Amey C Panchal

Introduction: The CLL14 study showed significant improvement of progression-free survival (PFS) and rates of undetectable minimal residual disease (uMRD) with venetoclax-obinutuzumab (Ven-Obi) as compared to chlorambucil-obinutuzumab (Clb-Obi) in patients (pts) with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions. The aim of this report is to provide updated efficacy and safety data from the ongoing follow-up of the CLL14 study with now all pts being off study treatment for at least 3 years. Methods: Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of Ven with 6 cycles of Obi or 12 cycles of Clb with 6 cycles of Obi. Primary endpoint was investigator-assessed PFS. Key secondary endpoints were safety, response rates, rates of minimal residual disease (MRD) and overall survival. Results: Of the 432 enrolled pts, 216 were randomly assigned to receive Ven-Obi and 216 to receive Clb-Obi. After a median follow-up of 52.4 months (interquartile range 49.5-56.2), PFS continued to be superior for Ven-Obi as compared to Clb-Obi (median not reached (nr) vs. 36.4 months; HR 0.33 [95% CI 0.25-0.45], p < 0.0001)(Fig A). At 4 years after randomization, the estimated PFS rate was 74.0% in the Ven-Obi arm and 35.4% in the Clb-Obi arm. This improvement was observed across all clinical and biological risk groups, including pts with TP53 mutation/deletion (4-year PFS 53.0% vs 20.8%) and unmutated IGHV status (4-year PFS 68.0% vs 19.8%)(Fig B,C). Overall, 35 disease progressions in the Ven-Obi arm have been observed, compared to 122 in the Clb-Obi arm. Time to next treatment was significantly longer in the Ven-Obi arm (4-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p < 0.0001)(Fig D). The majority of pts received and responded to BTK inhibitor monotherapy as a second-line treatment after progressive disease in both arms (57.1% in Ven-Obi arm, 55.6% in Clb-Obi arm). Assessment of MRD by NGS in peripheral blood 30 months after the end of treatment showed that 26.9% of pts in the Ven-Obi arm had uMRD (<10‒4), 21.8% had low (L)-MRD (≥10‒4 and <10‒2) and 13.4% high (H)-MRD (≥10‒2), compared to 3.2% uMRD, 8.8%% L-MRD, 28.2% H-MRD in the Clb-Obi arm. No difference in overall survival has been observed between the Ven-Obi and Clb-Obi arm; at 4 years 85.4% pts were alive in the Ven-Obi arm and 83.1% in the Clb-Obi arm (HR 0.85 [0.54-1.35], p = 0.49)(Fig E). Second primary malignancies were reported in 40 (18.9%) pts in the Ven-Obi arm and 30 (14.0%) in the Clb-Obi arm. No new safety signals were observed. Conclusion: The 4-year follow-up confirms the superior efficacy with longer PFS and deep remissions after fixed-duration Ven-Obi compared to Clb-Obi. The majority of pts remains without relapse three years after completing Ven-Obi therapy. Fixed-duration Ven-Obi continues to be an effective treatment for all pts with CLL and coexisting conditions. EA – previously submitted to EHA 2021. The research was funded by: Hoffmann-La Roche Ltd.; AbbVie Inc. Keywords: Combination Therapies, Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract O. Al-Sawaf Honoraria: Roche, AbbVie, Janssen, Gilead, AstraZeneca Research funding: Roche, AbbVie, Janssen, Beigene Educational grants: Roche, AbbVie, Janssen, Gilead, AstraZeneca M. Tandon Employment or leadership position: Roche Products Ltd Stock ownership: Roche Products Ltd. A. Panchal Employment or leadership position: Roche Products Ltd. A.-M. Fink Honoraria: Celgene, Janssen, Hoffmann-LaRoche E. Tausch Honoraria: Roche, AbbVie M. Ritgen Honoraria: Hoffmann-LaRoche, AbbVie Research funding: Hoffman-LaRoche K.-A. Kreuzer Honoraria: Hoffmann-LaRoche, AbbVie Research funding: Roche, AbbVie S. Kim Employment or leadership position: AbbVie C. Wendtner Honoraria: Hoffmann-LaRoche, AbbVie, Janssen-Cilag, Gilead, MorphoSys B. Eichhorst Honoraria: Hoffmann-LaRoche, AbbVie, Celgene, Bovartis, ArQule, BeiGene, Gilead, AstraZeneca, Oxford Biomedica (UK), Adaptive Biotechnologies Research funding: Hoffmann-LaRoche, AbbVie, Janssen S. Stilgenbauer Honoraria: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem Research funding: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem Y. Jiang Employment or leadership position: Genentec Inc. M. Hallek Honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie, Boehringer Ingelheim Research funding: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie K. Fischer Honoraria: AbbVie, Hoffmann-LaRoche

Introduction: The CLL14 study has established fixed-duration treatment with the BCL2 inhibitor venetoclax and the CD20 antibody obinutuzumab (Ven-Obi) for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). The aim of this report is to provide a population-based exploratory analysis of MRD growth dynamics and to compare growth trajectories after stopping Ven-Obi and chlorambucil-Obi (Clb). Methods: Pts were randomized 1:1 to receive 12 cycles (cy) of Ven with 6 cy of Obi or 12 cy of Clb with 6 cy of Obi. MRD was analyzed by NGS (clonoSEQ Assay). Samples from peripheral blood (PB) are collected every 3-6 months. For the longitudinal analyses of MRD growth dynamics, a population-based logistic growth model with nonlinear mixed effects (NLME) approach was developed to estimate population and individual patient parameters. Cases with at least two measurable timepoints were included; data < LLOQ were incorporated by likelihood-based method. Prognostic markers were screened as covariates for impact on key model parameters based on statistical and graphical assessments. Results: Of 432 enrolled pts, 216 were assigned to receive Clb-Obi and 216 to Ven-Obi. At follow-up month 30, 7 (3.2%) pts in the Clb-Obi arm and 58 (26.9%) pts in the Ven-Obi arm had uMRD levels <10-4 (Fig A,B). Based on the inclusion criteria for the population analysis, 154 pts from Clb-Obi and 153 pts from Ven-Obi arm were included. The model was well calibrated, and high concordance between observed and predicted values was confirmed (Fig C). The median MRD level at EoT was significantly lower after Ven-Obi than after Clb-Obi (10-6.00 vs 10-3.26, p < 2e-16). Within the Ven-Obi arm, end of treatment MRD values did not differ between pts with low-risk and high-risk features, such as IGHV status (10-5.79 for mutated IGHV vs 10-6.12 for unmutated IGHV) or TP53 deletion/mutation (10-5.38 for deletion/mutation vs 10-6.03 for non-deleted/mutated). The median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median days 84 versus 67 days, p = 3.3e-5)(Fig D). The median time from EoT to MRD level increase to 10-2 was also longer after Ven-Obi therapy compared to Clb-Obi therapy (median 1225 days versus 227 days, p < 2e-16)(Fig D). Based on a covariate screening of 28 biological and clinical features, the final model showed a significant impact on MRD growth dynamics by Ven-Obi treatment, high MRD levels at the start of treatment, high CLL-IPI, del11q, higher disease burden, response to treatment, and IGHV status (Fig E,F). Conclusion: This analysis establishes a robust, population-based model of MRD growth dynamics that allows description of growth trajectories and treatment effects after treatment cessation. In addition to more effective MRD eradication with Ven-Obi, our results demonstrate that MRD growth is modulated more efficiently by BCL2-targeting treatment in contrast to genotoxic chemoimmunotherapy. The research was funded by: Hoffmann-La Roche Ltd.; AbbVie Inc. Keywords: Diagnostic and Prognostic Biomarkers, Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract O. Al-Sawaf Consultant or advisory role: Roche, Abbvie Honoraria: Roche, Abbvie Research funding: Roche, Abbvie Educational grants: Roche, Abbvie T. Lu Employment or leadership position: Genentec Inc. M. Z. Liao Employment or leadership position: Genentec Inc. A. Panchal Employment or leadership position: Roche Products Ltd. T. Ching Employment or leadership position: Adaptive Biotechnologies Corp. A.-M. Fink Honoraria: Celgene, Janssen, Hoffmann-LaRoche E. Tausch Honoraria: Roche AG, AbbVie M. Ritgen Honoraria: Hoffmann-LaRoche, AbbVie Research funding: Hoffmann-LaRoche K.-A. Kreuzer Honoraria: Roche, AbbVie Research funding: Roche, AbbVie S. Kim Employment or leadership position: AbbVie Inc. D. Miles Employment or leadership position: Genentec Inc. C. Wendtner Honoraria: Hoffmann-LaRoche, AbbVie, Janssen-Cilag, Gilead, MorphoSys S. Stilgenbauer Honoraria: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-LaRoche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem Research funding: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-LaRoche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem B. Eichhorst Honoraria: Hoffmann-LaRoche, AbbVie, Celgene, Novartis, ArQule, BeiGene, Gilead, AstraZeneca, Oxford Biomedica (UK), Adaptive Biotechnologies Research funding: Hoffmann-LaRoche, AbbVie, Janssen Y. Jiang Employment or leadership position: Genentec Inc. M. Hallek Honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie Research funding: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie K. Fischer Honoraria: AbbVie, Hoffmann-LaRoche

We present a case of febrile neutropenia in a patient with acute myeloid leukemia caused by an uncommon bacterial species. The patient was treated with antibiotics for 14 days before being discharged. Pantoea agglomerans is a plant soil and water-dwelling agricultural organism. It is both a commensal and pathogen of animals and humans, according to earlier research. In conclusion, p. agglomerans should be considered a bacterial threat in cancer patients who are undergoing highly myelotoxic chemotherapy.