Danielle M. Brander, MD, assistant professor of medicine, Duke Cancer Institute, discusses targeted agents in chronic lymphocytic leukemia (CLL).

Targeted inhibitors in CLL and other B-cell lymphomas can be categorized by those that target important proteins along the B-cell receptor signaling pathway and those that induce apoptosis, explained Brander. Agents that target the B-cell receptor pathway include ibrutinib (Imbruvica) and acalabrutinib (Calquence); these target BTK specifically, which is one component of that pathway.

Other important components in that signaling pathway are PI3K inhibitors, adds Brander. Approved PI3K inhibitors include idelalisib (Zydelig) and duvelisib (Copiktra). PI3K inhibitors can be specific to PI3K-delta or PI3K-gamma, adds Brander. The type of isoform will determine whether the agent is tested in CLL versus other lymphomas.&#8232;

Anti-apoptotic inhibitors include venetoclax (Venclexta), which is a specific BCL-2 inhibitor. In CLL, there is a defect in programmed cell death. The idea of an anti-apoptotic inhibitor is to tip the balance towards apoptosis, explains Brander. Ongoing trials with combination therapies may augment current approaches in targeting the B-cell receptor signaling pathway.

Videos

Dr. Brander on Targeted Agents in CLL

Danielle M. Brander, MD, assistant professor of medicine, Duke Cancer Institute, discusses the safety and efficacy of the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

In the phase II CLARITY (NCT02267590) trial, investigators are examining the combination of ibrutinib and venetoclax in patients with relapsed/refractory CLL. Preliminary results from the trial showed that the combination was both safe and effective, says Brander. No unanticipated toxicities were observed when the agents were combined. What sets this study apart from prior studies is that patients were treated with 3 months of ibrutinib before they were given the combination. As a result, patients experienced a reduction in tumor lysis risk and disease bulk, subsequently enhancing the safety profile of the regimen, says Brander.

In terms of efficacy, the results from the first preplanned analysis showed that approximately 76% of patients achieved undetectable levels of minimal residual disease negativity, she adds. Furthermore, almost all patients achieved an objective response with the combination. Although longer follow-up will be necessary, these results suggest that patients who are eligible to receive the combination may have lower toxicity and time on treatment in the face of MRD negativity.

Dr. Brander on the Safety and Efficacy of Ibrutinib/Venetoclax in CLL

Danielle M. Brander, MD, assistant professor of medicine, Duke Cancer Institute, discusses the frontline treatment of patients with chronic lymphocytic leukemia (CLL).

There have been a lot of changes in the treatment options for patients with CLL, says Brander, both in the frontline and relapsed/refractory settings. In frontline, Brander says that much of the effort in the past few years has gone towards identifying patients who may still benefit long-term from chemoimmunotherapy. These are often patients who are young, have a favorable risk indicated by an 

-mutation, and no high-risk deletion 11q or 17p. Patients who match this profile can experience 10- to 12-year remissions from frontline therapy with fludarabine-cyclophosphamide-rituximab (Rituxan). Additionally, there may be patients with favorable risk who might be older who may experience a meaningful remission from frontline chemotherapy such as bendamustine and rituximab.

The only FDA-approved targeted agent for the frontline treatment of patients with CLL is ibrutinib (Imbruvica). Recently, a study looking at long-term 5-year follow-up of a cohort of patients who were mainly frontline showed that patients who were not high-risk had very low progression-free survival with ibrutinib.

Danielle M. Brander, MD, assistant professor of medicine, Duke Cancer Institute, discusses the frontline treatment of patients with chronic lymphocytic leukemia.

Dr. Brander Discusses the Frontline Treatment of CLL

Danielle Marie Brander, MD, assistant professor of medicine, Duke Cancer Institute, discusses the treatment landscape for patients with high-risk chronic lymphocytic leukemia (CLL).

High-risk patients with CLL have benefitted from recent novel therapies, says Brander, but their prognosis is still concerning. As a result of these novel therapies, patients are grateful that they do not have to receive chemotherapy, particularly if they are 

However, there is a subset of patients who are intolerant to the newer agents. Additionally, resistance poses an issue for a lot of patients, especially for those who develop resistance to ibrutinib (Imbruvica). In recent studies, patients who stopped or progressed on ibrutinib went to venetoclax (Venclexta) and showed greater than 60% response rates. However, physicians know that the patients who never experience a deep response eventually relapse.

Additionally, physicians are struggling to make recommendations for patients who develop acquired resistance to more than one novel agent. In those cases, Brander suggests other consolidation options such as allogeneic stem cell transplant. It is an area of need that may one day be met with chimeric antigen receptor T-cell therapy or immunotherapy, she says.

Danielle M. Brander, MD

Articles

Dr. Brander on Targeted Agents in CLL

Dr. Brander on the Safety and Efficacy of Ibrutinib/Venetoclax in CLL

Dr. Brander Discusses the Frontline Treatment of CLL

Dr. Brander on the Treatment Landscape for Patients With High-Risk CLL