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
Authors: Niemann Carsten Utoft , Dubois Julie , Brieghel Christian , Kersting Sabina , Enggaard Lisbeth , Veldhuis Gerrit J , Mous Rogier , Mellink Clemens , Dobber Johan A , Poulsen Christian Bjørn , Frederiksen Henrik , Janssens Ann , Schjødt Ida , Dompeling Ellen C , Ranti Juha , Mattsson Mattias , Bellido Mar , Nasserinejad Kazem , Tran Hoa Thi Tuyet , Levin Mark-David , Kater Arnon P. 
Published: November 2021

Abstract

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 (&lt;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 (&gt;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.
Figure 1 Figure 1.

Disclosures
Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. 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: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding.

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