Constantine S. Tam, MD
The first-line combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to a 75% undetectable minimal residual disease (uMRD) rate in peripheral blood and 72% in bone marrow in the treatment of patients with chronic lymphocytic leukemia (CLL) <70 years old, according to findings from the MRD-cohort of the phase II CAPTIVATE trial presented at the 2019 ASH Annual Meeting.1
“Ibrutinib plus venetoclax represents an all-oral, once-daily, chemotherapy-free regimen that provides high rates of undetectable MRD in peripheral blood and bone marrow in the first-line treatment of CLL,” lead study author Constantine S. Tam, MBBS, MD, hematologist and disease group lead, Low Grade Lymphoma and Chronic Lymphocytic Leukemia, said in a presentation during the meeting.
“These excellent results validate synergism shown in preclinical studies,” he added. “The favorable [safety] profile of the combination with a low rate of discontinuation because of an adverse event (AE)—5% of patients had to stop because of an AE—and [the fact that] 90% of patients completed the intended treatment, really underscores this treatment as a viable option for [these patients].”
In the international, multicohort, phase II CAPTIVATE trial (NCT02910583), investigators enrolled 164 treatment-naïve patients with CLL who required treatment as per International Workshop on Chronic Lymphocytic Leukemia criteria. Patients must have been <70 years old and had an ECOG performance status of 0 to 1.
Ibrutinib was initially administered alone in a lead-in stage at 420 mg daily for the first 3 cycles. After this stage, venetoclax was added and eventually escalated to a 400-mg daily dose. MRD was defined as <0.01% CLL cells by flow cytometry in the peripheral blood after 6 cycles of combination therapy and measured again by bone marrow after 12 cycles of ibrutinib plus venetoclax. Data presented at the 2019 ASH Annual Meeting were from the pre-randomization phase of the double-blind CAPTIVATE-MRD cohort.
Findings from the MRD-guided randomization phase of the trial are not yet available. In this phase, patients are randomized 1:1 to receive ibrutinib or placebo (undetectable MRD) or ibrutinib or ibrutinib/venetoclax (detectable MRD). Time-limited therapy with 12 cycles of ibrutinib combined with venetoclax are to be evaluated in a separate fixed-duration cohort (n = 159).
The median age of patients was 58 years (range, 28-69), and 32% had Rai stage III/IV disease. Twenty percent of patients had 17p deletion (del17p)/TP53
mutations, 17% had 11q deletions, and IGHV
was unmutated for 59% of patients. The median creatinine clearance (CrCl) was 95.0 mL/min and 30% of patients had clearance <80 mL/min.
Although the trial was not intended to enroll high-risk patients, Tam explained that investigators ended up accruing a notable amount of those with high-risk cytogenetics.
Earlier findings from this study, which were presented at the 2018 ASCO Annual Meeting, showed that the frontline combination of ibrutinib and venetoclax demonstrated a 100% objective response rate (ORR) for patients with CLL, and 77% of patients tested negative for MRD in the peripheral blood after 6 cycles.2
Moreover, in 11 patients who were treated with 12 cycles of ibrutinib and venetoclax with available bone marrow data, the complete remission (CR) rate was 36% and the rate of CR with incomplete hematologic recovery (CRi) was 18%. Remaining responses consisted of nodular partial remissions (nPR; 9%) and PRs (36%). All patients with a CR/CRi had confirmed uMRD in the bone marrow. Sixty percent of those with a PR/nPR were MRD negative.
In the data presented at the 2019 ASH Annual Meeting, results showed that after 3 cycles of ibrutinib lead-in, hospitalization for tumor lysis syndrome (TLS) was avoided in 76% of at-risk patients. Among patients who had high baseline TLS risk, 90% became medium or low risk, and 74% were not hospitalized when initiating venetoclax. Additionally, no patients with medium or low TLS risk became high risk, Tam noted.
Five patients discontinued ibrutinib prior to starting venetoclax; 4 were because of AEs and 1 was due to Richter’s transformation. Seven patients discontinued the combination treatment due to AEs (n = 4), as well as disease progression, patient withdrawal, and investigator decision (n = 1 each). Ninety percent of patients (n = 152) completed all 12 cycles of ibrutinib/venetoclax combination therapy, with a median treatment duration of 14.7 months (range, 0.5-19.9) and 12 months (range, 0.8-12.7) with ibrutinib and venetoclax. No patients have died.
uMRD was evaluated in peripheral blood (n = 163) and bone marrow (n = 155). Results also showed that in patients with undetectable MRD at cycle 16 in the peripheral blood with matched bone marrow samples, 93% had uMRD in both peripheral blood and bone marrow.