Commentary

Article

Risk Factors Could Inform BTK Inhibitor and Venetoclax Sequencing in CLL/SLL

Author(s):

Changchun Deng, MD, PhD, discusses factors to consider when sequencing covalent BTK inhibitors and venetoclax in patients with CLL/SLL.

Changchun Deng, MD, PhD

Changchun Deng, MD, PhD

Determining if a patient with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma harbors any high-risk cytogenetic factors, such as TP53 mutations or 17p deletions, could help inform sequencing decisions for covalent BTK inhibitors and venetoclax (Venclexta)-based regimens, according to Changchun Deng, MD, PhD.

“You have to choose the [BTK inhibitor] regimen [based on] the patient. Every patient is different, and their CLL/SLL is also different,” Deng explained in an interview with OncLive®.

In the interview, Deng expanded on factors that inform BTK inhibitor selection in CLL/SLL; explained when high-risk cytogenetics can play a role when sequencing a BTK inhibitor and venetoclax; and provided updates from the Hodgkin lymphoma and B-cell lymphoma realms.

Deng is an associate professor of hematology and oncology at University Hospitals Seidman Cancer Center and a member of the Immune Oncology Program at Case Comprehensive Cancer Center in Cleveland, Ohio.

OncLive: What factors inform BTK inhibitor selection for patients with CLL/SLL?

Deng: A patient’s overall health, cardiac function, and previous treatment history all play into the decision-making tree.

Additionally, pirtobrutinib [Jayprica] is now available, and [the noncovalent BTK inhibitor] represents a new class of drugs. It does inhibit the same target as some of the previously approved [BTK inhibitors], but it hits BTK in a different way; therefore, patients have an additional option [after a prior covalent BTK inhibitor]. In addition to being quite effective in patients whose disease relapsed on a previous covalent BTK inhibitor, pirtobrutinib is quite remarkable for having a very favorable safety profile. For example, it doesn't have the cardiac toxicity associated with previously approved BTK inhibitors.

When considering a covalent BTK inhibitor vs a venetoclax-based regimen, how do you approach sequencing decisions for patients with CLL/SLL?

In my practice, I still consider a few things. First, are there any high-risk center genetic factors associated with the patient’s CLL/SLL? If you look at the literature, there are a number of high-risk factors, but to me, the important ones are the TP53 mutation and 17p deletion. Furthermore, 11q deletions and unmutated IDH are high-risk factors, but I don't believe they play into the choice of a BTK inhibitor vs a BCL2 inhibitor as much as TP53 mutations and 17p deletions.

To elaborate, if a patient has a 17p deletion and TP53 mutation and they need treatment, if they are not against the idea that the treatment will be continued indefinitely, then I would prefer to give them a covalent BTK inhibitor. At this point, we have three approved covalent BTK inhibitors: zanubrutinib [Brukinsa], acalabrutinib [Calquence], and ibrutinib [Imbruvica]. [Choosing between the three covalent BTK inhibitors] will depend on a few things, including whether the patient is at high risk for atrial fibrillation, which is one of the main things associated with those BTK inhibitors, particularly with the first-generation BTK inhibitor ibrutinib.

What advancements have been seen in Hodgkin lymphoma?

In the Hodgkin lymphoma field, the latest [update] is that you could now maximize up-front treatment by incorporating a PD-1 antibody. In this case, the best data [we have are] from nivolumab [Opdivo], so you could give nivolumab plus chemotherapy with doxorubicin, vinblastine, and dacarbazine [AVD]. The new nivolumab plus AVD data [from the phase 3 SWOG S1826 trial (NCT03907488)], which were presented at the 2023 ASH Annual Meeting, are quite remarkable].

Going back to PD-1–based therapy for first-line treatment, there are also some recent data for the combination of nivolumab and brentuximab vedotin [Adcetris], which is an anti-CD30 antibody-drug conjugate, Data show that when these two [agents plus doxorubicin and dacarbazine were given] to patients with Hodgkin lymphoma, [results from the phase 2 SGN35-027 trial (NCT03646123) showed the combination elicited an overall response rate of 93%]. These results are quite exciting, especially for patients who have stage I or II, or early stage III disease. This is one of the biggest [advances] in the field of Hodgkin Lymphoma.

How have CAR T-cell therapies and bispecific antibodies shifted the treatment paradigm for B-cell lymphoma?

In B-cell lymphoma, a lot of people have been excited about the CD19 CAR T-cell therapies. We have three CD19 CAR T-cell therapies approved in the United States for treating the most common aggressive [B-cell] lymphoma: [lisocabtagene maraleucel (Breyanzi), tisagenlecleucel (Kymriah), and axicabtagene ciloleucel (Yescarta)]. The majority of responses [with these CAR T-cell therapies] are complete responses.

There are also data in the second-line setting. If a patient has refractory disease, meaning their lymphoma comes back quickly after first-line treatment, in that setting in the past, typically you would try to give them salvaging chemotherapy and hopefully get them into a complete remission, then do an autologous stem cell transplant [ASCT], which always requires chemotherapy for conditioning. However, now you have all these CAR T-cell therapies, and they were compared with ASCT, and they are studies that have shown pretty compelling data that CAR T-cell therapy outperforms ASCT [in the second-line setting]. It’s critical to comment that for CAR T-cell therapy, you need the time [for manufacturing]. For vein-to-vein time, it could still take a full 5 weeks.

What about off-the-shelf treatment, where you could just have immunotherapy and give it to a patient right away without having to wait? That option is now available because you have multiple bispecific antibodies, which function [similar to] CAR T cells by activating a patient’s T cells to attack the lymphoma cells. [With bispecific antibodies], there is no waiting time [to start treatment].

There are some emerging data showing that even in a patient who has a relapse after CAR T-cell therapy, [you could] give them a bispecific antibody. What's approved now is a CD20 x CD3 bispecific antibody [epcoritamab-bysp (Epkinly)], and there are still a good number of patients who will have partial and complete responses [with the agent after prior CAR T-cell therapy]. Overall, in the B-cell lymphoma field, the immunotherapy is showing great promise.

Related Videos
Comparative Efficacy of Bruton Tyrosine Kinase Inhibitors in the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis
Consuelo Bertossi, MD
David L. Porter, MD
Mazyar Shadman, MD, MPH
BTK Inhibitors in CLL : Second Generation Drugs and Beyond
David L. Porter, MD
Kathleen A. Dorritie, MD
David L. Porter, MD, director, Cell Therapy and Transplant, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, Penn Medicine
Jean L. Koff, MD, MS
David L. Porter, MD, director, Cell Therapy and Transplant, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, Penn Medicine