A REGIMEN COMBINING ibrutinib (Imbruvica) and venetoclax (Venclexta) in previously untreated patients with chronic lymphocytic leukemia (CLL) greatly reduced the risk of venetoclax-associated tumor-lysis syndrome and led to promising rates of undetectable minimal residual disease (MRD) in the phase II CAPTIVATE study, William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues reported at the 2018 ASCO Annual Meeting.1
“We saw tumor debulking and a reduction in risk for venetoclax-associated tumor-lysis syndrome after 3 [28-day] cycles of lead-in single-agent ibrutinib, and the early MRD data showed very encouraging results, with 77% of the first 30 patients having undetectable MRD in the blood after just 6 cycles of combined treatment,” Dr. Wierda said.
“We are seeing very promising results, with a high proportion of patients with undetectable MRD in blood or bone marrow after 6 months or 1 year of combined treatment.”— William G. Wierda, MD, PhD
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Strong Rationale for Combination
IBRUTINIB IS a frequent treatment in the first-line and relapsed CLL. Continuous treatment with ibrutinib is utilized because most patients achieve partial remission as their best response, with residual disease typically persistent in the peripheral blood and/or bone marrow if the drug is stopped. Venetoclax is a BCL2 inhibitor (inducing apoptosis in CLL cells) approved for relapsed patients with del(17p). The majority of patients respond to single-agent venetoclax, with most responses being durable partial remissions. Residual disease typically manifests as persistently enlarged lymph nodes, but venetoclax is highly effective at clearing disease from blood and bone marrow, he said.
Together, ibrutinib and venetoclax have shown synergy and complementary clinical activity in preclinical and ongoing clinical studies. The all-oral combination offers the potential for deeper remissions and treatment holidays for ibrutinib and a reduction in the risk for tumor-lysis syndrome with an ibrutinib lead-in, he said.
CAPTIVATE Trial Details
DR. WIERDA PRESENTED the planned interim analysis of the phase II CAPTIVATE trial, which enrolled 164 treatment-naive patients with CLL, all of whom had an indication for treatment. Subjects received 3 months of ibrutinib monotherapy as a lead-in treatment (to debulk disease and prevent tumor-lysis syndrome) followed by 1 year of combined ibrutinib and venetoclax.
In the lead-in phase, patients received ibrutinib at 420 mg once daily for 3 cycles (each cycle = 28 days), followed by ibrutinib plus venetoclax dose escalated to 400 mg once daily for 12 cycles. At baseline and after 3 cycles of ibrutinib, patients were assessed for venetoclax-associated tumor-lysis syndrome. After cycles 9, 12, and 15, they underwent MRD assessment in the peripheral blood; after cycle 15, they were evaluated for MRD in blood and bone marrow and had staging computed tomography (CT) scan (ie, underwent assessment of full response).
FIRST-LINE IBRUTINIB PLUS VENETOCLAX IN CLL
- The combination of ibrutinib plus venetoclax in treatment-naive patients with CLL was studied in the phase II CAPTIVATE trial.
- In the interim analysis, three cycles of ibrutinib lead-in significantly reduced the risk for tumor-lysis syndrome and converted many high-risk patients to low or medium risk.
- Among 30 patients who received 9 cycles, 77% had confirmed undetectable MRD in the peripheral blood. In the cohort of 14 patients who completed all 15 cycles, 93% were MRD-negative in the blood and 86% were MRD-negative in the bone marrow; 79% were MRD-negative in both the blood and bone marrow.
After 12 cycles of combination treatment, patients will be randomized based on MRD status. Those who were confirmed to have undetectable MRD (< 0.01% CLL cells/leukocytes) will be randomized to receive continued ibrutinib monotherapy or placebo. The objective was to determine whether ibrutinib could be discontinued in MRD-negative patients without compromising disease-free survival. Patients in whom undetectable MRD could not be confirmed (ie, MRD-positive) were randomized to receive ibrutinib monotherapy or continued combination ibrutinib/venetoclax.
There were 164 patients for whom safety was assessed, up to the point of randomization. A total of 30 patients received 6 months of combined treatment and had MRD assessment of the blood. There were 14 patients who completed 12 cycles of combined treatment and had both blood and bone marrow assessments and staging CT; of them, 11 were available for assessment of full response.
Reduction in Tumor-Lysis Syndrome
“WE FOUND THAT 3 cycles of ibrutinib in the lead-in phase markedly reduced the risk for tumor-lysis syndrome and bulky disease,” Dr. Wierda said.
After lead-in ibrutinib, 90% of patients deemed to be at high baseline risk for tumor-lysis syndrome shifted to medium or low risk. There were 19% with a medium baseline risk and creatinine clearance < 80 mL/min who shifted to low risk. “There were no hospitalizations in 77% of patients whose baseline status could have required hospitalization for monitoring of tumor-lysis syndrome,” he reported.
“The spectrum of adverse events was consistent with the historic safety profile of single-agent ibrutinib and with adverse events that are expected with venetoclax, with no new safety signals,” Dr. Wierda said.
As for adverse events of special interest, atrial fibrillation was seen in five patients (3.0%; grade 3 in 1.2%) during ibrutinib lead-in and in seven patients (4.3%; grade 3 in 0.6%) during combination treatment; there were no grade 4 events. Fewer than 5% of patients discontinued treatment, mostly for adverse events.
High Rates of Undetectable MRD
IN THE COHORT of 30 patients who received 6 cycles of the combination, 77% had confirmed undetectable MRD in blood. In the cohort of 14 patients who completed 12 cycles of the combination, 93% had undetectable MRD in blood and 86% had undetectable bone marrow MRD; after 12 cycles, 79% of this cohort was MRD-negative in both the blood and bone marrow, he reported. “We are seeing very promising results, with a high proportion of patients with undetectable MRD in blood or bone marrow after 6 months or 1 year of combined treatment,” Dr. Wierda commented.
The objective clinical response rate was 100%, of which 36% were complete responses. Complete response and complete response with incomplete blood count recovery were achieved by the two patients who had del(17p) and by four of the nine patients without del(17p).
All patients with lymphadenopathy and all with splenomegaly had reductions in lymph node bulk and spleen size, respectively, with many cases completely resolving.
Fixed-duration ibrutinib/venetoclax as first-line CLL treatment is being further studied in the phase III GLOW/CLL3011 trial (ClinicalTrials.gov identifier NCT03462719). ■
DISCLOSURE: Dr. Wierda has served as a consultant or advisor to Genzyme and has received research funding from AbbVie, Acerta Pharma, Emergent BioSolutions, Genentech, Gilead Sciences, GlaxoSmithKline/Novartis, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, and Pharmacyclics.
REFERENCE
1. Wierda W, Siddiqi T, Flinn I, et al: Phase 2 CAPTIVATE results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia. 2018 ASCO Annual Meeting. Abstract 7502. Presented June 3, 2018.
