Combined targeted therapy with BTK inhibitors and venetoclax (VEN) is an effective, time-limited treatment for patients (pts) with treatment-naïve (GLOW, FLAIR) and relapsed (CLARITY) CLL when administered as definitive treatment and our group reported activity with VEN as a consolidation strategy for pts already receiving BTK inhibitors. We previously reported a phase 2 trial that added VEN for up to two years to ongoing ibrutinib (IBR) in pts who had received ≥12 months of IBR, had measurable CLL and had at least one high-risk feature defined as one of the following: TP53 mutation, del(17p), del(11q), complex karyotype (≥3 separate abnormalities), or elevated β2-microglobulin (Thompson PA et al Leukemia 2023). Pts who achieved complete response (CR) with undetectable measurable residual disease at 10-4 sensitivity (uMRD4) in bone marrow (BM) by flow cytometry on two consecutive occasions, 6 months apart, ceased VEN. Pts who had detectable MRD4 at the end of treatment continued IBR monotherapy as maintenance, while those with uMRD4 could continue or stop IBR at physician discretion. The aim of this report is to update progression-free survival (PFS) and the kinetics of MRD4 re-emergence.

45 pts were enrolled between Dec 2017 and Dec 2019. Median number of prior therapies was 1 (range 0–3); 22/45 pts were receiving IBR as initial therapy. Pre-treatment characteristics included TP53 mutation and/or del(17p) in 63% and complex karyotype in 31% of pts. Of all pts enrolled, 33/45 (73%) achieved uMRD4 by completion of up to 24 cycles of VEN; of these, 22 discontinued IBR therapy and 11 continued IBR maintenance. The 12 pts who remained MRD4-detectable remained on IBR.

The 5-year PFS probability is 77%; median overall follow-up was 5.5 years. Eleven pts experienced progression of CLL, including 1 pt who developed Richter transformation while on observation after completing combined treatment. Four of the 11 pts had continued IBR after completion of VEN consolidation and 7 had discontinued both VEN and IBR at the time of completion of VEN consolidation. The best response to VEN consolidation for these 11 pts was CR in 7 pts (uMRD4 in 3) and PR in 4 pts (uMRD4 in 1). Genomic features prior to VEN treatment of the 11 pts with progression showed complex karyotype in 7 and del(17p)/TP53 mutation in 3 pts, which did not differ from the cohort as a whole. Mutation in BTK C481S were detected in 3 of these pts at the time of disease progression, 1 who had remained on IBR 20 months after discontinuing VEN, 2 while on observation 4 and 5 years after completing VEN consolidation. No BCL2 mutations observed.

Forty-one pts are alive, and 4 died for an overall survival of 91% at 5 years. Two pts died from non-CLL malignancies: 1 from metastatic melanoma and 1 from AML who had received chemoimmunotherapy before starting IBR. One pt was lost to follow-up and died of unknown causes after developing disease progression and 1 pt died of progressive CLL.

Among the 33 pts who achieved BM u-MRD4, peripheral blood (PB) MRD4 was monitored every 6 months, and 17 pts (52%) showed MRD4 re-emergence with a median time to re-emergence of 4.1 years (range: 2.6 months – 4.6 years). Among the 17 pts with MRD4 re-emergence 14 had discontinued IBR and 3 continued IBR at the time of completion of VEN consolidation.

At the time of MRD4 re-emergence: 10 pts were in complete remission (CR) and 7 pts were in partial remission (PR) indicating that MRD4 re-emergence preceded clinical relapse. We reviewed the genomic features prior to VEN treatment of the pts with MRD4 re-emergence and there were no pre-treatment clinical or genomic features that predicted for early MRD4 re-emergence.

In summary, VEN consolidation for up to two years added to IBR with an MRD4-adapted treatment duration was associated with durable off-treatment remissions in high genomic-risk pts who achieved uMRD4. The strategy as a whole yielded favorable long-term PFS, with low-risk for developing treatment-emergent BTK or BCL2 mutations.

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2025
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