Combining Ibrutinib and Venetoclax Produces High MRD-Negative Rates in Treatment-Naïve CLL

The all-oral regimen of single-agent ibrutinib followed by combined ibrutinib and venetoclax increased the odds that patients with treatment-naïve chronic lymphocytic leukemia (CLL) will achieve minimal residual disease (MRD)–negativity, according to results from the phase II CAPTIVATE trial presented at the 23rd Congress of the European Hematology Association.

Combining ibrutinib with venetoclax also appeared to reduce the risk of tumor lysis syndrome (TLS), which has been a concern with venetoclax treatment, the authors, led by Paolo Ghia, MD, noted.

“Combining ibrutinib and venetoclax allows us to deliver deeper responses and to achieve a promising rate of MRD-negativity, with more than 80 percent of patients having undetectable MRD in the bone marrow (BM) after 12 cycles of combined treatment,” Dr. Ghia, from the Vita-Salute San Raffaele University in Milan, Italy, told ASH Clinical News.

CAPTIVATE is a multicenter, two-phase trial that enrolled 163 patients (median age = 58 years; age range = 18-70 years) with previously untreated CLL. In the first phase, participants received 420 mg ibrutinib monotherapy for a total of three cycles. Following the single-agent regimen, investigators administered 12-cycles of therapy consisting of ibrutinib plus oncedaily venetoclax 400 mg (following a 5-week ramp-up period) to evaluate MRD response (primary endpoint).

Once MRD status was confirmed, study researchers randomized patients to either continued treatment or placebo until progression of clinical disease or unacceptable toxicity.

At baseline, 14 percent of patients had CLL with del17p, 15 percent had del11q, and 33 percent had bulky disease (defined as longest lymph node diameter [LDi] ≥5 cm).

At the time of study presentation, 97 of the 163 enrolled patients completed the ibrutinib lead-in phase and had started on combined ibrutinib and venetoclax. Fourteen patients completed the safety analysis of ibrutinib lead-in therapy and underwent at least six cycles of combined therapy.

At 24 months of follow-up, all 14 of these patients responded to treatment (overall response rate = 100%), including 13 partial remissions and a complete remission in one of the five patients with BM results evaluable at the time of analysis.

Of the 11 patients evaluable for MRD testing, nine achieved MRDnegativity in peripheral blood samples.

During the safety run-in phase, there were no reported dose-limiting toxicities associated with treatment and “the adverse events (AEs) reported with ibrutinib and venetoclax combination are in line with those that are expected with either monotherapy,” said Dr. Ghia. Among the 97 participants who were exposed to combination therapy, the following AEs occurred:

  • diarrhea (39%)
  • fatigue (23%)
  • nausea (23%)
  • arthralgia (21%)

The most common grade ≥3 AEs occurring in patients exposed to combined therapy included:

  • neutropenia (10%)
  • hypertension (3%)
  • thrombocytopenia (3%)

According to the researchers, there were no clinically confirmed cases of TLS, though one patient met laboratory parameters for the syndrome. Early results also suggested that three cycles of ibrutinib lead-in reduced tumor bulk: In the 30 patients who presented with a baseline LDi of ≥5 cm, single-agent ibrutinib was associated with a reduction of LDi to <5 cm in 19 patients (63%).

For 17 of the 22 patients (77%) who were considered to be at high risk for developing TLS, lead-in treatment with ibrutinib also reduced their risk level to low or medium.

“Based on early phase II data from this study,” Dr. Ghia concluded, “we show the potential for deeper responses and treatment holidays.”

Because the findings are based on early data from an uncontrolled, phase II trial, the investigators noted that “additional follow-up for confirmation of durability of response and a prospective randomized study for comparison with standard treatments [are needed].”

Dr. Ghia reports financial relationships with Pharmacyclics and Janssen, which provided support for the CAPTIVATE trial.


Ghia P, Tam C, Siddiqi T, et al. Ibrutinib lead-in followed by venetoclax in patients with chronic lymphocytic leukemia: phase 2 CAPTIVATE early safety and efficacy results. Abstract #S806. Presented at the EHA 23rd Congress, June 16, 2018; Stockholm, Sweden.