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

Abstract

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.

Graphical abstract

Figure 1.

PFS. (A) PFS in all 51 patients. (B) PFS by prior treatment (previously untreated and relapsed/refractory). Cum, cumulative.

Figure 2.

OS. (A) OS in all 51 patients. (B) OS by prior treatment (previously untreated and relapsed/refractory).

Figure 3.

Swimmers plot of 17 patients with termination of treatment due to uMRD. Length of the bar shows duration of treatment (red), observation after treatment discontinuation (green) and start of next treatment line (dark blue). The time point of first documentation of uMRD in peripheral blood and bone marrow is indicated with a circle and a black dot, respectively. Documentation of progressive disease, Richter transformation, and death are as described in the symbol key in the image. BM, bone marrow; PB, peripheral blood.