Molecular analysis supports ibrutinib-venetoclax in poor-risk CLL patients

Findings from the phase III NCRI* FLAIR** trial demonstrate the benefit of MRD***-guided ibrutinib + venetoclax (I+V) in chronic lymphocytic leukaemia (CLL) patients with gene aberrations compared with ibrutinib and fludarabine, cyclophosphamide, and rituximab (FCR).

“[In this] molecular analysis of almost 1,500 patients … MRD-guided I+V has a significant impact on progression-free survival (PFS) and overall survival (OS) for previously poor-risk molecular subtypes of CLL,” said Dr Surita Dalal from the Leeds Teaching Hospitals NHS Trust, Leeds, UK, at ASH 2025.

“Approximately two-thirds of patients in these poor-risk groups and half of those with TP53 mutations (TP53m) achieved MRD negativity and stopped I+V treatment after 2 or 3 years,” Dalal added.

FLAIR is an ongoing trial comparing ibrutinib + rituximab (IR) and FCR in previously untreated, fit CLL patients requiring therapy. In 2017, the study was subsequently adapted to compare I+V and I alone with FCR. In this analysis (n=1,488; median age 62 years, 72.1 percent men), comparisons were made between I+V and FCR (arm 1), I+V and I&IR (arm 2), and I&IR and FCR. [ASH 2025, abstract 679]

Looking at prognostic markers, 49.5 percent were IGHV^#-unmutated (IGHV-UM), 36 percent were IGHV-mutated (IGHV-M), and 6.4 percent had stereotyped subset #2 (S#2). “Despite often being IGHV-M, S#2 appears to be associated with a poorer outcome following chemoimmunotherapy,” Dalal noted.

The most frequently mutated genes were SF3B1, ATM, and NOTCH1 (17, 14.4, and 11.7 percent, respectively), and 4.7 percent had TP53m. According to Dalal, TP53m confers the worst outcome in CLL, and patients with TP53m are deemed unsuitable for chemotherapy.

Outcomes by IGHV

In the IGHV-UM subgroup, I+V had a significant advantage over FCR and I&IR for both PFS (hazard ratios [HRs], 0.08 and 0.2 for arms 1 and 2, respectively; p<0.001 for both) and OS (HR, 0.16; p=0.002 and HR, 0.26; p=0.024, respectively).

At 5 years, 94.9 percent of IGHV-UM I+V recipients were progression-free, 97.4 percent were alive, and two-thirds stopped treatment by 3 years as per MRD stopping rules. Conversely, none in the I&IR arm achieved the MRD stopping criteria. “Approximately 87 percent of IGHV-UM FCR recipients went on to receive second-line targeted treatment following relapse,” Dalal added.

For IGHV-M patients, I+V was superior to FCR in terms of PFS (HR, 0.47; p=0.0021) but not OS (HR, 0.77; p=0.508) and was not superior to I&IR (HR, 0.64; p=0.192 [PFS] and HR, 0.95; p=0.898 [OS]). At 5 years, 90.1 percent were progression-free, and 92.2 percent were alive.

S#2, ATM aberrations

In the S#2 subgroup, approximately 60 percent were IGHV-M, 38 percent had SF3B1m, and 27 percent had ATMm. I+V and I&IR conferred superior PFS over FCR (HR, not evaluable [NE]; p=0.002 and HR, 0.32; p=0.003). All 16 I+V recipients with S#2 remained alive and progression-free despite 60 percent having stopped therapy by year 3.

In patients with del11q and/or ATMm, about three-quarters were IGHV-UM. I+V had a significant advantage over FCR and I&IR in PFS (HR, 0.02; p<0.001 and HR, 0.06; p=0.006) and OS (HR, NE; p=0.001 and HR, NE; p=0.007). Of the 70 I+V-treated patients with ATMm, all were alive, and all but one were progression-free, despite treatment cessation in 65 percent after 2 or 3 years.

TP53

Among patients with TP53m (70 percent IGHV-UM), I+V conferred a significant PFS advantage over FCR and I&IR (HR, NE; p=0.005 and HR, NE; p=0.039). None of the I+V recipients with TP53m progressed or died, despite half ceasing therapy after 2 or 3 years.

Of the 11 patients with TP53m who received I+V, six stopped therapy as per MRD stopping criteria, but two restarted upon achieving MRD positivity without disease progression. Another patient stopped therapy after contracting COVID but remained MRD undetectable. Four patients went off treatment with no detectable MRD.

“Further follow-up and more patients with TP53 disruptions are required to make a definitive conclusion; however, the results for MRD-guided I+V are promising,” noted Dalal.

SF3B1, NOTCH1

In patients with SF3B1m, 60 percent carried the p.K700Em. The most common co-occurring mutation was ATM (20 percent). The 5-year PFS with I+V was significantly superior to FCR (HR, 0.11; p=0.002) and I&IR (HR, 0.21; p=0.034). Looking at OS, there was a trend favouring I+V (HR, 0.29; p=0.227 and HR, 0.32; p=0.277 for arms 1 and 2, respectively).

Of those with NOTCH1m, 80 percent had IGHV-UM and 91 percent had the frameshift hotspot p.P2514Rfs*4m. Trisomy 12 co-occurred in 35 percent of patients. Consistent with the SF3B1 subgroup, the 5-year PFS with I+V was also superior to FCR (HR, 0.12; p=0.005) and I&IR (HR, 0.22; p=0.043). All 34 I+V recipients were alive at 5 years (HR, NE; p=0.005 and HR, NE; p=0.053 for arms 1 and 2, respectively).

“In both groups, two-thirds had stopped treatment according to MRD stopping rules by 3 years,” Dalal said.

A highly effective Tx

“[Taken together, the findings show] that targeted treatment with MRD-guided I+V is highly effective in overcoming the adverse prognostic effects associated with IGHV-UM status, S#2, and recurrent poor-risk genetic aberrations when treated with chemoimmunotherapy,” Dalal concluded.