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PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.

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 < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .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.

Background: Glofit is a novel, CD20xCD3 T-cell-engaging bispecific antibody that provides monovalent binding to CD3 on T cells and bivalent binding to CD20 on B cells. As monotherapy, Glofit has shown promising response rates with manageable safety in R/R B-cell non-Hodgkin lymphoma (B-NHL) patients (pts; [Carlo-Stella et al. EHA 2021]). Because of their distinct and complementary mechanism of action, there is a rationale for combining Glofit with the anti-CD79b-targeted antibody-drug conjugate, Pola. NP39488 (NCT03533283) is a Phase Ib/II, open-label, multicenter, dose-escalation (DE) and expansion study evaluating Glofit + Pola or atezolizumab in R/R B-NHL pts (Hutchings et al. ASH 2019). Here, we report preliminary safety and efficacy data for Glofit + Pola in pts with R/R DLBCL during DE and expansion at the recommended Phase II dose (RP2D). Methods: To mitigate the risk of cytokine release syndrome (CRS), a single 1000mg dose of obinutuzumab pre-treatment was administered on Cycle (C) 1 Day (D) 1 alongside step-up dosing (SUD) of Glofit on C1D8 and C1D15. Glofit was subsequently administered at the target dose from C2D1, every 3 weeks up to C12. Pola was administered at 1.8mg/kg on C1D2 and then on D1 of each subsequent cycle up to C6. The primary objective was to establish the RP2D of Glofit in combination with Pola. Results: As of June 10, 2021 (clinical cut-off date [CCOD]), 44 pts were treated with ≥1 cycle; median follow-up was 3.2 months (95% confidence interval: 1.4-3.5). In the first DE cohort, 7 pts had received Glofit at 2.5mg (C1D8)/10mg (C1D15)/10mg (C2D1 onwards) plus Pola. In the second DE cohort, 4 pts received the Glofit target dose of 30mg on C1D15 and this was established as the RP2D. During the expansion phase at RP2D, an additional 34 pts were treated with ≥1 cycle. Of 44 pts, 29 (66%) had histology of R/R DLBCL, 8 (18%) had R/R high-grade B-cell lymphoma (HGBCL; 2 HGBCL not otherwise specified; 5 double-hit DLBCL; 1 triple-hit DLBCL) and 7 (16%) had R/R transformed follicular lymphoma. Pts (61% male) had a median age of 65.5 years (range: 29-82) and received a median of two prior lines (range: 1−5). Twenty-eight (64%) pts were refractory to their last therapy; 2 pts had not been treated with Glofit at the CCOD. The most frequent adverse event (AE) was CRS (55%; 23/42 pts): Grade (Gr) 1 (n=18); Gr 2 (n=7); no Gr ≥3 CRS events were observed (Lee et al. 2019 ASTCT criteria). Of the 7 pts with Gr 2 CRS, 5 were treated with tocilizumab and fluids for hypotension, and 4 pts were treated with low-flow oxygen due to hypoxia. None of the pts required vasopressors or intensive care unit admission. Gr >3 AEs occurred in 52% (n=23) of pts; most commonly, neutropenia (27%) and anemia (23%). For neurological AEs (NAEs), 13 events were reported in 13 patients (29.5%, 13/44 pts), all were limited to Gr 1−2. The most common NAEs were headache and (11%, 5/44 pts) and insomnia (4.5%, 2/44 pts). No immune effector cell-associated neurotoxicity syndrome-like AEs were reported. Peripheral neuropathy due to Pola was reported in 5/44 pts (11%); all events were Gr 1. Serious AEs occurred in 22 pts (52%); none were CNS or neurological events. One pt experienced fatal COVID-19 pneumonia (not related). Study treatment was discontinued in 2 pts due to AEs (Gr 4 thrombocytopenia, and Gr 3 worsening of pre-existing renal impairment; both events were related to Glofit and Pola). At CCOD 33/44 pts were evaluable for interim (after 2 cycles, 1 target dose of Glofit) or primary (after 8 cycles) response; 6/33 pts had experienced progressive disease and discontinued study treatment. Overall response (OR) rate for both dosing cohorts was 73% (24/33) and complete response (CR) rate, per investigator was 51.5% (17/33). Of 7 pts treated with 2.5/10/10mg SUD Glofit, OR and CR rates were both 86% (6/7); durable responses at ≥6 months post-end of treatment were observed. Of 26 pts treated with 2.5/10/30 mg SUD Glofit, OR rate was 73% (19/26) and CR rate was 46% (12/26); 11.5% (3/26) pts had stable disease after 2 cycles of therapy. Duration of response and time on study by dosing cohort is shown in Figure. Biomarker and pharmacokinetic data will be provided. Conclusions: Glofit in combination with Pola showed tolerable safety and encouraging preliminary efficacy in R/R DLBCL pts. CRS and NAEs were limited to Gr 1 or 2, no new safety signals were detected for this combination, and the safety profile was consistent with that of the individual drugs. Updated data will be presented. Figure 1 Figure 1. Disclosures Hutchings: Genmab: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Terol: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; BMS: Consultancy; Hospital Clinico Valencia: Current Employment; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Corradini: KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Larsen: Novartis: Consultancy; Gilead: Consultancy; Odense University Hospital, Denmark: Current Employment; Celgene: Consultancy; BMS: Consultancy. Rueda Dominguez: Hospital Regional Universitario de Malaga: Current Employment; Roche: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Merck Serono: Consultancy; BMS: Consultancy; MSD: Consultancy. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Wang: F. Hoffmann-La Roche Ltd: Current Employment; Peking University Third Hospital, Beijing, China: Ended employment in the past 24 months. Filézac De L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Tandon: Roche Products Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sellam: Roche: Current Employment, Current equity holder in publicly-traded company. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies.

Background The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and ...

Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942.Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma).2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia.F Hoffmann-La Roche and AbbVie.

Background The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. Methods In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). Results As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. Conclusions The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. Trial registration ClinicalTrials.gov, NCT02593760. Registered November 2, 2015.

Background Measurement of minimal residual disease (MRD) is an established and sensitive prognostic tool to assess the depth of response during and after treatment of chronic lymphocytic leukemia (CLL) and to understand disease dynamics after treatment. Retracing these kinetics is paramount to understand which group of patients is at risk of relapsing despite initial MRD response. To this end, we here provide an analysis of clonal growth patterns in patients treated within the CLL14 trial. Methods In total, 432 patients with previously untreated CLL and co-existing conditions were randomized to receive chlorambucil or venetoclax (216 patients per arm) until completion of cycle 12 (à 28 days), and in combination with obinutuzumab for the first 6 cycles. The primary endpoint was progression-free survival (PFS), MRD was a secondary endpoint. MRD was analyzed by ASO-PCR and, as reported here, by next-generation sequencing (Adaptive clonoSEQ Assay, cut-off: 10-4, 10-5 and 10-6). The limit-of-quantification of the clonoSEQ Assay is less than 10-6. Samples from peripheral blood (PB) are collected every 3 to 6 months until 9 years from last patient enrolled; for this analysis, the longest follow-up MRD sample was from month 24 after treatment completion. A patient-specific clonal growth rate model was formed: MRD level at time t is defined as MRD(t) = λ0 x 10μt, where λ0 is the baseline MRD (i.e. MRD at end of treatment (EoT)), and μ is the growth rate parameter. For the time from MRD status λ0 to new MRD state λ1 , tchange was assumed (1/μ) x log10 (λ1/λ0). An exponential regression model was fitted to each patient to estimate each respective λ0 and μ, by which the patients' MRD clone doubling time was calculated. Data are reported in relation to the intention-to-treat population; p-values are exploratory only. For modelling, only patients with at least two MRD assessments after EoT and who had not experienced PD before EoT were included. Results Two months after treatment completion (follow-up month 3), 40% (7%) of patients in the Ven-Obi arm (Clb-Obi arm) had uMRD levels Most patients (56%) who had undetectable MRD (uMRD) levels at EoT already had uMRD levels at cycle 7, i.e. after completing Ven-Obi therapy. In 25% of the Ven-Obi treated patients, MRD response deepened after continuing with 6 cycles of venetoclax monotherapy (Figure B). In a PFS landmark analysis after EoT, patients in the Ven-Obi arm with MRD levels ≤10-5 had a 2-year PFS after EoT of approximately (approx.) 93%, while patients with detectable MRD >10-2 had a 2-year PFS of approx. 37% (Figure D). Patient-specific clonal growth rates were estimated for 123 patients in the Ven-Obi arm and 143 patients in the Clb-Obi arm (Figure C). Of note, 38 patients in the Ven-Obi arm and 4 patients in the Clb-Obi arm had MRD results below the assays limit of quantification (LOQ), indicating the deepest response beyond the assay's sensitivity. These patients were not included as a growth rate could not be accurately assessed for those very-deep responders. The average clonal growth rate in the Ven-Obi arm (n=123) was µ = 0.0034 (95% CI: 0.0030-0.0038), translating into an MRD doubling time of approx. 89 days (95% CI: 79-102) and an increase of the MRD clone size by 1 with log10 scale within approx. 296 days (95% CI: 263-337) (Figure E). For patients in the Clb-Obi arm (n=143), µ was 0.0042 (95% CI: 0.0038-0.0047), corresponding to a doubling time of approx. 71 days (95% CI: 65-79), and an increase of the MRD clone size by 1 with log10 scale within approx. 237 days (95% CI: 215-263). The average growth rate was lower in the Ven-Obi arm compared to the Clb-Obi arm (p=0.0057). Analyses of growth rate patterns within various biological and clinical risk groups as well as genetic subgroups are currently being conducted and will be presented at the meeting. Conclusions This analysis demonstrates that individual clonal growth rates can be used to estimate the MRD doubling time after a fixed-duration treatment. Clonal growth was lower after Ven-Obi than after Clb-Obi, indicating more effective MRD eradication and clonal growth modulation with Ven-Obi. In a considerable subgroup of Ven-Obi treated patients, no clonal growth was measurable during observation, indicating deepest remissions. Figure Disclosures Al-Sawaf: AstraZeneca: Consultancy, Honoraria, Other: personal fees; BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding. Wilson:Roche Products Limited: Current Employment. Tandon:Roche Products Ltd.: Current equity holder in publicly-traded company. Ching:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Fink:Janssen: Honoraria; Celgene: Research Funding; AbbVie: Other: travel grants. Ritgen:Gilead: Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; BMS: Consultancy, Honoraria, Other: travel grants; Pfizer: Consultancy, Honoraria. Tausch:Janssen-Cilag: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Kreuzer:AbbVie: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Schary:AbbVie: Current Employment, Current equity holder in publicly-traded company. Wendtner:AbbVie: Consultancy; MorphoSys: Consultancy; Hoffmann-La Roche: Consultancy; Gilead: Consultancy; Janssen-Cilag: Consultancy. Eichhorst:AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Other, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: 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; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding. Jiang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Hallek:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria.

8027 Background: The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG) in patients with previously untreated CLL and coexisting conditions. Here, we report follow-up data on safety and efficacy. Methods: Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. Primary endpoint was investigator-assessed progression-free survival. Key secondary endpoints were response rates, rates of minimal residual disease (measured every 6 months up to 5 years after last patient enrolment) and overall survival. Follow-up is ongoing but all patients are off study treatment. This trial was registered with ClinicalTrials.gov, number NCT02242942. Results: Of the 432 enrolled patients, 216 were randomly assigned to receive VenG and 216 to receive ClbG. After a median follow-up of 39.6 months (interquartile range 36.75 - 43.04), progression-free survival continued to be superior for VenG as compared to ClbG (median not reached vs 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p < 0.001). At 3 years, the estimated progression-free survival rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status. Of note, PFS was also significantly longer for VenG treated patients with mutated IGHV status. Assessment of minimal residual disease 18 months after end of treatment showed that 47.2% of patients in the VenG arm had undetectable (u) uMRD ( < 10−4), 13% had low (L)-MRD (≥ 10−4 and < 10−2) and 7.9% high (H)-MRD (≥ 10−2), compared to 7.4% uMRD, 17.1% L-MRD, 26.9% H-MRD in the ClbG arm. No difference has been observed (HR 1.027, 95% CI 0.602-1.753, p = 0.921) for overall survival; median overall survival has not been reached in either group. Second primary malignancies were reported in 36 (17%) patients in the VenG arm and 22 (10.3%) in the ClbG arm. No new safety signals were observed. Conclusions: The results suggest that the superior efficacy and deep remissions after fixed-duration VenG are maintained during extended follow-up, and show the long-term benefits of 12 cycles of VenG across all known risk categories. Clinical trial information: NCT02242942 .

Background In patients (pts) with chronic lymphocytic leukemia (CLL), tumor lysis syndrome (TLS) is a rare, but potentially life-threatening event. TLS is characterized by cytolysis leading to hyperkalemia, hyperphosphatemia, hyperuricemia and/or hypocalcemia, as defined by the Howard criteria. Analyses of patients (pts) treated with venetoclax monotherapy have reported TLS frequencies of up to 5%. In the CLL14 study, in which elderly, unfit pts were randomized to receive 12 cycles of venetoclax-obinutuzumab (VenG) or chlorambucil-obinutuzumab (ClbG), impaired renal function was reported for most pts at study entry. However, TLS was a very rare finding in CLL14; here, we analyze the efficacy of measures implemented to prevent TLS and preliminary stages of TLS. Methods The CLL14 protocol specified categorization of pts according to their risk for TLS based on lymph node size (via CT/MRI) and lymphocyte count. Obinutuzumab was administered three times in the first cycle with recommended dose splitting at first administration; venetoclax was added on cycle 1 day 22 with a dose of 20 mg. A five-week ramp-up dosing to the target dose of 400mg daily was used to mitigate TLS risk. Monitoring and preventative measures were implemented according to each patient's TLS risk and included medication with uric acid reducers, fluid intake and laboratory assessments. Additionally, patients with high TLS risk were hospitalized with intensified laboratory monitoring, intravenous hydration and prophylactic use of rasburicase. TLS events were defined as per Howard criteria. Adverse events (AEs) were graded using the NCI Common Toxicity Terminology Criteria for Adverse Events v4.0. Results 432 pts were randomized to either receive VenG (n=216) or ClbG (n=216). For VenG, TLS risk was categorized as low in 29 pts (13.4%), medium in 139 pts (64.4%) and high in 48 pts (22.2%). For ClbG, TLS risk was assessed as low in 26 (12.0%), medium in 147 (68.1%) and high in 43 (19.9%) pts. Median creatinine clearance was 65.2 ml/min in the VenG and 67.52 ml/min in the ClbG arm; overall, 57.5% of pts had a clearance below 70 ml/min. TLS occurred in 3 pts (0.5%) in the VenG arm and 5 pts (2.3%) in the ClbG arm. No clinical TLS was observed. All pts were hospitalized or hospitalization was prolonged due to TLS. All TLS events in the VenG arm occurred prior to the first dose of venetoclax and were associated with obinutuzumab; 1 pt was assessed as low-risk and 2 as medium-risk for TLS. All pts had received prophylaxis with allopurinol prior to treatment start. In all cases, TLS occurred on cycle 1 day 2 after the first infusion of obinutuzumab. For ClbG, TLS occurred in 1 pt with low risk, 3 with medium risk and 1 with high risk of TLS. All events occurred on cycle 1 day 1 or day 2. All but 2 pts received allopurinol prophylaxis. Apart from these AEs, 12 pts in the VenG arm experienced lab abnormalities consistent with Howard criteria during cycle 1 and 2. All but 2 pts had TLS prophylaxis documented. Six of these had medium and 6 had high risk of TLS. In 5 pts, lab abnormalities occurred after obinutuzumab and prior to venetoclax dosing. In 4 pts, 1 of the 2 lab values was already abnormal prior to Ven dosing (elevated uric acid in 3 pts and elevated phosphate in 1 pt). In 1 pt, lab abnormalities meeting Howard criteria were observed pre-dose. In 2 pts, lab abnormalities were observed post-dose. All of these abnormalities were assessed by the investigator as not-clinically significant, apart from 3 AEs of single electrolyte abnormalities (Table 1). No treatment was administered and no modifications to venetoclax dosing were performed due these laboratory abnormalities. For ClbG, 6 pts experienced lab abnormalities. One pt was assessed as low, 3 as medium and 2 as high risk for TLS. All pts received TLS prophylaxis. All abnormal values occurred after obinutuzumab infusion. Two AEs of single electrolyte abnormalities were reported (Table 1). One pt received rasburicase for treatment of hyperuricemia, otherwise no treatments were administered. Conclusion This report shows that, in the CLL14 protocol, treatment with VenG could be managed in a way that allowed control of TLS. Of high clinical relevance, not a single clinical or life-threatening TLS event was observed with venetoclax, indicating the measures used in the protocol were effective in preventing this condition, even in a population of elderly patients with relevant comorbidity including chronic kidney disease. Disclosures Al-Sawaf: Roche: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants; Celgene: Research Funding. Sinha:Roche Products Ltd: Employment. Tandon:Roche Products Ltd: Employment; Roche: Equity Ownership. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding. Fischer:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: travel grants. Hallek: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; AbbVie: Honoraria, 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.

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

7502 Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance -4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5,10-6). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P-4, 31% vs 4% at -6 and 35% vs 15% at ≥10-6–-5, respectively. Conclusions: Fixed-duration VenG induced deep (-6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.