The Phase 3 AMPLIFY Trial Assesses a New Treatment Paradigm in Patients With Treatment-Naive CLL

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Patients with chronic lymphocytic leukemia (CLL) who require therapy are typically treated with 1 of 2 approaches: either with a Bruton tyrosine kinase inhibitor (BTKi) administered until disease progression or intolerance^1-4 or with a fixed-duration regimen of venetoclax (Venclexta; AbbVie Inc) in combination with obinutuzumab (Gazyva; Genentech, Inc).⁵ While these therapies have significantly transformed the treatment landscape for CLL, the need for ongoing BTKi therapy and the eventual relapse observed in many patients highlight the opportunity to further optimize frontline treatment strategies.

Jennifer Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology at Harvard Medical School in Boston, Massachusetts, presented the interim results of the phase 3 AMPLIFY trial (NCT03836261) at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. Investigators of the AMPLIFY trial looked to compare the combination of acalabrutinib (Calquence; AstraZeneca) with venetoclax (AV) with or without obinutuzumab (AVO) for 14 cycles vs bendamustine with rituximab (Rituxan; Biogen and Genentech, Inc) (BR) or fludarabine with cyclophosphamide and rituximab (FCR) for 6 cycles in adult patients with treatment-naive (TN) CLL that meet the criteria for treatment. This study excluded patients with a 17p deletion or TP53 mutation who were known to have poor prognosis and outcomes to treatment.⁶

AMPLIFY Trial Design

The primary end point assessed progression-free survival (PFS) of AV vs FCR/BR. If this end point was met, multiple secondary end points were tested as well and included analysis of PFS of AVO vs FCR/BR, undetectable minimal residual disease (uMRD), and overall survival (OS) of AV/AVO vs FCR/BR.

During the trial, 867 patients were randomly assigned 1:1:1 with intention to treat to AV (n = 291), AVO (n = 286), and BR/FCR (n = 290). Ultimately 258 patients completed the study with AV, 212 completed AVO, and 208 completed BR/FCR.

Toxicity and Safety Data

Notable adverse events (AEs) included neutropenia, headache, infusion-related reactions (IRRs), and febrile neutropenia. Grade 3 or higher neutropenia was higher in the AVO arm vs AV or chemoimmunotherapy (35.2% vs 26.8% vs 32.4%, respectively); however, FCR/BR had higher rates of grade 3 or higher febrile neutropenia (9.3% vs 2.5% vs 1.7%, respectively) than AVO or AV. The BR/FCR arm also had higher rates of any-grade IRRs than AVO or AV (32.8% vs 19.7% vs 0%, respectively).

Regarding cardiac events, grade 3 or higher atrial fibrillation was comparable among patients receiving AV, AVO, and BR/FCR (0.3% vs 0.7% vs 0.8%, respectively). Grade 3 or higher hypertension was slightly higher in both the AV and AVO arms vs the BR/FCR arm (2.7% vs 2.1% vs 0.8%, respectively). Grade 3 or higher infections (any) were highest in the AVO arm, followed by the AV arm, and then the BR/FCR arm (23.6% vs 12.4% vs 10%, respectively). Because this study took place in the era of COVID-19, deaths due to COVID-19 were recorded and were higher in the AVO and FCR/BR arms vs the AV arm (8.7% vs 7.2% vs 3.4%, respectively).

Trial Results

At a median follow-up of 40.8 months, median PFS was not reached in the AV and AVO arms and was 47.6 months for the FCR/BR arm. The PFS rate at 36 months was 83.1% in the AVO arm vs 76.5% in the AV arm vs 66.5% in the FCR/BR arm.

In evaluable patients, rates of uMRD were highest in the AVO arm vs the FCR/BR or AV arms at the end of treatment (95% vs 72.9% vs 45%, respectively). The PFS rate at 36 months in this subgroup was 90.4% vs 74.8% vs 87.1%, respectively, which may indicate higher PFS rates in patients achieving uMRD in the targeted therapy arms in comparison with the chemoimmunotherapy arm.

OS was also prolonged with AV vs FCR/BR. The OS rate at 36 months was 94.1% vs 85.9%, respectively, with an HR of 0.33 (0.18-0.56). When censoring for COVID-19 deaths, both AV and AVO appeared to have an OS benefit vs FCR/BR. The HR of AV vs FCR/BR was 0.27 (0.1 1-0.60) and the HR of AVO vs FCR/BR was 0.47 (0.22-0.95).

Conclusion and Future Directions

The authors concluded that fixed-duration AV and AVO significantly improved PFS at the interim analysis of 40.8 months. Patients in the AVO arm achieved the highest rates of uMRD. In addition, the AVO arm had the longest PFS rate of the 3 arms. Patients also had longer OS with AV vs FCR/BR, and the benefit extended to AVO when COVID-19 deaths were censored. The incidence of cardiac AEs in both the AV and AVO arms remained low. Brown noted that results of this study were sent to the New England Journal of Medicine for publication.

Although this study demonstrated promising results, it remains uncertain whether it will replace the current treatment paradigm of continuous BTKi therapy or fixed-duration venetoclax plus obinutuzumab in the near future. A similar situation occurred with the results of the phase 2 CAPTIVATE trial (NCT02910583), which examined fixed-duration venetoclax and ibrutinib.⁷ One of the challenges at that time was the use of ibrutinib as the BTKi backbone, which is now less commonly initiated in patients with CLL than newer-generation BTK inhibitors. However, once the results of this study are fully published, the data most likely will be incorporated into the National Comprehensive Cancer Network guidelines for the treatment of TN CLL in patients without 17p deletion or TP53 mutation, as these patients were excluded from the study.

One patient group that could immediately benefit from this treatment option is the older patients without 17p deletion or TP53 mutation who prefer a fixed-duration approach but cannot tolerate or do not want obinutuzumab infusions. Patients in the AV arm experienced generally lower or comparable rates of AEs, including cardiac toxicity, grade 3 neutropenia, febrile neutropenia, infections, and complications from COVID-19, than the other arms. These patients have the option to initiate acalabrutinib for 2 cycles to debulk disease followed by a gradual ramp-up of venetoclax for a total of 14 cycles of fixed-duration treatment.

An important question that may arise is how to manage patients who remain MRD positive at the end of the 14 treatment cycles of AV. Questions remain regarding whether physicians should stop treatment at that point or continue with single-agent BTKi or combination therapy until uMRD is achieved. Notably, fewer than half the patients at the end of the trial reached uMRD, which was assessed using the less sensitive threshold of 10^–4 (uMRD4). With the availability of more sensitive assays capable of detecting MRD at the 10^–6 level (uMRD6), it is likely that some patients categorized as uMRD4 may still have residual disease detectable at uMRD6. The high rates of uMRD seen with AVO are promising, and it would not be surprising to see this regimen adopted for the treatment of young, fit patients as a preferred frontline option over venetoclax and obinutuzumab.

AMPLIFY represents a potential paradigm shift in the treatment of patients with TN CLL without 17p deletion or TP53 mutation. High rates of uMRD were achieved with the AVO regimen, and AV demonstrated a PFS benefit compared with BR/FCR at a median follow-up of 40.8 months. Whether this approach will replace the current fixed-duration venetoclax and obinutuzumab regimen remains to be seen, but the all-oral AV combination will likely offer significant utility for certain patient populations.

REFERENCES

1. Brown J, Seymour J, Wojciech J, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY. Paper presented at: American Society of Hematology 2024; December 7-10, 2024; San Diego, CA.

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6. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

7. Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi:10.1200/JCO.21.00807