Emerging Therapeutic Targets Are Expanding the CLL Treatment Armamentarium

Bhagirathbhai Dholaria, MBBS

Novel agents, such as BTK inhibitors and CAR T-cell therapies, are under evaluation for patients with chronic lymphocytic leukemia (CLL), and the efficacy of these agents in this population may mirror the successes seen in patients with other hematologic malignancies, according to Bhagirathbhai Dholaria, MBBS. However, additional research is necessary to reduce relapses and improve the accessibility of these therapies, he noted.

“The CLL treatment landscape has dramatically changed in the past 5 years with novel therapies, which are no longer novel,” Dholaria said in an interview with OncLive®.

In the interview, Dholaria discussed limitations in the current CLL standards of care (SOC) that necessitate more effective therapies; BTK inhibitors and degraders on the horizon for this population; and the potential future role of CAR T-cell therapy for patients with CLL.

The phase 1/2 BRUIN trial (NCT03740529) investigated the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) in patients with relapsed/refractory B-cell malignancies. In the population of patients with CLL or small lymphocytic lymphoma (SLL) who had previously received a BTK inhibitor, the agent generated an overall response rate (ORR) of 73.3% (95% CI, 67.3%-78.7%).¹ Dholaria contextualized these findings within the broader framework of pirtobrutinib indications throughout hematologic malignancies.

He also explained the implications of findings from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198), in which lisocabtagene maraleucel (liso-cel; Breyanzi) elicited an 18% complete response (CR) rate (95% CI, 9%-32%; P = .0006) in patients with relapsed/refractory CLL or SLL.²

Dholaria is an assistant professor of medicine (hematology/oncology) in the Division of Hematology and Oncology at Vanderbilt University Medical Center (VUMC) in Nashville, Tennessee.

OncLive: What are the benefits and limitations of chemoimmunotherapy for patients with CLL?

Dholaria: Chemoimmunotherapy, such as fludarabine, cyclophosphamide, and rituximab [FCR]–based therapy or bendamustine/rituximab [Rituxan]–based therapy, used to be a cornerstone of [treatment options for patients with] newly diagnosed CLL for many decades. These therapies are effective in newly diagnosed patients, [and they are associated] with high ORRs. In a subset of patients with IGHV-mutated CLL, the FCR regimen can potentially be curative, with long-lasting remissions in this group of patients.

However, these therapies are also [associated] with a lot of adverse effects, because they involve chemotherapy regimens. Additionally, most patients with CLL are older [and typically have several] comorbidities. Although [chemoimmunotherapy regimens] work well, many of these patients cannot tolerate them. Relapses are also frequent in patients with high-risk CLL, especially [in those with] IGHV-unmutated CLL or patients with a TP53 mutation.

What noncovalent BTK inhibitors have been explored in CLL?

Several [noncovalent BTK inhibitors are] currently being investigated. The frontrunner right now is a drug called pirtobrutinib. Pirtobrutinib received an FDA approval for [patients with] relapsed/refractory mantle cell lymphoma [in January 2023]. Pirtobrutinib was also tested in patients with relapsed/refractory CLL [in the BRUIN trial], and 62% of patients had a response to this drug. More importantly, patients who had BTK mutations because of prior exposure to other covalent BTK inhibitors also responded to this drug. Pirtobrutinib is quite promising.

The other drug, from Merck, nemtabrutinib (ARQ-53), was also tested. We have some early phase 1 data with that drug showing that responses appear to be good in patients with prior exposure to BTK drugs and a point mutation in the BTK pathway. There are several other players in the market, so we expect [those agents] to have more long-term clinical data with larger cohorts of patients in upcoming years.

What BTK degraders are under exploration in CLL?

A handful of compounds are currently all in phase 1 [trials]. With one compound, [NX-2127], made by Nurix Therapeutics, we saw some early [data from the phase 1 NX-2127-001 trial (NCT04830137) at the 2022 ASH Annual Meeting] showing that [all] patients in the study had prior exposure to BTK inhibitors. [Approximately] one-third of the patients had pirtobrutinib in the past, and a good number of patients had venetoclax-based treatment in the past, so these were heavily pretreated patients with CLL. When they received the BTK degrader, a subset of patients had a disease response, and responses deepened over time. The drug appears to be tolerable so far, [although] they’re still going through the different dose levels.

[At VUMC], we’ve been working with another company called Accutar Biotech, and they have their own version of a BTK degrader, [AC676], which is currently in a phase 1 trial [(NCT05780034) in patients with] various B-cell malignancies.

What has been seen with liso-cel in CLL, and what have been some of the limitations of CAR T-cell therapy in this population?

[In the] TRANSCEND CLL 004 trial, a single infusion of liso-cel was given to patients with relapsed/refractory CLL. [This was a] heavily pretreated patient population; all patients had prior BTK inhibitors. A good number of patients had prior venetoclax exposure with a BTK domain mutation. These patients received fludarabine and cyclophosphamide–based lymphodepletion, followed by a single dose of liso-cel.

Liso-cel achieved good disease control in most of these patients. In patients who had a CR, the median progression-free survival [PFS] was not reached at [a median] follow-up [of 24.0 months]. In patients who had a partial response, the median PFS was 26.9 months. Overall, the median PFS was 18.0 months. These numbers were comparable between the patients who had prior BTK inhibitors and BCL2 inhibitors vs the overall study population.

It seems that liso-cel cell can be effective in patients with relapsed CLL, and it can overcome some of the traditional risk factors of high-risk disease, such as BTK inhibitor–exposed status or BCL2 inhibitor–exposed status. However, the limitation is mainly both short-term and long-term toxicities of therapy. We have to use the lymphodepletion regimen for CAR T cells to expand in vivo, so these therapies might not be good options for old patients with multiple comorbidities. [Additionally], the risk of cytokine release syndrome and neurotoxicity is significant in the first few weeks after liso-cel administration. Relapses were also seen, so [liso-cel] is by no means a curative therapy. There needs to be further development of relapse-prevention strategies after patients have achieved initial responses to liso-cel.

An important limitation of CAR T-cell therapy is that it’s expensive, and access to this therapy is still limited to larger academic centers. That certainly limits the ability for patients to get this treatment.

What CLL research is ongoing at VUMC?

We have several phase 1 clinical trials. The most important one I’m excited about is the Accutar Biotech BTK degrader study. We also have a clinical trial using a novel, off-the-shelf, CD19 and CD20 dual-targeting CAR T-cell therapy, which will allow the treatment of patients with relapsed/refractory CLL. We also have [the phase 2 ZUMA-25 trial (NCT05537766) investigating brexucabtagene autoleucel (Tecartus), an] autologous CD19-directed CAR T-cell therapy from Gilead, [in] patients with Richter transformation. We have a handful of trials for patient who have progressed on SOC treatment options.

What is your main message for colleagues regarding the growing CLL treatment arena?

BTK inhibitors and BCL2 inhibitors are now used in most patients, both in the newly diagnosed and relapsed/refractory settings. However, when [patients] experience a relapse on these drugs, now we have this new armamentarium of the next generation of noncovalent BTK inhibitors, as well as a totally new class of BTK-targeting drugs, BTK degraders. Over the next several years, we are excited to see the data emerging from early-phase clinical trials.

Additionally, CAR T-cell therapy has done wonders in other high-grade B-cell malignancies. That success has not been duplicated in CLL so far, but with the liso-cel data, it appears that in the near future, we may have a good option with a CD19-targeting CAR T-cell therapy.

References

1. Mato AR, Woyach JA, Brown JR ,et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukeima. New Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8