Durable Remissions Following Combined Targeted Therapy in Patients with CLL Harboring TP53 Deletions and/or Mutations.

Abstract

Fifty-one of 189 evaluable patients from three prospective phase-II trials evaluating a sequential targeted treatment (clinicaltrials.gov NCT02345863, NCT02401503, NCT02689141) had high-risk CLL with a deletion 17p, TP53 mutation or both. Twenty-seven patients started treatment with bendamustine debulking prior to the induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13 and venetoclax/obinutuzumab (AG) in 17 patients. The primary endpoint was the overall response rate after eight months of induction treatment, which were 81%, 100% and 94% for IO, IG and AG, respectively. Minimal residual disease (MRD) was undetectable in peripheral blood (uMRD; <10-4 by flow cytometry) in 0%, 23% and 82% of patients, respectively. Median progression free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to undetectable MRD, nine of them progressed and two died without progression (median PFS: 28 months after discontinuation of treatment), while six patients remained in remission after a median observation time of 46 (range 6-47) months after discontinuation of treatment. Thus, MRD-guided fix-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation.