Abstract: Introduction: The CLL2-BCG trial is a prospective, open-label, multicenter phase-II study based on the "sequential triple-T" (tailored, targeted, total eradication of CLL) concept proposed earlier [Hallek M., Blood 2013; 122(23): 3723-34]. This concept consists of sequentially applied combinations of targeted agents and aims for achieving undetectable minimal residual disease (MRD). It uses a sequential application of bendamustine (Ben) for debulking, followed by obinutuzumab (Obi) plus idelalisib (Ide) as induction and maintenance therapy for an all-comer population of physically fit and unfit, treatment-naïve (t-n) and relapsed/refractory (r/r) CLL patients (pts) irrespective of high-risk genetic markers. Methods: Pts with an absolute lymphocyte count ≥ 25.000/µl and/or lymph nodes ≥ 5 cm were to receive 2 cycles of Ben as debulking (70 mg/m² d1 & 2 q28 d), unless contraindicated. In the induction phase Obi 1000 mg was administered on d 1, 8 and 15 of cycle 1 and d1 of cycles 2-6; Ide was added in cycle 2 (150 mg twice daily). In the maintenance phase, daily dosing of Ide was continued and Obi was administered every 3 months until achieving a MRD-negative complete response or for up to 24 months. The primary endpoint was the overall response rate (ORR) at the end of induction therapy, secondary endpoints included MRD assessment, safety and survival. Due to an increased incidence of opportunistic infections in other Ide trials, amendment 2 in March 2016 limited the recruitment to r/r CLL pts with high-risk features such as presence of a deletion 17p/TP53 mutation and/or ineligibility for ibrutinib treatment (refractoriness, intolerance or contraindications). Slow enrolment led to recruitment stop in September 2019. Results: Between May 2015 and September 2019, 48 pts were enrolled. Sixteen pts were t-n and 32 had r/r CLL with a median of 2 prior lines (range: 1-10); most common were BR and FCR, 6 pts each had received ibrutinib and venetoclax containing therapies. Median age was 66 (range 41-83) years, median CIRS score was 2 (0-13). Twenty-three pts (48%) were defined unfit by a CIRS score & gt;6 (7 pts) and/or an impaired renal function with a Creatinine Clearance & lt;70ml/Min (19 pts); 39 pts were male (81%). Nineteen pts (40%) had a del(17p) and/or TP53 mutation; 33 (70%) an unmutated IGHV status and 15 pts (42%) a complex karyotype, 36 pts (80%) had a high or very high CLL-IPI. Thirty-eight patients (79%, 16 t-n and 22r/r) received Ben debulking. However, 8 pts never started the induction phase due to protocol amendment 2. Forty pts (10 t-n, 30 r/r) received induction treatment (FAS [full analysis set]), 33 completed the full 6 cycles (PP [per protocol] collective). Twenty-seven (7 t-n, 20 r/r) continued in a maintenance phase. At the end of induction, 32 of 40 pts (FAS) and 28 of 33 pts with 6 induction cycles (PP) responded (ORR 80% and 85%, respectively); undetectable MRD levels ( & lt;10-4) by 4-color flow were achieved in 9 pts (23% and 27%, respectively) [Table 1]. Median progression-free survival was 44 months in t-n and 33 months in r/r CLL pts. Median overall survival was not reached for the t-n and 46 months in r/r pts; nine pts died, seven due to infections (two sepsis, including one in the context of severe enterocolitis, one pneumocystis jirovecii pneumonia and one influenza pneumonia, the other three after disease progression/start of subsequent treatment were considered unrelated to stud treatment), one cardiac arrest and one due to Richter´s transformation. As of June 8th 2020, 603 adverse events (AEs) were reported in the entire cohort; 313 (52%) were related to study drug and 127 (21%) were serious adverse events. 286 (47%) occurred in the induction treatment (see table 1). Of these, 69 (24%) were CTC grade 3 and 18 (6%) CTC grade 4, 4 had a fatal outcome. Most common AEs in the induction were infusion-related reactions, neutropenia, thrombocytopenia, anemia, nasopharyngitis, headache, and fatigue [Table 2]. Summary/Conclusion: Sequential treatment with Ben debulking, followed by Obi and Ide induction and maintenance achieved responses and even undetectable MRD levels in CLL patients with high-risk disease and extensive prior therapy. However, the study also confirmed the known toxicities of Ide. In light of the current, alternative therapeutic options, the BCG regimen reported here should be used with caution, but represents an alternative treatment option if ibrutinib and venetoclax have failed. Disclosures Cramer: Gilead: Other: travel support, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel support, Research Funding; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Beigene: Research Funding; AbbVie: Honoraria, Other: travel support; Novartis: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding. Von Tresckow:Celgene: Other: travel grants; AbbVie: Honoraria; Janssen-Cilag: Honoraria, Other: travel grants, Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding. Fink:AbbVie: Other: travel grants; Janssen: Honoraria; Celgene: Research Funding. Tausch:Janssen-Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Knauf:Janssen-Cilag: Honoraria; AbbVie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Mundipharma: Honoraria. Al-Sawaf:BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Honoraria, Other: personal fees, Research Funding; Gilead: Consultancy, Honoraria, Other: personal fees; Janssen: Consultancy, Honoraria, Other: personal fees, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: personal fees. 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. Fischer:F. Hoffmann-La Roche: Honoraria, Other: travel grants; AbbVie: Honoraria. Kreuzer:Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; AbbVie: 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. Ritgen:Gilead: Other: travel grants; BMS: Consultancy, Honoraria, Other: travel grants; F. Hoffman-La Roche: Consultancy, Honoraria, Other: travel grants, Research Funding; Pfizer: Consultancy, Honoraria. Kneba:AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding. Stilgenbauer:Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; 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; Genzyme: Consultancy, Honoraria, Other: travel support, 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. Eichhorst:Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

Abstract: 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 & lt;10-6, 26% (13%) ≥ 10-6 and & lt;10-5, 8% (14%) ≥ 10-5 and & lt;10-4, 5% (21%) ≥ 10-4 and & lt;10-2, and 3% (26%) ≥10-2 (Figure A). 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 & gt;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.

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.