Recently released data from the Phase II CAPTIVATE study showed that fixed-duration ibrutinib in combination with venetoclax led to deep, durable responses and continued progression-free survival among chronic lymphocytic leukemia (CLL) patients with high-risk genomic features. This research, which was published in the journal Clinical Cancer Research, also found that progression-free and overall survival rates in this patient population were similar to those without high-risk features (2023; doi: 10.1158/1078-0432.CCR-22-2779).
"Previously reported results from the CAPTIVATE study demonstrated deep and durable responses with sustained progression-free survival after fixed-duration therapy with ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia," said John Allan, MD, Associate Professor of Clinical Medicine at Weill Cornell Medicine, in a statement.
"The current analysis builds upon those results by demonstrating that these clinical outcomes are maintained at these early time points in patients with chronic lymphocytic leukemia harboring high-risk genomic features," he noted. "While further follow-up is required to understand longer-term outcomes, these results support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population."
Background & Methods
Historically, CLL patients with high-risk genomic features, including deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain (IGHV), have an increased risk of disease progression and death. Until recently, these patients-who typically don't respond to chemoimmunotherapy-had limited treatment options. The introduction of first-line targeted therapies, such as ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and venetoclax, a BCL-2 inhibitor, offer high-risk CLL patients new therapeutic avenues to explore.
"Synergistic antitumor activity with the combination of ibrutinib plus venetoclax has been demonstrated in preclinical models of chronic lymphocytic leukemia," explained Allan and colleagues. "The combination of ibrutinib plus venetoclax demonstrated high rates of undetectable minimal residual disease (uMRD) in both peripheral blood and bone marrow, high rates of progression-free survival, and durable treatment-free remissions in patients with previously untreated CLL/SLL treated with fixed-duration ibrutinib plus venetoclax in the CAPTIVATE and GLOW studies."
While previous findings from the CAPTIVATE trial suggested that fixed-duration ibrutinib plus venetoclax has potential as a first-line treatment for CLL, the benefit of this treatment regimen for high-risk CLL required further investigation.
"Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk chronic lymphocytic leukemia is important to determine how this regimen fits in the first-line treatment algorithm for the disease," Allan noted.
In CAPTIVATE-a multicenter, international, Phase II study-first-line ibrutinib plus venetoclax was investigated in two cohorts of CLL patients: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and fixed-duration (FD cohort). Patients in both cohorts received single-agent oral ibrutinib (420 mg once daily) lead-in for three 28-day cycles followed by 12 cycles of ibrutinib in combination with oral venetoclax (5-week ramp-up to 400 mg/day).
Individuals in the fixed-duration cohort received no further intervention regardless of MRD status at the end of treatment. In the MRD cohort, patients with confirmed uMRD after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment.
Eligibility criteria for this study included the following: adults aged >=18 to <70 years (MRD cohort) or <=70 years (FD cohort) with previously untreated CLL/small lymphocytic lymphoma; measurable nodal disease by computed tomography; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2; and adequate hepatic, renal, and hematologic function.
"Patients with known allergy to xanthine oxidase inhibitors and/or rasburicase were excluded due to the requirement for TLS prophylaxis per venetoclax prescribing information," noted the study authors.
In the exploratory post-hoc analysis of CAPTIVATE, data from the fixed-duration cohort and MRD cohort placebo arm were pooled for CLL patients with high-risk features who were treated with fixed-duration ibrutinib plus venetoclax. The research team excluded patients with unknown/missing status.
The clinical outcomes of interest were overall response rate; complete response (CR) rate, including CR with incomplete bone marrow recovery (CRi); undetectable MRD rates in peripheral blood and bone marrow; progression-free survival (PFS) by investigator assessment; overall survival; and safety.
Allan and colleagues monitored adverse events (AEs) during the treatment-emergent AE reporting period-from first dose until 30 days after the last dose of fixed-duration study treatment.
"Only serious adverse events considered related to study treatment and secondary malignancies continued to be collected during follow-up post-treatment," they stated. "Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Outcomes were analyzed for subgroups with versus without >=1 high-risk feature [del(17p), TP53 mutation, and/or unmutated IGHV]. Analyses of outcomes by individual high-risk features were also performed for patients with or without del(17p)/TP53 mutation and for patients with unmutated IGHV or mutated IGHV."
CAPTIVATE Findings
Allan and team enrolled 323 patients in CAPTIVATE-164 in the MRD cohort and 159 in the fixed-duration (FD) group. In total, 202 patients received with fixed-duration ibrutinib in combination with venetoclax in the fixed-duration (n=159) and MRD cohort placebo (n=43) arms.
Of the 195 patients with known status of genomic risk features at baseline, 129 (66%) had high-risk CLL. This included 29 patients with del(17p)/TP53 mutation and 119 patients with unmutated IGHV. Nineteen patients had both unmutated IGHV and del(17p)/TP53 mutation. Sixty-six patients did not have high-risk features. At the time of analysis, the study authors reported a median time on study of 38.9 months for patients with high-risk features, and 38.8 months for those without high-risk features. For the total pooled population, the median duration of post-treatment follow-up was 25.1 months.
Below are outcomes from the exploratory post-hoc analysis of CLL patients with high-risk genomic features treated with fixed-duration ibrutinib plus venetoclax. More than 95 percent of these patients had responses to the combination therapy, regardless of the presence of high-risk features. Sixty-one percent and 53 percent of patients with and without high-risk disease had complete responses, respectively.
Among patients who achieved complete response, data confirmed a duration of CR/CRi lasting 12 or more cycles in 92 percent of patients with high-risk features and 97 percent of those without high-risk disease.
"The 24-month landmark estimate for duration of CR/CRi was 93 percent (95% CI, 83-97) in patients with high-risk features and 100 percent (95% CI, 100-100) in those without high-risk features," Allan and colleagues reported. "In the subsets of patients with (n=29) and without del(17p)/TP53 mutation (n=169), CR/CRi rates were 52 percent (95% CI, 34-70) and 60 percent (95% CI, 52-67), respectively."
PFS of at least 36 months was observed in 88 percent of patients with high-risk CLL and 92 percent of patients without high-risk CLL. Additionally, the study authors found that more than 95 percent of patients with and without high-risk CLL were alive 36 months after starting treatment with this combination approach.
In terms of safety, this analysis showed that the safety profile of fixed-duration ibrutinib coupled with venetoclax was similar with and without the presence of high-risk genetic features. The most common adverse events were diarrhea (62% and 59% of patients with and without high-risk features, respectively), neutropenia (46% and 55%), nausea (42% and 44%), and arthralgia (33% and 32%).
Serious adverse events were seen in 22 percent of high-risk CLL patients compared with 21 percent of their low-risk counterparts. "During the fixed-duration treatment period, AEs led to discontinuation of ibrutinib only in 2 percent and 3 percent of patients with and without high-risk features, respectively, and discontinuation of both ibrutinib and venetoclax in 1 percent and 3 percent of patients, respectively," the researchers stated.
Allan and colleagues acknowledged that the exploratory nature of this research is a limitation and the analysis is not powered to perform statistical comparisons between patients with and without high-risk CLL.
"Complex karyotype was not included in the definition of high-risk genomic features in the current analysis given the lack of consensus in the definition for complex karyotype (e.g., >=3 or >=5 abnormalities) and lack of clear guidance on how complex karyotype should inform decision making in the clinic," the researchers noted. "In addition, data on complex karyotype was missing in many patients (particularly in the FD cohort) and exclusion of these patients with missing data would have further reduced the numbers of patients in already small subgroups, whereas del(17p), TP53 mutation, and IGHV mutation status were known for nearly all patients."
Key Takeaways
Findings from this exploratory, post-hoc analysis of the Phase II CAPTIVATE study, support the potential benefit of first-line ibrutinib plus venetoclax in CLL patients with and without high-risk genomic features.
"Results from the CAPTIVATE study demonstrated that first-line ibrutinib plus venetoclax provides deep, durable responses and sustained progression-free survival in patients with chronic lymphocytic leukemia," Allan and colleagues summarized, while noting that the current analysis confirms these clinical outcomes are maintained, even among patients with one or more high-risk genomic features, including del(17p), TP53 mutation, or unmutated immunoglobulin heavy chain, which are associated with increased rates of disease progression and poor responses to chemoimmunotherapy.
"These results support fixed-duration treatment with ibrutinib plus venetoclax as an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides clinically meaningful PFS and treatment-free remissions in the first-line treatment of patients with chronic lymphocytic leukemia, including those with del(17p), TP53 mutation, or unmutated IGHV," they concluded.
Catlin Nalley is a contributing writer.
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