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FIXED-DURATION VENETOCLAX PLUS OBINUTUZUMAB IMPROVES PROGRESSION-FREE SURVIVAL AND MINIMAL RESIDUAL DISEASE NEGATIVITY IN PATIENTS WITH PREVIOUSLY UNTREATED CLL AND COMORBIDITIES

S149

Fischer, K.1; Al-Sawaf, O.1; Bahlo, J.1; Fink, A.-M.1; Tandon, M.2; Dixon, M.2; Robrecht, S.1; Warburton, S.2; Humphrey, K.2; Samoylova, O.3; Liberati, A. M.4; Pinilla-Ibarz, J.5; Opat, S.6; Sivcheva, L.7; Le Dû, K.8; Fogliatto, Maria L.9; Niemann, Utoft C.10; Weinkove, R.11, 12; Robinson, S.13; Kipps, T. J.14; Boettcher, S.15; Tausch, E.16; Schary, W. L.17; Eichhorst, B.1; Wendtner, C.-M.18; Langerak, A. W.19; Kreuzer, K.-A.1; Goede, V.20; Stilgenbauer, S.16, 21; Mobasher, M.22; Ritgen, M.23; Hallek, M.24

doi: 10.1097/01.HS9.0000558816.91319.ce
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1Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany

2Roche Products Limited, Welwyn Garden City, United Kingdom

3Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod, Russian Federation

4Division of Onco-Hematology, Santa Maria Terni Hospital, University of Perugia, Perugia, Italy

5Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States

6Haematology Department, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia

7First Internal Department, MHAT Hristo Botev, AD, Vrasta, Vratsa, Bulgaria

8Hematology Department, Clinique Victor Hugo, Le Mans, France

9Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

10Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

11Malaghan Institute of Medical Research

12Wellington Blood & Cancer Centre, Capital & Coast District Health Board, Wellington, New Zealand

13Queen Elizabeth II Health Science Center, Halifax, NS, Canada

14Moores Cancer Center, University of California San Diego, San Diego, CA, United States

15Department III of Internal Medicine, University Hospital Rostock, Rostock

16Department III of Internal Medicine, Ulm University, Ulm, Germany

17AbbVie Inc, North Chicago, IL, United States

18Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany

19Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, Netherlands

20Oncogeriatric Unit, Dept. of Geriatric Medicine, St. Marien Hospital, Cologne

21Department for Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany

22Genentech Inc., South San Francisco, CA, United States

23Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel

24Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, CECAD (Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases), University of Cologne, Cologne, Germany

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Background:

The multinational, open-label, phase 3 CLL14 trial (NCT02242942) compared fixed-duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil-obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.

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Aims:

We present endpoint analyses with particular emphasis on progression-free survival (PFS) and minimal residual disease (MRD)-negativity.

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Methods:

Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD-negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10−4) and by next generation sequencing (NGS; cut-offs, 10−4, 10−5, 10−6).

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Results:

In total, 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 ml/min respectively. After 29 months median follow-up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23-0.53; P < 0.0001). MRD-negativity by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P < 0.0001]) and BM (57% vs 17% [P < 0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD-negativity was associated with longer PFS. MRD-negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 months after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12-0.30 (median time off-treatment: 19 months) (Figure 1b). MRD-negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD-negative status at <10−4, 35% vs 15% at ≥10−6-<10−5 and 31% vs 4% at <10−6, respectively.

Figure

Figure

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Summary/Conclusion:

Fixed-duration VenG induced deep, high (<10−4 in 3/4 of pts and <10−6 in 1/3 of pts), and long lasting MRD-negativity rates (with a low rate of conversion to MRD-positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.