Although there have been major advances in treating CLL, the disease remains incurable in most cases, so there is room for improvement,
During the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), the “Next Questions” session garnered interest, promoted discussion, and generated hypothesis-generating ideas across all hematologic malignancies. Respected investigators took the podium to identify clinical challenges, address the state of treatment in their respective cancer settings, and to look forward to emerging approaches on the horizon.
One of the investigators who presented during the session was Florence Cymbalista, MD, PhD, professor at Avicenne Hospital, AP-HP, Sorbonne Paris Nord University France, who addressed chronic lymphocytic leukemia (CLL).
In CLL, the emergence of novel, oral, and targeted therapies has almost entirely supplanted chemoimmunotherapy in treatment of the disease. These novel therapies include first-, second-, and third-generation Bruton tyrosine kinase (BTK) inhibitors, apoptosis regulator BCL-2 agents, and PI3Kδ inhibitors.
Advances in CLL have resulted in 5-year overall survival rates increasing from 65.1% in 1975 to 87.2% in 2021.1 These improved outcomes are attributed to the widespread adoption of targeted agents, improved preventive and curative measures, better knowledge of off-target adverse events (AEs), outpatient care, and patient advocacy groups.
“But there remains considerable biological knowledge that is unexploited in clinical practice,” Cymbalista said in an interview with The SOHO Daily News. These include the emergence of clonal hemopoiesis markers, a greater understanding of recurrent mutations and their effect on treatment response, genetic instability, and epigenetic markers.
The clinical challenge revolves around decision points about which first-line and later-line targeted agents should be considered based on the safety profile for each agent. For example, the phase 3 ELEVATE R/R trial (NCT02477696) compared first-generation BTK inhibitor ibrutinib (Imbruvica®; Janssen Biotech, Inc/Pharmacyclics LLC) with second-generation BTK inhibitor acalabrutinib (Calquence®; AstraZeneca Pharmaceuticals LP).2 In the trial, 533 patients with previously treated CLL were randomly assigned to receive oral acalabrutinib or ibrutinib until disease progression or unacceptable toxicity. At the median follow-up of 40.9 months, acalabrutinib was determined to be non inferior to ibrutinib. Investigators reported that the median PFS for both arms was 38.4 months (95% CI acalabrutinib, 33.0-38.6 and 95% CI ibrutinib, 33.0-41.6; HR, 1.00; 95% CI, 0.79 to 1.27).
However, all-grade atrial fibrillation was significantly lower with acalabrutinib vs ibrutinib (9.4%; vs 16.0% P = .02). Similarly, incidence of hypertension was lower in patients treated with acalabrutinib vs ibrutinib (9%) vs 23%.2
Another second-generation BTK inhibitor, zanubrutinib (Brukinsa®; BeiGene USA, Inc), was shown to have a lower incidence of atrial fibrillation when compared with ibrutinib in the ALPINE trial (NCT03734016).3
The third-generation BTK inhibitor pirtobrutinib, an oral, highly selective, and noncovalent inhibitor, had demonstrated efficacy and safety in heavily pretreated patients with R/R CLL. The major interest of pirtobrutinib is its activity regardless of C481 mutation status.4
“How does the clinician decide between these BTK inhibitors?” asked Cymbalista.
She pointed out another wrench in the treatment paradigm: discontinuation of treatment with ibrutinib remains a significant issue. Research suggests that 5-year discontinuation rates with the BTK inhibitor are 41% in the frontline setting5 and 54% for patients with relapsed/refractory disease, leading to consider the time limited treatment options.6
Another area of evaluation is looking at blocking B-cell receptor signaling through the inhibition of PI3K kinase activity, said Cymbalista. Historically, PI3K inhibitors demonstrated efficacy but there are notable gastrointestinal toxicities associated with them. New-generation PI3K inhibitors could be more selective or take advantage of dual delta and gamma inhibitors.
Cymbalista then turned to ongoing trials that are exploring the time limited combinations. For example, the ECOG trial NCT03701282 will seek to clarify if triplet combination will be more effective than doublet combinations. Another trial, NCT04608318, is recruiting previously untreated patients with CLL to determine efficacy comparing ibrutinib monotherapy vs fixed-duration venetoclax (Venclexta®; Genentech USA, Inc/AbbVie) plus obinutuzumab (Gazyva®; Genentech, Inc) vs fixed-duration ibrutinib plus venetoclax. She noted, however, that the question of combining or sequencing therapies remains unresolved at this point.
On the horizon, Cymbalista said, there are numerous pathways undergoing evaluation, many of which address disease resistance. There is research on myeloid leukemia cell-1 (MCL-1), a member of the BCL-2 family of proteins. This regulator of apoptosis may resensitize cells that become resistant to venetoclax.
A phase 1/2 study (NCT03088878) is evaluating cirmtuzumab and ibrutinib in mantle cell lymphoma and CLL. Cirmtuzumab is a monoclonal antibody that inhibits ROR1’s tumor-promoting activity and may improve response to ibrutinib.
B-cell activating factor (BAFF) promotes CLL proliferation and the BAFF receptor (BAFF-R) remains expressed during ibrutinib treatment. Trials evaluating VAY-736 are ongoing.
“There are several new pathways that are being targeted right now,” Cymbalista said. “And that might give rise to new drugs in the near future.”
Although there have been major advances in treating CLL, the disease remains incurable in most cases, so there is room for improvement, she added. “Investigators need to keep exploring the sequence of therapies as patients ultimately relapse after frontline approaches. There remains a need to integrate more biological data in order to develop more personalized therapies,” concluded Cymbalista.
1. Cancer stat facts: leukemia – chronic lymphocytic leukemia CLL). National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed September 15, 2022. https://bit.ly/3DsU4ds
2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
3. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. European Hematology Association Library. Accessed September 15, 2022. https://bit.ly/3LjzSfC
4. Coombs CC, Pagel JM, Shah NN, et al. Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Clin Lymphoma Myeloma Leuk. 2021;21(suppl 1):S315-S315. doi:10.1016/S2152-2650(21)01746-8
5. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x
6. Woyach JA, Ruppert AM, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi:10.1200/JCO.2016.70.2282