Targeted Approaches Improve Survival in CLL Compared with Chemo-Immunotherapy

Treatment strategies for chronic lymphocytic leukemia (CLL) have shifted away from chemo-immunotherapy-based approaches to more targeted therapeutics. During a presentation at NAMCP 2020 Virtual Spring Managed Care Forum, John Allan, MD, assistant professor of medicine at Weill Cornell Medicine, discussed the latest treatment options for CLL.

Various frontline phase III trials have assessed targeted therapy verses chemo-immunotherapy in CLL. The 2019 RESONATE-2 trial observed five-year benefits in overall survival (OS) and progress-free survival (PFS) with ibrutinib compared with chlorambucil in the first-line CLL setting. The 2019 iLLUMINATE trial demonstrated that ibrutinib plus obinutuzumab resulted in significantly longer PFS compared with chlorambucil plus obinutuzumab in untreated patients with CLL. The 2019 ELEVATE-TN study found that acalabrutinib alone or in combination with obinutuzumab improved PFS compared with obinutuzumab plus chlorambucil in treatment-naïve patients with CLL. Another 2019 study published in The New England Journal of Medicine found that among untreated patients with CLL, venetoclax plus obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab. Another 2019 study published in The New England Journal of Medicine found that ibrutinib plus rituximab improved PFS and OS compared with chemo-immunotherapy in patients with previously untreated CLL. Finally, the Alliance study found that ibrutinib had superior PFS compared with bendamustine plus rituximab in older patients with untreated CLL.

Then Dr. Allan discussed the role of PI3K in the management of relapsed/refractory CLL. PI3K inhibitors are not currently approved for frontline treatment, and their use is hampered by toxicities such as colitis, pneumonitis, infections, and hepatotoxicity. But these agents could have a potential role in patients with specific comorbidities and in combination with venetoclax, according to Dr. Allan.

Minimal residual disease (MRD) is predictive for PFS in patients with CLL, and MRD has the potential to guide de-escalation of therapy. Evaluating MRD has the potential to limit exposure to chemo-immunotherapy and can be used to identify immunoglobulin heavy chain-mutated patients that may have significant PFS. With continual therapy of a novel agent, such as Bruton tyrosine kinase inhibitors, MRD does not predict outcomes. However, if using a venetoclax-based therapy, undetectable MRD can identify patients who can de-escalate treatment.

He highlighted the phase II CAPTIVATE study that included 165 patients with previously untreated CLL and small lymphocytic leukemia who were younger than 70 years. Patients received ibrutinib 420 mg once daily for three cycles followed by ibrutinib 420 mg daily plus venetoclax ramp up to 400 mg daily for 12 cycles. MRD-guided randomized was then used to identify patients with undetectable and detectable MRD, and 75% of patients had undetectable MRD in the peripheral blood and 72% in the bone marrow, representing high rates of undetectable MRD following this treatment approach.

In the next phase of the trial, patients with undetectable MRD were randomized 1:1 to receive ibrutinib or placebo, while those with detectable MRD were randomized to receive ibrutinib with or without venetoclax. Findings from the MRD-guided randomization phase of the trial are not yet available.

Presentation: New Frontiers in the Treatment and Management of CLL: Expert Perspectives on Emerging Therapies and MRD. NAMCP 2020 Virtual Spring Managed Care Forum, April 16-17.