 in FCR arm). Forty-two of 51 patients (82.4%) with 17p deletion had a TP53 mutation. 5% of patients without 17p deletion (28/553) had a TP53 mutation. Patients with TP53 mutation showed lower complete response (CR) and overall response (OR) rates as compared to the group without TP53 mutation (6.9 vs. 36.4% and 62.1% vs. 95.3% (p 〈 .01)). Lower response rates were observed for the TP53 mutation groups in both arms (FC and FCR): CR (3.2% and 11.1%), CR+PR (51.6% and 74.1%). Response rates for patients without TP53 mutation were 24.2% (CR (FC)) and 92.2% ORR (FC) vs. 47.8 (CR FCR arm) and 98.2% (ORR FCR). Median progression free survival (PFS) was significantly shorter for patients with TP53 mutations (12.4 months vs. 45 months) (HR: 4.4 (3.29-5.87) p 〈 0.001). Median PFS was similar for the TP53 mutated subgroup in both treatment arms (FC 12.1 / FCR 15.4 months; HR 0.53 (0.31-0.9) p=0.19). PFS for the patients without TP53 mutations was 35.1 months in the FC arm and 51.9 months in the FCR arm (HR: 0.58 (0.45-0.75) p 〈 0.001). Patients with TP53 mutation showed a median OS of 39.3 months whereas median OS was not reached in all other patients (HR 6.01 (4.08-8.87) p 〈 0.001). Comparing OS separately for the treatment arms in the groups defined by presence or absence of TP53 mutation showed a slightly better outcome for the FCR arm for both subsets, although the comparison did not reach statistical significance (TP53 mutations HR: 0.64 (0.33-1.2) p=0.19; no TP53 mutation HR: 0.68 (0.43-1.2) p=0.09) (Fig. 1). Multivariate analysis was performed by Cox regression including age, stage, treatment arms, IGHV status, genomic aberrations and TP53 mutation. Regarding PFS (n=567), independent prognostic factors were 17p- (HR: 3.6; p 〈 .001), TP53 mutation (HR: 2.2; p 〈 .001), unmutated IGHV (HR: 1.7, p 〈 .001), age (HR: 1.4; p 〈 .001), and FCR treatment (HR: 0.52; p 〈 .001). Regarding OS (n=580), 17p- (HR: 3.5; p 〈 .001), TP53 mutation (HR: 2.6: p 〈 .001), unmutated IGHV (HR: 1.6; p=.035), and FCR treatment (HR: 0.6; p=0.019) were identified as independent factors. In conclusion, 17p deletion and TP53 mutation remain powerful prognostic markers after 1st line FC and FCR treatment in CLL. When considering the genetic profile and treatment in a multivariate model, FCR improves PFS and OS compared to FC in CLL. TP53 mutations are associated with poor response and survival independent of 17p deletion. Fig. 1 Overall survival of patients in the CLL8 trial based on treatment arm and presence / absence of TP53 mutation. Fig. 1. Overall survival of patients in the CLL8 trial based on treatment arm and presence / absence of TP53 mutation. Disclosures Zenz: Roche: Honoraria. Patten:Roche Molecular Systems: Employment. Truong:Roche Molecular Systems: Employment. Wu:Roche Molecular Systems: Employment. Fingerle-Rowson:Roche: Honoraria. Fischer:Roche: Travel reimbursment. Fink:Roche: Travel reimbursment. Jäger:Roche: Honoraria, Research Funding. Böttcher:Roche: Research Funding. Kneba:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wenger:Roche: Employment. Mendila:Roche: Employment. Hallek:Roche: Consultancy, Research Funding. Döhner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

Abstract: Abstract 2427 Introduction: The introduction of chemo-immunotherapy (R-FC) has led to impressive improvement of response, PFS and remarkably overall survival in CLL. Irrespective of these improvements, the genetic markers remain important predictors of outcome. With increasing intensity of 1st line treatment, the proportion of patients with refractory disease is decreasing. At the same time the selective pressure on tumor cells increases. Relatively little is known about the genetic profile of risk groups as defined by the length of 1st remission. We therefore analysed the CLL8 cohort (FC vs. FCR in untreated and fit patients with CLL) to identify the genetic profile (before 1st line treatment) of patients either not responding to (refractory) or relapsing early after first line therapy. Methods and material: In order to characterize the genetic profile of refractory CLL and CLL with early relapse we formed 4 cohorts based on response and response duration after initial therapy. We selected F-refractory (no PR/CR or PR/CR 〈 6 months), patients with PFS 6− 〈 12 months, 12− 〈 24 months and ≥ 24 months for the analysis. Median follow-up was 37.7 months. Genetic characterization was performed in a central laboratory (Ulm). Data was available for IGHV (n=587), TP53 mutation (n=592), and FISH (n=581). Results: Based on the above definition 84/767 (11%) patients were F-refractory. Very short PFS was observed in 43/767 (5.6%)(6− 〈 12 months) and 110/767 (14.3%)(12− 〈 24 months). The overall survival (OS) of patients in the 4 categories was significantly different with median OS (from study entry) of 21.9 months (F-refractory patients), 21.2 months (PFS 6− 〈 12 months), and 47.3 months (12− 〈 24 months) compared to not reached in patients with a median PFS ≥24 months. When comparing the treatment arms, the overall number of patients with short remission was lower in the FCR arm (Table 1). As shown in Table 1, the incidence of 17p- and TP53 mutation is highest in the F-refractory group with similar distribution in both treatment arms (34.4% 17p-; 43.8% TP53). In the subgroup of patients with very short PFS (6− 〈 12 months) the incidence of highest risk genetic aberrations was still high (17p- 28.1%; TP53 mutation 23.5%). In contrast the fraction of patients with these aberrations was very low (1.5 and 4.1% resp.) in the group of patients with long PFS (≥24 months). Conversely, the incidence of good risk genetics (e.g. 13q- single) increased with length of remission (Table 1). Similarly, the incidence of trisomy 12 was higher in patients with longer PFS (11.3% and 11.4% for PFS 12− 〈 24 months)(Table 1). Conclusion: Early relapse (within 24 months) is associated with high risk genetics (TP53 mutation and 17p deletion). In addition to patients with F-refractory CLL, patients relapsing within 6–12 and 12–24 months after intense 1st line treatment have a poor overall survival. Decisions on 2nd line treatment options should integrate genetic characterisation and remission duration. Disclosures: Zenz: Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Fink: Roche: Travel grant. Fischer: Roche: Travel grant. Kneba: Roche: Honoraria, Research Funding. Boettcher: Roche: Research Funding. Mendila: Roche: Employment. Wenger: Roche: Employment. Hallek: Roche: Honoraria, Research Funding. Döhner: Roche: Research Funding. Stilgenbauer: Roche, Celgene, GSK, Boehringer, Genzyme: Honoraria, Research Funding.

Abstract: Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P  & lt; .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.