Fixed-duration ibrutinib/venetoclax combo feasible in first-line CLL/SLL treatment

Patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) who achieve undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM) after 12 cycles of first-line treatment with ibrutinib plus venetoclax have similar 1-year disease-free survival (DFS) rates regardless of whether ibrutinib is continued or not, results of the phase II CAPTIVATE study have shown.

According to the investigators, this finding supports a fixed-duration treatment approach in CLL/SLL, with the ibrutinib/venetoclax combination offering an all-oral, once-daily, chemotherapy-free option that provides highly concordant, deep MRD remissions in PB and BM in the first-line setting. [Wierda WG, et al, ASH 2020, abstract 123]

In the study, 164 patients with previously untreated active CLL/SLL (median age, 58 years; Rai stage III/IV disease, 32 percent; del(17p)/TP53 mutation, 20 percent; del(11q), 11 percent; complex karyotype, 19 percent; unmutated IGHV, 60 percent) were given three cycles of ibrutinib (420 mg QD) lead-in, followed by 12 cycles of ibrutinib (420 mg QD) plus venetoclax (ramped up to 400 mg QD). Patients with confirmed uMRD (defined as <10^-4 serially over ≥3 cycles in both PB and BM) after 12 cycles of combination therapy were randomized 1:1 to receive double-blind treatment with placebo or ibrutinib, while those without confirmed uMRD were randomized to receive open-label treatment with ibrutinib or ibrutinib plus venetoclax. The primary endpoint was 1-year DFS (defined as freedom from MRD relapse [≥10^-2 confirmed on two separate occasions] without disease progression or death) rate in patients with confirmed uMRD.

After 12 cycles of combination therapy, uMRD rate was 75 percent in PB and 72 percent in BM. Confirmed uMRD rate was 93 percent in patients with matched PB and BM samples.

“Among 86 patients with confirmed uMRD, 1-year DFS rate was 95.3 percent in those randomized to receive placebo vs 100 percent in those who received ibrutinib [p=0.1475], after a median post-randomization follow-up of 16.6 months,” reported investigator Dr William Wierda of the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

In patients without confirmed uMRD after 12 cycles of ibrutinib/venetoclax combination therapy, additional combination therapy led to increases in uMRD rates from 50 percent to 69 percent in PB, and from 31 percent to 66 percent in BM. With additional ibrutinib monotherapy, uMRD rate increased from 32 percent to 42 percent in BM, but remained unchanged at 45 percent in PB.

“After a median on-study follow-up of 31.3 months, 30-month progression-free survival [PFS] rate was 95.3 percent in all patients, 95.3 percent vs 100 percent in patients with confirmed uMRD who were randomized to receive placebo vs ibrutinib, and 95.2 percent vs 96.7 percent in patients without confirmed uMRD who continued ibrutinib monotherapy vs ibrutinib/venetoclax combination therapy,” Wierda reported.

Adverse events (AEs) were primarily grade 1/2 and generally decreased after the first 6 months of ibrutinib/venetoclax combination therapy, with no new safety signals observed. The most common grade ≥3 AEs were neutropenia, hypertension, and infections.

In the confirmed uMRD cohort, AEs led to dose reduction in 2 percent vs 7 percent of patients in the placebo vs ibrutinib group, and to discontinuation in none of the patients. In patients without confirmed uMRD, AEs led to ibrutinib dose reduction in 6 percent of patients in treatment each group, ibrutinib discontinuation in 3 percent vs 6 percent of patients receiving continued ibrutinib vs ibrutinib plus venetoclax, and venetoclax discontinuation in 6 percent of patients in the combination therapy group.

“Three cycles of ibrutinib lead-in reduced the risks of tumour lysis syndrome [TLS] and hospitalization,” Wierda pointed out. “After ibrutinib lead-in, 90 percent of patients with high TLS risk at baseline shifted to a medium or low TLS risk category, and 66 percent of patients for whom hospitalization would have been indicated for venetoclax initiation no longer required hospitalization. Overall, 82 percent of patients initiated venetoclax after ibrutinib lead-in without hospitalization.”