CLL Investigators Look to Write the Next Chapter of BCL-2 Inhibition

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When Mary Ann Anderson, MBBS, PhD, FRACP, FRCPA, explains the history of venetoclax, the revolutionary BCL-2 inhibitor that has transformed the management of chronic lymphocytic leukemia (CLL) and other hematologic malignant tumors, her explanation sounds more like an epic story than a scientific presentation. “Sharing the story of venetoclax and BCL-2 as a target is a wonderful example of translational medicine and how science can transform, in a very tangible way, the lives of patients,” Anderson, a clinical scientist at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, said.

But although the story she tells has plenty of twists and turns, it still lacks one thing: an ending. Since its first approval for CLL in 2016, venetoclax (Venclexta®; Genentech, AbbVie) has given new hope and better options to a notoriously hard-to-treat patient group. But its impact is only temporary; patients will eventually experience relapse, and at that point, the question of treatment gets harder.

Anderson will discuss the latest research in BCL-2 inhibition and its implications for the management of CLL on Friday, September 8, 2023, in the Plenary III session of the Society of Hematologic Oncology (SOHO) 2023 Eleventh Annual Meeting in Houston, Texas. Her talk is titled “Emerging BCL-2 Inhibitors.”

Venetoclax’s Origin Story

Although Anderson’s work has emerged as a driving force behind the new era of CLL therapy, she is quick to acknowledge that the story of BCL-2 and its role in CLL goes back long before her days in a laboratory coat. BCL-2 was first discovered in 1984 by scientists investigating follicular lymphoma. Over the next 2 decades, scientists at Anderson’s institute, working alongside other scientists internationally, were able to learn more about BCL-2. They figured out that it not only helps keep cells alive but also promotes cancer development and durability. “When cancers overexpress BCL-2, they are less likely to die when exposed to chemotherapy,” she explained.

That finding was critical because, up to that point, chemotherapy had been the standard of care for hematological malignant tumors, even though the patient population tended to be older and often had frailty. The new findings helped to explain why some patients were insensitive to the therapy.

Anderson, a CLL specialist, said CLL has been at the center of BCL-2 research because the cancer type is reliant on the presence of BCL-2 to keep cancer cells alive in the blood and bone marrow. “What that immediately suggests is that if you can find a way of turning BCL-2 off, you will take away the key survival factor for these cells,” she said.

Finding out how to do that, however, proved easier said than done. Anderson said the first wave of so-called BCL-2 inhibitors did not actually work as advertised because they were not selective or sensitive enough. “They weren’t the real deal,” she said.

The first true BCL-2 inhibitor, she said, was navitoclax. It led to modest activity in patients with CLL but not to the level that investigators were hoping for. The problem, it turned out, was that although navitoclax was capable of inhibiting BCL-2, it also inhibited a cousin of BCL-2, BCL-XL. The latter is essential for the survival of platelets, according to Anderson. “Navitoclax was turning off BCL-2 and killing cancer cells, but it was also turning off BCL-XL and killing platelets,” she said. “So we could never increase the dose of navitoclax to a good therapeutic level because it killed platelets and patients would be at risk of bleeding.”

Anderson and her colleagues thus set out on a mission to develop a better BCL-2 inhibitor, one that would more selectively target BCL-2 without the adverse effects of BCL-XL. What they eventually developed was ABT-199, better known today as venetoclax. The drug, which first entered clinical trials in 2011, was designed to attack BCL-2 but not BCL-XL.

Findings from the pivotal phase 1 trial (NCT01328626) were published in 2016.1 Findings from the trial showed venetoclax had a high response rate, even in the difficult-to-treat patient population.

“[Findings from] the phase 1 clinical trial established that there was an overall response rate of 80%,” Anderson said. “And this had been a group of patients who at the time were considered priorities, because we didn’t have any other standard-of-care treatment, the median number of prior lines of therapy was 4, they had bulky disease, and they had adverse genetics.”¹

The therapy was found to be particularly effective in patients with 17p deletion, which is why its first approval by the FDA was for patients with CLL and 17p deletion.² Other approvals followed quickly. Venetoclax is now used for a variety of cancers, including acute monocytic leukemia, mantle cell lymphoma, and other hematological malignant tumors. “It was quickly embraced by those people who [manage] a lot of CLL as a new paradigm for [management] of CLL,” she said.

Two years later, however, the case for venetoclax grew even stronger. Findings from the MURANO study (NCT02005471) showed venetoclax plus rituximab (Rituxan®; Genentech, Biogen) led to significantly better progression-free survival (PFS) in patients with CLL compared with bendamustine (Treanda) plus rituximab.³ Findings from the trial showed that in a patient population with relapsed or refractory CLL, venetoclax plus rituximab led to a 2-year PFS of 84.9% compared with just 36.3% in the bendamustine plus rituximab group (HR for progression or death, 0.17; 95% CI, 0.11-0.25; P<.001).

Finding the Limits of Venetoclax

However, the story was not yet over. As so often happens in science, Anderson said, the more scientists learned about venetoclax and its effect on CLL, the more they realized there was much work to be done. The initial euphoria over the new treatment option eventually gave way to the realization of its limitations. “It was an incredibly exciting time,” she said. “But over a period of some years, what we realized was that we were not curing anyone with venetoclax.”

Particularly in the relapsed or refractory setting, she said, even patients with deep responses to therapy will eventually experience relapse. They may respond to retreatment, but over time, resistance develops. “What that has led to is a drive by a number of companies to develop better BCL-2 inhibitors or at least newer BCL-2 inhibitors,” she said.

Next Generation of BCL-2 Inhibitors

In her plenary session, Anderson will discuss some of the latest efforts to develop new types of BCL-2 inhibitors. Those efforts have taken a number of forms, she said. Some therapies are designed to improve upon venetoclax, whereas others are specifically tailored to evade known mechanisms of resistance to venetoclax.

Part of the problem, Anderson said, is that there’s no single mechanism of resistance to tackle. In some patients, BCL-2 itself mutates so as not to succumb to inhibition. “But within the same individual, we can also identify upregulation of other BCL-2 family members,” she said. “So even though you’re turning off BCL-2, its cousins—BCL-XL, MCL-2, etc—are conferring resistance in the cell.”

The environment of CLL also likely contributes to the problem. “The space in which CLL sits in the human body—the lymph nodes and bone marrow—provides a layer of additional protection to the cells from cell death,” Anderson said.

Given the wide range of resistance mechanisms, Anderson said it is unlikely any single BCL-2 inhibitor can solve all possible avenues of resistance. However, she said there is hope of improving upon the standard of care and finding new ways to optimize the usage of venetoclax.

Among the therapies currently in clinical trials is BeiGene-11417. A clinical trial (NCT04277637) is currently recruiting patients with relapsed or refractory CLL or small lymphocytic leukemia to participate in a phase 2 study.⁴ The central question of that trial, Anderson said, is whether patients who have previously been treated with venetoclax can respond well to newer-generation BCL-2 inhibitors.

Other trials are looking at venetoclax retreatment to see whether it can elicit responses in the same patients multiple times. A research letter published in the past year found a nearly 80% overall response rate for venetoclax in patients with relapsed or refractory CLL who had previously undergone a venetoclax-based treatment regimen.⁵ However, although findings from that study supported the safety of venetoclax retreatment and the study was believed to be the largest case series of its kind, it only included 46 patients. The authors said despite its limitations, the study’s high response rate suggests venetoclax retreatment ought to be the focus of additional research. Anderson said it will likely be years before it is clear whether new BCL-2 inhibitors or venetoclax retreatment will be the better option.

Other BCL-2 inhibitors being studied include AZD4320. Like navitoclax, AZD4320 inhibits both BCL-2 and BCL-XL. Unlike navitoclax, the newer therapy was designed to minimize the risk of thrombocytopenia^.6

LP-108 is a BCL-2 inhibitor that investigators say appears to be equally potent or perhaps more potent than venetoclax within in vitro testing.⁷ It is currently the subject of ongoing research in other types of hematologic malignant tumors.

Phase 1 data presented in the past year about the BCL-2 inhibitor BGB-11417 showed it was well tolerated when used alongside a Bruton tyrosine kinase (BTK) inhibitor in patients with relapsed or refractory CLL.⁸ The early data suggest the combination led to significant positive responses in patients. Similarly, investigators in July published safety and tolerability data for lisaftoclax (APG-2575), indicating that the therapy was well tolerated and achieved clinical responses worthy of additional study.⁹

Advice to Community Oncologists

As research into newer BCL-2 therapies and approaches continues, clinicians operating in the new paradigm have a number of options to consider. In her clinic, Anderson said they routinely test patients with CLL for BCL2 mutations to help guide care. “If a patient has recognized BCL2 mutations, that may influence decisions about retreating with venetoclax, considering a different BCL-2 inhibitor, or even changing classes of drug,” she said.

Anderson said she practices in a cancer center with a molecular laboratory eager to perform such testing. She acknowledged, however, that not all clinics can perform BCL2 mutational testing, but she is hopeful that in the next decade or so, it will become more accessible and common.

Clinicians can also strategize by comparing notes with other colleagues. Anderson said she is excited about the opportunity to speak in person with her colleagues at SOHO, something she was not able to do at the height of the COVID-19 pandemic. “There’s the who’s who of hematology coming to this conference,” she said. “And being able to sit down and chat to them about collaborations, etc, is something that I’m enormously excited about.”

The Story Continues

In the meantime, the long story of BCL-2 research is about to enter its fifth decade. Considering those early steps, her research into venetoclax, and the possible next steps in CLL therapy, Anderson said she has been amazed at how much has changed in the past 7 years.

“When I started my career, we had FCR [fludarabine, cyclophosphamide, and rituximab], we had Campath® [alemtuzumab; Genzyme], we had transplant, we had palliation, and that was all we had for CLL,” she said. “And all those treatments are enormously toxic. They interfere with quality of life, and often they don’t buy patients a huge amount of time.”

However, in approximately a decade, the paradigm has shifted to a point where she “wouldn’t dream of giving chemotherapy to a patient with CLL. That is incredibly inspiring, because my trainees may never give chemotherapy for this indication. And that’s remarkable.”

Instead, Anderson said, her trainees can expect to achieve good disease control in their patients without the toxicities of chemoimmunotherapy. While they do, she and her team will look to write the next chapter of CLL therapy, one that builds on the current knowledge but hopefully leads to a new paradigm. “It really does need to be multidisciplinary and collaborative,” she said. “It involves many hundreds of people to actually get a success story like this, but it’s worth it.”

_References

_{1. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. doi:10.1056/NEJMoa1513257}

_{2. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. News release. FDA. April 11, 2016. Accessed July 24, 2023. https://bit.ly/43ARN9f}

_{3. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976}

_{4. Study of BGB-11417 in participants with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. ClinicalTrials.gov. Updated July 19, 2023. Accessed July 24, 2023. https://clinicaltrials.gov/study/NCT05479994}

_{5. Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Adv. 2022;6(15):4553-4557. doi:10.1182/bloodadvances.2022007812}

_{6. Balachander SB, Criscione SW, Byth KF, et al. AZD4320, a dual inhibitor of Bcl-2 and Bcl-xL, induces tumor regression in hematologic cancer models without dose-limiting thrombocytopenia. Clin Cancer Res. 2020;26(24):6535-6549. doi:10.1158/1078-0432.CCR-20-0863}

_{7. Walker AR, Bergua Burgues JM, Montesinos P, et al. Phase 1 study of LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). J Clin Oncol.2022;40(suppl 16):TPS7071. doi:10.1200/jco.2022.40.16_suppl.tps7071}

_{8. Cheah CY, Tam CS, Lasica M, et al. A phase 1 study with the novel B-cell lymphoma 2 (Bcl-2) inhibitor Bgb-11417 as monotherapy or in combination with zanubrutinib (ZANU) in patients (pts) with CLL/SLL: preliminary data. Blood. 2022;140(suppl 1): 2321-2323. doi:10.1182/blood-2022-169662}

_{9. Ailawadhi S, Chen Z, Huang B, et al. Novel BCL-2 inhibitor lisaftoclax in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies: first-in-human open-label trial. Clin Cancer Res. 2023;29(13):2385-2393. doi:10.1158/1078-0432.CCR-22-3321}