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A fixed-duration, first-line combination of ibrutinib (Imbruvica) plus venetoclax (Venclexta) appeared feasible for chronic lymphocytic leukemia (CLL) patients who achieved undetectable minimal residual disease (MRD) status, results of the randomized CAPTIVATE study showed.

With a median follow-up of 16.6 months, the 1-year disease-free survival (DFS) rate was not significantly different between the group who continued on ibrutinib monotherapy following combination treatment, and those assigned to placebo (100% vs 95.3%; P=0.1475), reported William Wierda, MD, PhD, of MD Anderson Cancer Center in Houston.

The findings support "a fixed-duration treatment with 12 cycles of combined ibrutinib plus venetoclax, and treatment discontinuation for patients who achieve confirmed undetectable MRD," Wierda said during his presentation at the American Society of Hematology (ASH) virtual meeting.

But he stopped short of calling the results of the phase II trial practice-changing, saying additional data are needed from ongoing phase III trials.

"This is an initial study, it's a multicenter, international study, and it clearly shows the efficacy in terms of depth of remission with this combination," said Wierda.

The MRD cohort of the included 164 CLL/small lymphocytic lymphoma patients who received first-line treatment with ibrutinib plus venetoclax (three cycles of daily 420 mg ibrutinib alone, then 12 cycles of ibrutinib and venetoclax, up to 400 mg). Previously reported results showed that the first-line combination led to undetectable MRD in three-fourths of patients (75% in peripheral blood; 72% in bone marrow).

Patients with confirmed undetectable MRD (n=86) at the end of the combination period were then randomized 1:1 to either further treatment with ibrutinib alone or to placebo, while patients with unconfirmed undetectable MRD (n=63) were randomized 1:1 to ibrutinib alone or continued combination treatment. (Fifteen patients were not eligible for randomization).

Across all randomized arms, the 30-months progression-free survival (PFS) rate from the time of initial treatment was greater than 95%. In the confirmed undetectable MRD group, the 30-months PFS was 95.3% with placebo and 100% with ibrutinib. In the unconfirmed undetectable group, rates were 95.2% with ibrutinib monotherapy and 96.7% with combination treatment.

For patients who did not achieve confirmed undetectable MRD at the end of 12 cycles of combination therapy, greater improvements in MRD status was seen with continued combined therapy versus single-agent ibrutinib.

In bone marrow, the best overall undetectable MRD rates improved from 32% after initial combination treatment to 42% with ibrutinib monotherapy, while improving from 31% to 66% among those assigned to continued ibrutinib plus venetoclax. In peripheral blood, the rate remained steady at 45% with the switch to ibrutinib monotherapy and improved from 50% to 69% with continued combination therapy.

"We don't have a sufficient amount of data yet to be prescriptive about duration of treatment with these combinations," Wierda said during a question and answer portion. He noted that in studies of the combination conducted at MD Anderson, some patients have remained MRD positive even after 24 cycles of combination therapy.

He noted that there were no safety concerns with the "highly active combination."

Few patients required dose adjustment or drug discontinuation. Adverse events (AEs) occurred most frequently during the initial combination period prior to randomization, and tended to decrease thereafter, said Wierda. The most common grade 3/4 AEs included neutropenia in 36%, hypertension in 10%, and thrombocytopenia and diarrhea in 5% each.

Study Details

Patients had a median age of 58, 60% had unmutated IGHV, 20% had del(17p) or TP53 mutations, 19% had complex karyotype, and 17% had del(11q). More than a third of patients had one or more cytopenias, 32% had bulky lymph nodes (≥5 cm), and three-fourths had an absolute lymphocyte count of greater than 25 × 10⁹/L at enrollment.

Wierda pointed out that the lead-in phase of ibrutinib shifted 90% of patients at high risk for tumor lysis syndrome -- a known complication with venetoclax -- to medium or low risk. Overall, 82% started the combination portion without hospitalization.

Undetectable MRD (<10^-4 by 8-color flow cytometry) was confirmed serially over three cycles in both the peripheral blood and bone marrow. The DFS rate was defined as the proportion of patients who remained MRD negative and without clinical progression or death.

A higher proportion of patients with unmutated IGHV disease ended up having confirmed undetectable MRD (70% vs 46% in the unconfirmed arm). For randomization imbalances, Wierda noted a trend toward a higher proportion of patients with high-risk features assigned to ibrutinib in the confirmed undetectable MRD group.

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