MRD4 Eradication at 6 Months and Early Clearance of MRD with Combination of Ibrutinib Plus Venetoclax Results in Sustained Clinical and MRD Responses: Exploratory Analysis of the Blood Cancer UK TAP Clarity Study

Abstract

Background: Treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeting the B-cell receptor pathway with inhibitors such as ibrutinib (IBR), and molecules that reactivate apoptosis such as venetoclax (VEN). The Blood Cancer UK TAP CLARITY trial combined IBR with VEN to eradicate detectable CLL with the intention of stopping therapy. Methods: CLARITY is a Phase II trial combining IBR with VEN in 50 patients with relapsed/refractory (R/R) CLL. After 2 months of IBR monotherapy, VEN was added at a daily dose of 10mg/day or 20mg/day, escalating weekly to a final daily dose of 400mg/day. The primary outcome was the proportion of patients eradicating MRD (<0.01%) in the bone marrow (BM) at Month 14. Secondary outcomes included the proportion of patients eradicating MRD at Months 8, 26 and 38 and IWCLL response at Months 14, 26 and 38, progression-free and overall survival. CLL MRD was quantified using >6 color ERIC-standard flow cytometry (detection limit 10-5/0.001%). Paired PB and BM samples were assessed at Months 8, 14, 26 and longitudinal PB samples were taken at additional intermediate time points. Therapy was discontinued upon confirmation of a CR according to the IWCLL2008 criteria and MRD reduction to <10-4 CLL cells in PB and BM (MRD4). MRD4 at Month 8 indicated to stop IBR and VEN at Month 14; MRD4 in PB and BM at Months 14 and/or 26 indicated to stop IBR and VEN at Month 26; while detectable MRD at Month 26 indicated to stop VEN and to continue IBR until progression or toxicity. The original trial protocol limited venetoclax to 24 months of treatment, but this was later amended in January 2019 to allow patients, who had not obtained an MRD4 at month 26, to have an extra 12 months of VEN in addition to IBR. The aim of this exploratory analysis is to ascertain whether 2 log reduction in MRD at 2 months of combination or achievement of MRD4 at 6 months of combination results in persistence of MRD and clinical responses with prolonged follow-up. Results: Fifty-four patients were recruited from May 2016 to November 2017. The median number of prior therapies was 1 (range: 1-6). 20% patients had del(17p); 25% del(11q); 75% had unmutated IGVH. Four patients that discontinued treatment due to ibrutinib-related adverse events in the first 8 weeks before starting VEN were replaced so that, in total, 50 patients received the combination of IBR and VEN. Of the 50 evaluable participants recruited to the study, 14 patients achieved MRD-negativity at a level of <0.01% in PB and BM at 6 months of combination of IBR and VEN. At month 38 of follow-up, one patient has relapsed but not needed treatment. 10/14 patients continue at MRD4 levels and 3/14 have a missing MRD sample at Month 38 but all three patients were MRD-negative at Month 26. There were no clinical progression in the 13 patients to date. Of the 25 patients achieving 2 log reduction in MRD levels at 2 months of combination of IBR and VEN, 15/25 patients were still MRD-negative at levels of <0.01% at month 38; 4/25 patients were MRD-positive at Month 38. 6/25 patients had missing samples at month 38; 5 patients were still MRD-negative at month 26 with only one patient being MRD-positive at month 26. There were two clinical progressions to date at month 41 and 42 respectively. Conclusions: Early MRD eradication with IBR+VEN results in sustained MRD and clinical responses in R/R CLL. Achievement of MRD <0.01% with 6 months of combination or 2 log reduction in MRD levels at 2 months of combination co-related with sustained MRD and clinical responses at 3 years follow-up suggesting that this approach may help to ascertain the best responders to this combination.