Durable remissions following combined targeted therapy in patients with CLL harboring TP53 deletions and/or mutations

Blood. 2021 Nov 11;138(19):1805-1816. doi: 10.1182/blood.2020010484.


Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<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 uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-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 (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / therapeutic use
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bendamustine Hydrochloride / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Female
  • Gene Deletion
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Male
  • Middle Aged
  • Mutation / drug effects
  • Piperidines / therapeutic use*
  • Progression-Free Survival
  • Prospective Studies
  • Sulfonamides / therapeutic use*
  • Tumor Suppressor Protein p53 / genetics*


  • Antibodies, Monoclonal, Humanized
  • Bridged Bicyclo Compounds, Heterocyclic
  • Piperidines
  • Sulfonamides
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ibrutinib
  • Bendamustine Hydrochloride
  • Adenine
  • ofatumumab
  • venetoclax
  • obinutuzumab

Associated data

  • ClinicalTrials.gov/NCT02689141
  • ClinicalTrials.gov/NCT02401503
  • ClinicalTrials.gov/NCT02345863