Fixed-Duration Ibrutinib/Venetoclax Elicits Meaningful Survival Benefit in High-Risk CLL/SLL

Ryan Jacobs, MD

Treatment with fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta) resulted in meaningful survival benefits, as well as durable responses and an acceptable safety profile, in high-risk subgroups of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to findings from the 5.5-year follow-up of the phase 2 CAPTIVATE study (NCT02910583) that were presented at the 2024 EHA Congress.¹

The median progression-free survival (PFS) was not reached in the fixed-duration treatment cohort, and the 5-year overall survival (OS) rates were 90% or greater regardless of genomic risk features. The 5-year PFS rates were 67% (95% CI, 59%-74%) in all treated patients (n = 159); 54% (95% CI, 39%-67%) in patients with 17p deletions (del(17p)), TP53 mutations, or complex karyotype (n = 51); and 77% (95% CI, 66%-85%) in patients without del(17p), TP53 mutations, or complex karyotype (n = 85).The 5-year OS rates were 96% (95% CI, 91%-98%) in all treated patients; 90% (95% CI, 77%-96%) in patients with del(17p), TP53 mutations, or complex karyotype; and 100% (95% CI, 100%-100%) in patients without del(17p), TP53 mutations, or complex karyotype.

“[These outcomes] with fixed-duration ibrutinib plus venetoclax correlate to achievement of undetectable minimal residual disease [MRD],” first study author Ryan Jacobs, MD, of Levine Cancer Institute in Charlotte, North Carolina, and coauthors, stated in a poster presentation of the data. “Patients with high-risk genomic features, including del(17p) [and] TP53 mutations, complex karyotype, and unmutated IGHV, derive meaningful survival benefits from fixed-duration ibrutinib plus venetoclax.”

What to Know About the CAPTIVATE Study

The investigative combination is currently approved for the first-line treatment of patients with CLL/SLL across 78 countries in Asia, Europe, the Middle East, and South America, as well as in Canada, Australia, and New Zealand. Investigators evaluated the combination in patients with high-risk genomic features enrolled onto the fixed-duration cohort of CAPTIVATE. They also examined retreatment outcomes in patients in the same cohort, as well as in those in the MRD cohort placebo arm.

Patients up to 70 years or of age with previously untreated CLL/SLL were eligible for enrollment without restriction on genomic risk features onto 1 of 2 cohorts in CAPTIVATE: the MRD-guided randomized discontinuation cohort or the fixed duration cohort. Patients then received 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib plus venetoclax. Ibrutinib was administered at 420 mg orally daily, and venetoclax was administered at a 5-week ramp up to 400 mg orally daily.

Patients with confirmed undetectable MRD at a sensitivity of less than 10⁴ by 8-color flow cytometry serially over at least 3 cycles in both bone marrow and peripheral blood after 12 treatment cycles were randomly assigned 1:1 to receive either placebo or ibrutinib. Notably, patients who experienced disease progression following completion of 12 cycles of the fixed-duration ibrutinib-plus-venetoclax regimen were permitted to restart single-agent ibrutinib in the fixed-duration or MRD cohort placebo arms. Only the placebo arm was included in the current analysis. Those with disease progression occurring more than 2 years after completing treatment could re-initiate the fixed-duration ibrutinib-plus-venetoclax regimen in the fixed-duration cohort.

The median time on study was 61.2 months (range, 0.8–66.3) at the time of data analysis.

Understanding the High-Risk Patient Profiles

In the fixed-duration cohort of patients, the median age was 60 years (range, 33-71), 67% of patients were male, and 28% of patients presented with Rai stage III or IV CLL. Regarding high-risk genomic features, there was presence of unmutated IGHV (56%), del(17p)/TP53 mutations (17%), del(17p) without TP53 mutations (13%), 11q deletions (del(11q); 18%), and complex karyotype (23%). Notably, complex karyotype status was not available for 26 patients, and del(17p) status was missing for 3 patients.

Furthermore, 34% of this patient cohort had some form of cytopenia. This included 8% of patients with an absolute neutrophil count at or below 1.5 × 10⁹/L, 23% of patients with hemoglobin levels at or below 11 g/dL, and 13% of patients with a platelet count at or below 100 × 10⁹/L. In addition, 30% of patients had bulky lymph node disease of at least 5 cm. The median absolute lymphocyte count (ALC) was 70 × 10⁹/L (range, 1 × 10⁹-503 × 10⁹); 75% of patients had an ALC at or above 25 × 10⁹/L.

Four patients with Richter transformation were enrolled. These patients were characterized by different subtypes of lymphoma, including diffuse large B-cell lymphoma (DLBCL) and Hodgkin disease. Patient 1 was a 68-year-old male with DLBCL who was diagnosed with Rai stage I disease with a time from CLL diagnosis to study enrollment of 46.5 months. This patient had bulky lymph node disease measuring at least 5 cm and exhibited high-risk genomic features, including unmutated IGHV and complex karyotype. Patient 2 was a 58-year-old male diagnosed with Rai stage II Hodgkin disease who had a time from CLL diagnosis to study enrollment of 13.3 months and presented with bulky lymph node disease; this patient had unmutated IGHV and del(11q).

Patient 3 was a 48-year-old male with DLBCL who was diagnosed at Rai stage IV and had a time from CLL diagnosis to study enrollment of 6.3 months. This patient did not have bulky lymph node disease but exhibited unmutated IGHV, a del(17p)/TP53 mutation, and complex karyotype. Patient 4 was a 55-year-old female with DLBCL who was diagnosed at Rai stage I and had a time from CLL diagnosis to study enrollment of 9.4 months. This patient did not have bulky lymph node disease and presented with high-risk genomic features, including unmutated IGHV and complex karyotype.

Among patients who were retreated (n = 32), the median age was 59 years (range, 39-71), most were male (66%), and 19% had Rai stage III or IV disease. High-risk genomic features included unmutated IGHV (78%), del(17p)/TP53 mutations (31%), del(11q) (22%), and complex karyotype (34%). Thirty-four percent of patients had bulky lymph node disease measuring at least 5 cm.

Additional Efficacy and Safety Data With the Fixed-Duration Treatment

“5-Year PFS rates were improved in patients who achieved undetectable MRD4 (at a sensitivity of less than 10⁴ by 8-color flow cytometry) in peripheral blood or bone marrow in the fixed-duration cohort,” the authors wrote. “In high-risk genomic subgroups...the 5-year PFS rates were also consistently higher in patients with undetectable MRD4 in peripheral blood or bone marrow at 3 months after end of treatment than in those without undetectable MRD4.”

Among patients with unmutated (n = 89) and mutated (n = 66) IGHV, the respective 5-year PFS rates were 56% (95% CI, 45%-66%) and 80% (95% CI, 68%-88%). When excluding patients with del(17p), TP53 mutations, or complex karyotype, these respective rates were 68% (95% CI, 50%-80%) and 85% (95% CI, 69%-93%).

The 5-year PFS rates by individual high-risk feature were as follows:

• 41% (95% CI, 21%-59%) in patients with del(17p) or TP53 mutations (n = 27) vs 73% (95% CI, 64%-80%) in those without (n = 129)
• 57% (95% CI, 37%-72%) in patients with complex karyotype (n = 31) vs 72% (95% CI, 61%-80%) in those without (n = 102)
• 64% (95% CI, 30%-85%) in patients with del(11q) (excluding those with del(17p) or TP53 mutations; n = 11) vs 79% (95% CI, 67%-87%) in those without (n = 74)

The 5-year OS rate was 93% (95% CI, 85%-97%) in patients with unmutated IGHV vs 100% (95%, 100%-100%) in those with mutated IGHV.

“The 5-year OS rates were 95% or greater regardless of MRD status in peripheral blood or bone marrow at 3 months after end of treatment or in peripheral blood at 12 months after end of treatment,” the authors added.

Additionally, of 61 patients with CLL disease progression following completion of fixed-duration treatment, 52% initiated retreatment with single-agent ibrutinib (n = 25) or combination treatment (n = 7). Notably, the median time on retreatment during the study was 21.9 months (range, 0.0-50.4) with single-agent continuous treatment with ibrutinib vs 13.8 months (range, 3.7-15.1) with 15-month fixed-duration combination treatment.

Among evaluable patients who received single-agent ibrutinib retreatment (n = 22), the overall response rate (ORR) was 86%, including complete response (CR) and partial response (PR) rates of 5% and 81%, respectively. Among evaluable patients who received retreatment with ibrutinib plus venetoclax (n = 7), the ORR was 71%, including CR and PR rates of 14% and 57%, respectively.

The 5-year PFS rates by MRD status at 3 months after end of treatment were 84% (95% CI, 73%-90%) in patients with undetectable MRD in bone marrow (n = 83; del(17p)/TP53 mutations [evaluable n = 16], 65% [35%-84%]; complex karyotype [evaluable n = 19], 79% [95% CI, 53%-92%]; unmutated IGHV [evaluable n = 56], 74% [95% CI, 60%-84%]), 83% (95% CI, 73%-89%) in patients with undetectable MRD in peripheral blood (n = 90; del(17p)/TP53 mutations [evaluable n = 8], 0% [NE-NE]; complex karyotype [evaluable n = 10], 20% [95% CI, 3%-48%]; unmutated IGHV [evaluable n = 25], 24% [95% CI, 10%-42%]), 48% (95% CI, 35%-61%) in patients without undetectable MRD in peripheral blood (n = 57; del(17p)/TP53 mutations [evaluable n = 11], 60% [25%-83%]; complex karyotype [evaluable n = 17], 82% [95% CI, 55%-94%]; unmutated IGHV [evaluable n = 49], 72% [95% CI, 57%-83%]), and 50% (95% CI, 36%-62%) in patients without undetectable MRD in bone marrow (n = 56; del(17p)/TP53 mutations [evaluable n = 12], 21% [4%-48%]; complex karyotype [evaluable n = 12], 25% [95% CI, 6%-51%]; unmutated IGHV [evaluable n = 26], 3% [95% CI, 16%-51%]).

The 5-year PFS rates by MRD status at 12 months after end of treatment were 88% (95% CI, 77%-94%) in patients with undetectable MRD in peripheral blood (n = 70) and 58% (95% CI, 45%-69%) in those without (n = 65).

Regarding safety, no new serious adverse effects (AEs) have been reported since previous analyses. A total of 18 second malignancies were observed in 13 patients. 10 events occurred in 8 patients who received the fixed-duration combination during the treatment-emergent AE (TEAE) period. Six events occurred in 4 patients after the TEAE period and before retreatment, and 2 events occurred in 2 patients during the TEAE period for ibrutinib-based retreatment.

Overall, 202 patients completed treatment with fixed-duration ibrutinib plus venetoclax (fixed-duration cohort, n = 159; MRD cohort placebo arm, n = 43). Sixty-three of these patients have had progressive disease (PD) to date, 61 patients had CLL PD (including 2 patients who subsequently had Richter transformation during retreatment), and 2 patients had Richter transformation. PD occurred more than 2 years after end of treatment in 68% of those with PD.

Among patients 1, 2, 3, and 4 with Richter transformation, the respective times from first dose to Richter transformation were 12.7 months (0.2 months before end of treatment), 28.1 months (14.3 months before end of treatment), 50.9 months (after 1.0 months of single-agent ibrutinib retreatment), and 55.3 months (after 27 months of single-agent ibrutinib retreatment).

The most frequently recorded AEs across the single-agent ibrutinib and combination retreatment arms, respectively, were COVID-19 (20%; 29%), diarrhea (20%; 43%), hypertension (16%; 57%), pyrexia (12%; 0%), upper respiratory tract infection (12%; 0%), and nausea (4%; 29%); also recorded were grade 3/4 AEs (24%; 29%) and AEs leading to treatment discontinuation (4%; 0%). No AEs led to dose reduction.

“Based on the safety profiles of fixed-duration ibrutinib plus venetoclax and ibrutinib-based retreatment, this treatment approach appears to have a positive benefit-risk profile,” the authors concluded.

Reference

Jacobs R, Wierda WG, Barr PM, et al. Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma: up to 5.5 years of follow-up in the phase 2 CAPTIVATE study. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Poster P675.