The ongoing VISION/HOVON 141 phase 2 study (NCT03226301) is evaluating the feasibility of minimal residual disease (MRD)-guided treatment cessation and reinitiation in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) treated with ibrutinib + venetoclax; results of the third 15-month, preplanned interim analysis (including data only for the first 51 eligible patients) were presented at the 2019 ASH annual meeting and are summarized here.
Eligible patients received ibrutinib monotherapy (420 mg daily) for 2 28-day cycles; venetoclax ramp-up was initiated during cycle 3, reaching full dosage of 400 mg daily from the start of cycle 4, with continued combination treatment for an additional 12 cycles. At cycle 15 day 15, patients achieving at least partial remission (PR) and undetectable (u)MRD in blood and bone marrow (BM; by central flow cytometry, <10-4 level) were randomized 1:2 to receive either maintenance ibrutinib or observation (stopping therapy). The same ibrutinib + venetoclax regimen was reinitiated in patients who became MRD positive (>10-2) during observation. Patients who were MRD positive at cycle 15 remain on ibrutinib maintenance therapy until progression.
A total of 230 patients were enrolled in the study. The median age of study population was 67 years (range, 40-83); 71% were male, 65% had World Health Organization performance status 0, 84% had Binet stage B/C, and 71% had received prior standard chemoimmunotherapy. With regard to genomic alterations, 18% had TP53 aberrations and 57% had IGHV unmutated status.
Of the 51 patients included in the current analysis, 49 completed the first 2 cycles of ibrutinib monotherapy and 43 patients completed all 15 cycles of treatment. Reasons for treatment discontinuation included refusal to continue (n = 2), toxicity or intolerance (n = 2), second malignancy (n = 2), and death (n = 2).
Grade 2 adverse events (AEs) were experienced by 16% of patients, grade 3 AEs by 50%, and grade 4 AEs by 26% of patients. AEs of special interest included atrial fibrillation (10 [20%]) and bleeding (7 [14%]).
Of the 51 efficacy-evaluable patients, complete remission was achieved by 29 patients (57%) and PR by 13 patients (43%). Improvement in depth of response in peripheral blood (PB) was noted during the treatment period, with 55% achieving uMRD at cycle 15 and 39% also achieving uMRD in BM. The concordance between uMRD status in PB and BM was 71%, with the remaining 29% showing uMRD in PB but with low MRD positivity (<10-2) in BM.
Based on these results, the study investigators concluded that ibrutinib + venetoclax therapy was associated with a favorable benefit–risk profile consistent with the known safety profile for the individual drugs in patients with R/R CLL, with uMRD achieved in PB by more than half the patients.
Niemann CU, et al. ASH Abstract 4292. Session 642.