CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 13, 2025
Expiration: September 12, 2025
CAPTIVATE: 5.5-Year Follow-up Analysis From Fixed-Duration Cohort of First-line Ibrutinib + Venetoclax for CLL/SLL
Now let’s focus on the available data for combinations of the 2 treatment modalities that revolutionized CLL/SLL treatment, namely BTK inhibitors and BCL-2 inhibitors.47,48
The phase II CAPTIVATE trial evaluated ibrutinib plus venetoclax as first-line therapy in young and physically fit patients with CLL/SLL (N = 159). The study showed good efficacy for the drug combination, with a 5-year PFS rate of 67% (95% CI: 59-74) for all treated patients. There also appears to be some prognostic impact of del(17p) status, TP53 status, complex karyotype, and IGHV status regarding PFS. In patients with unmutated IGHV, the 5-year PFS rate was 56%. By contrast, in patients with mutated IGHV, the 5-year PFS rate was 80%.
FLAIR: FCR vs Ibrutinib vs Ibrutinib + Venetoclax in Previously Untreated CLL
The randomized phase III FLAIR study evaluated the ibrutinib plus venetoclax combination vs ibrutinib monotherapy; IR; or FCR as first-line therapy in young and physically fit patients with CLL.35,49 The coprimary endpoint of the study was PFS and measurable residual disease (MRD). Here, I focus on the comparison of ibrutinib plus venetoclax vs FCR.
Of importance, ibrutinib plus venetoclax was not given with a fixed treatment duration but was instead guided by MRD status. MRD in peripheral blood (PB) and bone marrow (BM) was assessed with multiparameter flow cytometry 9 months after randomization, then PB MRD was measured at 12 months and every subsequent 6 months. If a patient was found to have a complete response and be PB MRD negative (MRD <0.01%), the patient was reassessed for PB MRD 3 months later and was reassessed for PB MRD and BM MRD after an additional 3 months. At that point, if both PB and BM MRD were negative, the treatment time was doubled, up to the first negative PB MRD assessment in the sequence. The earliest therapy completion time was 2 years following randomization. Ibrutinib treatment could be reinitiated if the patient became MRD positive before Year 6. Note that this treatment approach is only experimental. Ibrutinib plus venetoclax is only approved by the EMA with a fixed duration of 12 months of use as combined therapy (three 28-day cycles of ibrutinib followed by 12 cycles of combination therapy).50
FLAIR: PFS and OS With Ibrutinib + Venetoclax vs FCR
MRD-guided treatment in the FLAIR trial resulted in significantly longer PFS in patients treated with ibrutinib plus venetoclax vs FCR (HR: 0.13; 95% CI: 0.07-0.24; P <.001) and OS (HR: 0.31; 95% CI: 0.15-0.67).35 However, this was at the cost of prolonged treatment with ibrutinib plus venetoclax, because at 3 years only 58% of patients had stopped their treatment because of undetectable MRD. The duration of the combined treatment was nearly triple the EMA-approved duration for the majority of patients, leading to good outcomes, but also prolonged toxicity from treatment.
FLAIR: Safety
The safety data show that ibrutinib plus venetoclax was better tolerated than FCR and high-grade AEs were infrequent.35 In both the CAPTIVATE and FLAIR trials and across all grades of AEs, we see that ibrutinib plus venetoclax is generally well tolerated. The class-associated atrial fibrillation/arrhythmia of grade 1/2 was observed in 4% of patients and grade ≥3 in 0.8% of patients treated with ibrutinib plus venetoclax.
GLOW: Ibrutinib + Venetoclax vs OC in Previously Untreated CLL
The randomized phase III GLOW study evaluating ibrutinib plus venetoclax vs OC in patients with previously untreated CLL led to marketing authorization of this combination in Europe.50-52 Patients in the experimental arm received 3 lead-in cycles of ibrutinib monotherapy followed by 12 cycles of ibrutinib plus venetoclax combination therapy. Patients in the standard-of-care arm received OC for six 28-day cycles. The trial included patients who were older and/or physically unfit with previously untreated CLL and no del(17p) alteration. The primary endpoint was PFS by IRC assessment.
GLOW: 4-Year Follow-up PFS
The GLOW trial demonstrated statistically significantly longer median PFS by IRC assessment at the 4-year follow-up in favor of ibrutinib plus venetoclax vs OC (NR vs 21.7 months, respectively; HR: 0.214; P <.0001) with similar improvement at the 5-year PFS update (67% vs 20%, respectively; HR: 0.256).34,53 A PFS benefit was also seen in patients with mutated and unmutated IGHV, and although unmutated IGHV carried a worse prognosis overall, those patients still did substantially better with ibrutinib plus venetoclax treatment vs OC treatment regarding median PFS (69.8 vs 15.0 months, respectively).34
AMPLIFY: First-line Fixed-Duration Acalabrutinib + Venetoclax ± Obinutuzumab vs Chemoimmunotherapy in CLL
The interim results from the randomized phase III AMPLIFY trial evaluating acalabrutinib plus venetoclax with or without obinutuzumab vs FCR or BR in patients with previously untreated CLL and no del(17p) or TP53 mutation, but who required treatment according to 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, were presented at the 2024 American Society of Hematology annual meeting.54 The primary endpoint of the study was PFS by IRC assessment for acalabrutinib plus venetoclax vs FCR or BR.
Unlike the GLOW trial, patients in AMPLIFY could have some comorbidities, but they were fit enough to receive either FCR or BR in the standard-of-care arm. The median patient age in AMPLIFY was 61 years, which is 10 years younger than it was for patients enrolled in the GLOW trial, where the median patient age was 71 years.52,54
The age of patients included in these 2 trials is of consequence because it may affect treatment outcomes.
AMPLIFY: PFS per IRC
Treatment with acalabrutinib plus venetoclax resulted in superior median PFS vs FCR or BR (NR vs 47.6 months, respectively; HR: 0.65; P = .0038). Moreover, the benefit in median PFS was further enhance when obinutuzumab was added to the acalabrutinib plus venetoclax arm (NR vs 47.6 months with FCR or BR; HR: 0.42; P <.0001).54
AMPLIFY: PFS Subgroup Analyses
Subgroup analyses in the AMPLIFY trial also showed that the combination of acalabrutinib plus venetoclax was beneficial in patients with unmutated IGHV, improving the median PFS to 51.5 months vs 43.3 months with FCR or BR (HR: 0.69). Here again, adding obinutuzumab further extended the benefit in median PFS vs FCR or BR (NR vs 43.3 months; HR: 0.35).54
AMPLIFY: OS
Regarding the OS results, it is important to note that the trial was conducted during the COVID-19 pandemic, so the acalabrutinib, venetoclax, and obinutuzumab and FCR/BR arms were particularly affected by an increase of COVID-19–related deaths.
When deaths related to COVID-19 are censored in the OS analysis, the outcome of the acalabrutinib, venetoclax, and obinutuzumab and FCR/BR arms is improved, whereas the outcome of the acalabrutinib/venetoclax arm is not affected because of a lower rate of COVID-19–related deaths in that arm.54
AMPLIFY: AEs of Clinical Interest
The AEs of interest in the acalabrutinib-containing arms included cardiac events (eg, atrial fibrillation/ ventricular tachyarrhythmias), hemorrhage, neutropenia, and infections. With the exception of neutropenia/neutrophil count decrease and infections, these AEs of interest were primarily grade 1/2.54 Of note, the frequency of neutropenia and infections was greater with the addition of obinutuzumab. By contrast, the FCR or BR arm showed higher rates of hematologic toxicity, with decreased neutrophil counts, thrombocytopenia, and febrile neutropenia overall.
AMPLIFY: Summary
The combination of acalabrutinib, venetoclax, with or without obinutuzumab, once licensed, will provide another valuable treatment option of finite duration for our patients. The combination of acalabrutinib, venetoclax, and obinutuzumab leads to improved efficacy but also increased toxicity and may be an option for fit patients. The place of acalabrutinib/venetoclax and acalabrutinib/venetoclax/obinutuzumab as compared to ibrutinib/venetoclax, obinutuzumab/venetoclax, and continuous BTK inhibitor therapy may be settled with longer follow up of AMPLIFY.
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