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

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.