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69 Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD – Primary Analysis from the Randomized Phase II Vision HO141 Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Combination Small Molecules
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphoid Leukemias, Adults, CLL, Non-Biological, Clinical Research, Elderly, Diseases, Therapies, Lymphoid Malignancies, Pharmacology, Study Population
Saturday, December 11, 2021: 10:00 AM

Carsten Utoft Niemann, MD, PhD1, Julie Dubois2*, Christian Brieghel, MD, PhD3*, Sabina Kersting4*, Lisbeth Enggaard, MD1*, Gerrit J Veldhuis5*, Rogier Mous, MD, PhD6*, Clemens Mellink7*, Johan A Dobber8*, Christian Bjørn Poulsen, MD9*, Henrik Frederiksen10*, Ann Janssens11*, Ida Schjødt, MD, PhD12*, Ellen C Dompeling13*, Juha Ranti14*, Mattias Mattsson, MD15*, Mar Bellido16*, Kazem Nasserinejad, PhD17*, Hoa Thi Tuyet Tran18*, Mark-David Levin, MD, PhD19 and Arnon P. Kater, MD, PhD20

1Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
2Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
3Department of Hematology, Rigshospitalet, Copenhagen University Hospital, København Ø, Denmark
4HAGA Hospital, Den Haag, Netherlands
5Department of Hematology, Antonius Ziekenhuis, Sneek, Netherlands
6Universitair Medisch Centrum Utrecht, Academic Medical Center, Utrecht, NH, Netherlands
7Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
8Laboratory of Hematology, Amsterdam University Medical Centers, Amsterdam, Netherlands
9Department of Haematology, Zealand University Hospital, Roskilde, Denmark
10Department of Hematology, Odense University Hospital, Odense, Denmark
11Hematology Department, University of Leuven, Leuven, Belgium
12Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
13Isala Ziekenhuis, Zwolle, Netherlands
14Department of Hematology, Turku University Central Hospital, Turku, Finland
15Department of Hematology, Uppsala University Hospital, Uppsala, Sweden
16Department of Hematology, Univerisity Medical Center Groningen, Groningen, Netherlands
17HOVON data center, Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
18Department of Hematology, Akershus University Hospital, Lørenskog, Norway
19Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands
20Amsterdam UMC, Amsterdam, NH, Netherlands

Background: For patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL), targeted time-limited treatment options are warranted. Thus far, therapeutic options are based on a (one-size-fits-all) fixed treatment duration or treatment until progression independent of individualized responsiveness. Post-treatment minimal residual disease (MRD) predicts outcome for patients receiving venetoclax-based therapy.

Aim: To evaluate Progression-Free Survival (PFS) for patients with R/R CLL 12 months after MRD guided treatment cessation of venetoclax + ibrutinib (V+I) treatment (arm B) with the option to reinitiate V+I based on MRD reappearance.

Methods: Patients (BTK inhibitor naïve) received ibrutinib lead-in (420 mg daily) for two (28-day) cycles. Venetoclax ramp-up was initiated during cycle 3, reaching 400 mg daily at cycle 4 with continued V+I during cycle 4-15. Patients reaching at least partial remission (PR) and undetectable (u)MRD (<10-4) in blood (PB) and bone marrow (BM, by central 8-color flow cytometry) at cycle 15 day 15 were randomized 1:2 between ibrutinib maintenance (arm A) or treatment cessation (arm B). Patients later becoming MRD positive (>10-2) in arm B reinitiated V+I. MRD positive patients at cycle 15 remained on ibrutinib until progression.

Results: 225 patients were enrolled: median age 68 years (range 36-87), median CIRS score 2 (range 0-12), Binet stage B/C 84%, IGHV unmutated: 64%, TP53 aberrations (deletions and/or mutations): 24%. Planned treatment until randomization was completed by 194 (86%) patients, 8 patients went off protocol due to toxicity, 5 (2%) patients died during the first two cycles of ibrutinib lead-in (unknown cause, myocardial infarction, intracranial hemorrhage, Richter’s transformation and tick-borne viral encephalitis), 15 patients went off protocol due to refusal to continue or other reasons and 3 patients progressed. At cycle 15, 81 (36%) patients achieved uMRD in both PB (112, 50%) and BM (84, 37%) and overall responses were 86%, of which 145 pts (64%) CR(i). Patients with uMRD were randomized to ibrutinib maintenance arm A (n 24 11%) or observation arm B (n 48 21%). Patients who did not achieve uMRD (n 125, 56%) continued ibrutinib maintenance without randomization while 5 patients went off protocol.

The primary endpoint of the trial was met; PFS was achieved for 47 (98%) of 48 patients randomized to observation arm B at 12 months after randomization (27 months after starting therapy). One patient died during observation due to myelodysplastic syndrome and 1 patient, without sign of progression, reinitiated per protocol due to MRD positivity. A similar proportion of uMRD patients randomized to ibrutinib maintenance (arm A) or observation (arm B) remained uMRD after 12 months (month 27 after treatment start); 75% and 71%, respectively; see figure. No difference in blood uMRD at cycle 15 was seen neither between TP53 aberrated/wildtype (uMRD: 46%, 52%) nor between IGHV unmutated/mutated patients (uMRD: 50%, 50%).

The most frequent adverse event (AE, only grade ≥2) was infections with 68 (30%) grade 2 and 62 (28%) grade ≥3 during the first 15 cycles, while 14 (58%) and 6 (12%) infections appeared after randomization in the treatment arm A and observation arm B, respectively. Atrial fibrillation was reported for 29 (13%) patients during the first 15 cycles, for 4 (3%) during ibrutinib maintenance (arm A + non-randomized) while no patients were reported with atrial fibrillation in arm B. Hypertension was reported for 23 (10%) patients during the first 15 cycles and for 10 (7%) patients during ibrutinib maintenance while no events were reported in arm B. One fatal bleeding event was reported in addition to 32 (14%) grade 2-3 bleeding events during the first 15 cycles; 12 (9%) grade 2-3 bleeding events were reported during ibrutinib maintenance, while no events were reported in arm B. Laboratory tumor lysis grades 2-3 was reported for 11 (5%) of patients.

Conclusion: MRD guided time-limited treatment with ibrutinib and venetoclax in the setting of R/R CLL is feasible and demonstrates a favorable benefit-risk profile. No new safety signals were detected. No patients progressed after treatment cessation while patients becoming MRD positive successfully reinitiated therapy, thus proving MRD-guided cessation and reinitiation of targeted therapy feasible in CLL.

Disclosures: Niemann: Abbvie, Janssen, AstraZeneca, Novo Nordisk Foundation: Research Funding; Abbvie, Janssen, Roche, AstraZeneca, CSL Behring, Genmab, Takeda, Octapharma: Consultancy. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Brieghel: AstraZeneca: Consultancy. Kersting: Cellgene: Other: travel grant. Enggaard: Abbvie: Consultancy; Janssen: Consultancy. Mellink: Financial support related to microarray analysis of Murano samples: Research Funding; Genome Diagnostics Laboratory, AUMC: Current Employment; Cytogenetic Field: Consultancy. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Frederiksen: Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau. Mattsson: Gilead: Research Funding. Bellido: Janssen: Other: educational funding. Tran: Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy; Astra Zeneca: Consultancy. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee.

OffLabel Disclosure: The combination of ibrutinib and venetoclax is not registered for treatment of CLL, both drugs are separately registered for treatment of CLL

*signifies non-member of ASH