Venetoclax loses its shine in BTKi-exposed CLL

Blood cancers

By Mardi Chapman

1 Feb 2024

Real-world data shows covalent BTKi-exposed patients with CLL can benefit from time-limited venetoclax-rituximab (VEN-R) but not to the same extent as seen in clinical trials of largely BTKi-naive cohorts.

An Australian study, published in Blood Advances [link here], comprised a review of 47 consecutive patients treated with venetoclax-containing therapy at four major metropolitan hospitals between November 2016 and February 2023.

Their most common first cBTKi was ibrutinib and in about 80% of patients, progressive disease was the most common reason for BKTi cessation.

Thirty-two patients (68%) of patients received time-limited VEN-R while the remainder (32%) received continuous venetoclax monotherapy.

The study found the objective response rate (ORR) to VEN-R was 81% (26/32) and the complete response rate (CR) was 19% (6/32).

“The median PFS after VEN-R initiation was 25.9 (95%CI 9.2-42.2) months and the median OS was 46.1 (95%CI 21.9-not estimable [NE]) months,” the study found.

However this compares poorly compared to the median PFS of 53.6 months and median OS not reached, as demonstrated in the MURANO trial [link here].

The study said the presence of del(17p) and/or TP53 mutations was significantly associated with inferior PFS (HR 3.55 [95%CI 1.03-12.17]; p= 0.044).

“The median PFS and OS for patients receiving continuous VEN-monotherapy was 10.5 (95%CI 1.1-28.9) and 30.5 (95%CI 1.1-NE) months, respectively,” the investigators said.

The investigators, including first author Dr Thomas Lew from The Royal Melbourne Hospital, Peter MacCallum Cancer Centre and Walter and Eliza Hall Institute, also noted that Richter transformation (RT) at disease progression was common (8/12; 67%).

“Clinicians and patients should be cognizant that prolonged treatment-free remissions are uncommon after prior BTKi exposure, particularly among patients with TP53-aberrant disease, limiting the potential for future VEN retreatment,” they said.

“Given the high rate of RT and poor salvageability anticipated at PD, consolidative strategies such as alloSCT or other immune-based therapies should be considered in appropriate patients with responsive disease.”

The Australian findings are largely consistent with those of a US study presented at the ASH Annual Meeting late last year.

The study from the Fred Hutchinson Cancer Center in Seattle, found median PFS was significantly inferior in patients who experienced disease progression on prior cBTKi compared with those who were intolerant to prior cBTKi (17 months vs. 55 months, p=0.002).

The investigators said their findings suggested that venetoclax-containing therapy following cBTKi may only be feasible in a subset of patients who stopped cBTKi because of intolerance rather than disease progression.

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