Does 1 + 1 = 2? Combining Targeted Agents in Frontline Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the world, with an incidence of 23,690 cases per year in the U.S.^1,2  It is also one of the first malignancies to see a shift away from chemoimmunotherapy (CIT) for most patients to such frontline (1L) treatment options as continuous use of single-agent Bruton tyrosine kinase inhibitors (BTKis)^3-6  and fixed-duration therapy of venetoclax and obinutuzumab (VO).^7-9  However, these alternative treatments are not without their drawbacks. VO requires intravenous (IV) infusion and is associated with increased risk of neutropenia. And BTKis can increase the risk of bleeding and cardiovascular issues, although the rate and severity of these events has decreased with the coadministration of second-generation agents such as acalabrutinib and zanubrutinib.^6,10-11  In clinical practice, the choice among these options is dependent on age, comorbidities, and patient and/or physician preference.

BTKis and venetoclax have been safely combined in the treatment of several hematologic malignancies, demonstrating improved efficacy compared to the use of each agent alone in some cases^7,12-15  In the global, randomized phase III AMPLIFY study,¹⁶  Jennifer R. Brown, MD, PhD, and colleagues explored the combination of acalabrutinib and venetoclax (AV) with or without obinutuzumab versus an investigator choice of CIT (bendamustine-rituximab [BR] or fludarabine-cyclophosphamide-rituximab [FCR]). FCR was restricted to patients aged 65 and younger. All the treatments were administered in 28-day cycles. The patients in the AV group received acalabrutinib at a dose of 100 mg twice daily during cycles 1 to 14 and venetoclax once daily during cycles 3 to 14 (including a five-week ramp-up of venetoclax from 20 mg once daily to the target dose of 400 mg once daily). The patients in the acalabrutinib-venetoclax-obinutuzumab (AVO) group received the same doses of acalabrutinib and venetoclax as described above plus IV obinutuzumab at a dose of 1,000 mg during cycles 2 to 7 according to the standard dosing protocol. The patients in the CIT group received IV FCR or BR during cycles 1 to 6 according to standard dosing protocols. The study enrolled 867 patients, with 291 assigned to receive AV, 286 receiving AVO, 143 receiving FCR, and 147 receiving BR. The primary efficacy endpoint was PFS with AV as compared with CIT (as assessed by blinded independent central review). Patients were randomized in a 1:1:1 ratio.

At the data cutoff date of April 30, 2024, 92.4% of the patients in the AV group, 85.7% of those in the AVO group, and 72.8% of the CIT group remained in the trial. The median follow-up from the end of treatment was 30.9 months (range, 0 to 52). Among the patients who initiated all the treatments in the assigned regimen, 90.2% of those in the AV arm, 76.8% of those in the AVO arm, and 80.6% of those in the CIT arm received their respective treatment for the protocol-specified number of cycles. At a median follow-up from randomization of 40.8 months (range, 0 to 59), estimated 36-month PFS was 76.5% with AV (95% CI 71.0-81.1), 83.1% with AVO (95% CI 78.1-87.1), and 66.5% with CIT (95% CI 59.8-72.3) (hazard ratio [HR] for disease progression or death with AV vs. CIT 0.65 [95% CI 0.49-0.87; p=0.004]; for AVO vs. CIT, p<0.001). Undetectable minimal residual disease (uMRD) as assessed by means of flow cytometry (<10⁻⁴) at the prespecified time points was 26.8% for AV, 66.4% for AVO, and 51.0% for CIT (HR for uMRD with AV vs. CIT, 0.5 [95% CI 0.4-0.7; p<0.001]; for AVO vs. CIT, 1.3 [95% CI 1.1-1.5; p<0.001]). The estimated 36-month overall survival (OS) was 94.1% with AV (95% CI 90.7-96.3); 87.7% with AVO (95% CI 83.2-91.0); and 85.9% with CIT (95% CI 81.0-89.6) (HR for death with AV vs. CIT, 0.33 [95% CI 0.18-0.56; p<0.001]; for AVO vs. CIT, 0.76 [95% CI 0.49-1.18; not significant]). The estimated 36-month event-free survival (EFS) as assessed by blinded independent central review was 75.9% with AV, 82.8% with AVO, and 64.5% with CIT. The percentage of patients who had a response to treatment but subsequently had disease progression or died at any time during the per-protocol follow-up period up to the data cutoff date was 28.1% with AV, 15.1% with AVO, and 33.9% with CIT.

Adverse events (AEs) were highest with AVO (94.7%; ≥ grade 3, 69.4%), followed by CIT (91.1%; ≥ grade 3, 60.6%) and AV (92.8%; ≥ grade 3, 53.6%). AEs leading to discontinuation of acalabrutinib occurred in 7.6% of patients treated with AV and 13.7% of those treated with AVO. AEs leading to dose reduction of any trial medication occurred in 14.1% of patients treated with AV, 20.8% of those treated with AVO, and 11.2% of those receiving CIT. Infections and neutropenia were the most common AEs resulting in treatment interruption, while neutropenia was the most common AE resulting in dose reduction across all groups. Serious AEs were reported in 72 patients receiving AV (24.7%), 109 receiving AVO (38.4%), and 71 receiving CIT (27.4%).

AMPLIFY is the first randomized study to compare the effectiveness of acalabrutinib-based combinations versus CIT in untreated patients with CLL, reporting an improved PFS at 36 months for the acalabrutinib-based combinations compared to CIT, as well as an improved OS for AV (but not AVO) at 36 months compared to CIT. Similar to other trials, this study indicates that targeted agents are a better choice for 1L therapy than CIT. The major question is whether this finding supports the use of AV over acalabrutinib monotherapy or VO in 1L CLL.

Given that indefinite therapy is one of the drawbacks to BTKis in 1L CLL, the combination of AV or AVO has merit, as both of these treatments are fixed. The estimated 48-month PFS rates from ELEVATE TN,⁵  the study which led to the approval of 1L acalabrutinib, was 87.0% for acalabrutinib-obinutuzumab (AO) and 77.9% for acalabrutinib. In the AO and acalabrutinib monotherapy arms, 48-month PFS rates were 85.7% and 77.1%, respectively, in patients with unmutated immunoglobulin heavy chain variable region genes (IGHVs). These PFS rates compare favorably to the acalabrutinib arms in AMPLIFY (76.5% with AV and 83.1% with AVO at 36 months), although treatment with acalabrutinib was continuous in ELEVATE TN. This is an important point of emphasis favoring the combinations used in AMPLIFY considering the incurable nature of CLL, mutations that can occur with continuous BTK receptor suppression, and the long-term AEs associated with continuous BTKi exposure.

Based on the early outcomes of AMPLIFY, it remains difficult to ascertain the best way forward in treating CLL. While AVO appears to be the most effective option, it has yet to demonstrate an OS benefit in this patient population. Timing has likely affected this arm of the study, considering the heavy toll that the COVID-19 pandemic seems to have inflicted on those randomized to AVO. Will longer follow-up allow for AVO to rise above? Or will the addition of obinutuzumab to AV prove of limited use other than for those with higher-risk features such as unmutated IGHV? In AMPLIFY, the AVO arm had a 36-month PFS of 82.8% in patients with unmutated IGHV compared to 68.9% in the AV arm and 56.8% in the CIT arm. For historical comparison, the PFS for those with an unmutated IGHV at 72 months in the CLL14 study was 47.2% in the VO arm.⁹