Lisaftoclax (APG-2575) Safety and Activity As Monotherapy or Combined with Acalabrutinib or Rituximab in Patients (pts) with Treatment-Naïve, Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): Initial Data from a Phase 2 Global Study

Davids, Matthew S.; Chanan‐Khan, Asher; Mudenda, Boyd; Nogaieva, Larysa; Kriachok, Iryna; Usenko, Hanna; Ivanov, V.; Kyselova, Olena; Perekhrestenko, Tetiana; Muzhychuk, Ivan; Myasnikov, Alexander G.; Maslyak, Z; Proidakov, Andrew; Uspenskaya, Olga; Borisenkova, Elena; Marlton, Paula; Siddiqi, Tanya; Winter, Allison M.; Lysa, Tamila; Бакиров, Б. А.; Fu, Lei; Chen, Zi; Yu, Miao; Li, Mingyu; Glass, Laura A.; Ahmad, Mohammad; Карпенко, Олена; Osipov, Iurii; De, Asit K.; Paudyal, Ben; Wang, Hengbang; Winkler, Robert L.; Gabrail, Nashat; Ganju, Vinod; Константинова, Т. С.; Samoylova, Olga; Yang, Dajun; Zhai, Yifan

doi:10.1182/blood-2022-160386

Cited by 11 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, Lisaftoclax, which selectively binds Bcl2 and prevents BCL2:BIM complexes allowing pore formation in mitochondria, demonstrated significant antitumor activity in preclinical trials [ 45 ] . This prompted progression to a phase I/II clinical trial in relapsed/refractory CLL patients with an ORR of 65% in the monotherapy group, 98% ORR in combination with acalabrutinib, and 87% in combination with Rituximab [ 46 ] . The average number of previous treatments was 2, with 12% of the patients progressing on BTK inhibitors and/or venetoclax [ 46 ] .…”

Section: Methods To Overcome Resistancementioning

confidence: 99%

“…This prompted progression to a phase I/II clinical trial in relapsed/refractory CLL patients with an ORR of 65% in the monotherapy group, 98% ORR in combination with acalabrutinib, and 87% in combination with Rituximab [ 46 ] . The average number of previous treatments was 2, with 12% of the patients progressing on BTK inhibitors and/or venetoclax [ 46 ] .…”

Section: Methods To Overcome Resistancementioning

confidence: 99%

See 1 more Smart Citation

Targeting BCL2 pathways in CLL: a story of resistance and ingenuity

Reyes,

Siddiqi

2023

Cancer Drug Resist

Self Cite

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) is common amongst leukemic malignancies, prompting dedicated investigation throughout the years. Over the last decade, the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2 (BCL2), Bruton’s tyrosine kinase, and CD20. Single agents or combinations of these targets have proven efficacy. Unfortunately, resistance to one or multiple of the new treatment targets develops. Our review investigates various mechanisms of resistance to BCL2 inhibitors, including mutations in BCL2, alterations in the Bcl protein pathway, epigenetic modifications, genetic heterogeneity, Richter transformation, and alterations in oxidative phosphorylation. Additionally, the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies, Bruton’s tyrosine kinase (BTK) degraders, non-covalent BTK inhibitors, and chimeric antigen receptor T (CART).

show abstract

Section: Methods To Overcome Resistancementioning

confidence: 99%

Section: Methods To Overcome Resistancementioning

confidence: 99%

Targeting BCL2 pathways in CLL: a story of resistance and ingenuity

Reyes,

Siddiqi

2023

Cancer Drug Resist

Self Cite

View full text Add to dashboard Cite

show abstract

“…The recommended dose of 600 mg once a day had manageable side effects. (Davids et al, 2022) toxicity and prevent the development of severe side effects, particularly tumor lysis syndrome (Roberts et al, 2016). Notably, nearly 70% of patients receiving a daily dose of 400 mg of venetoclax experienced progression-free survival (PFS) for an impressive 15 months.…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 99%

“…Importantly, during the initial phases of clinical testing, there was no evidence of tumor lysis syndrome, a serious concern in cancer treatment (Ailawadhi et al, 2023). Additionally, a 600 mg dose of lisaftoclax from a phase II study displayed activity in patients with relapsed or refractory leukemia and exhibited a tolerable safety profile (Davids et al, 2022).…”

Section: Natural Compounds and Small Molecules Targeting Bcl‐2 Family...mentioning

confidence: 99%

Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

Iksen,

Witayateeraporn,

Hardianti

et al. 2024

Phytotherapy Research

View full text Add to dashboard Cite

Cancer has a considerably higher fatality rate than other diseases globally and is one of the most lethal and profoundly disruptive ailments. The increasing incidence of cancer among humans is one of the greatest challenges in the field of healthcare. A significant factor in the initiation and progression of tumorigenesis is the dysregulation of physiological processes governing cell death, which results in the survival of cancerous cells. B‐cell lymphoma 2 (Bcl‐2) family members play important roles in several cancer‐related processes. Drug research and development have identified various promising natural compounds that demonstrate potent anticancer effects by specifically targeting Bcl‐2 family proteins and their associated signaling pathways. This comprehensive review highlights the substantial roles of Bcl‐2 family proteins in regulating apoptosis, including the intricate signaling pathways governing the activity of these proteins, the impact of reactive oxygen species, and the crucial involvement of proteasome degradation and the stress response. Furthermore, this review discusses advances in the exploration and potential therapeutic applications of natural compounds and small molecules targeting Bcl‐2 family proteins and thus provides substantial scientific information and therapeutic strategies for cancer management.

show abstract

“…The ORRs with lisaftoclax monotherapy, lisaftoclax + acalabrutinib, and lisaftoclax + rituximab were 65%, 98%, and 87%, respectively. 93 Sonrotoclax (BGB-11417) is a novel highly selective and potent BCL2i with a favourable pharmacokinetics profile and a broad therapeutic index. 94 According to the preliminary data for CLL/SLL in the phase 1 BGB-11417-101 trial, the ORRs with sonrotoclax monotherapy and in combination with zanubrutinib were 67% (6/8) and 95% (19/25), respectively.…”

Section: Novel Targeted Therapies For Double Refractory Diseasementioning

confidence: 99%

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

Hayama,

Riches

2024

OTT

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell lymphoproliferative disease with a high annual incidence in Western countries. As B-cell receptor (BCR) signaling and intrinsic apoptotic resistance play critical roles in the development and survival of CLL cells, therapeutic approaches targeting these pathways have been extensively investigated to tackle this incurable disease. Over the last decade, several Phase 3 trials have confirmed the superior efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, over chemoimmunotherapy. This has been demonstrated in both the treatment-naïve and relapsed/refractory (RR) settings and includes patients with high-risk molecular features. However, these drugs are not curative, with patients continuing to relapse after treatment with both cBTKis and BCL2is, and the optimal treatment strategy for these patients has not been defined. Several novel agents with distinct mechanisms have recently been developed for CLL which have demonstrated efficacy in patients who have previously received cBTKis and BCL2i. In particular, novel BCR-signaling targeting agents have shown promising efficacy in early-phase clinical trials for RR-CLL. Furthermore, cancer immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cells have also shown anti-tumor activity in patients with heavily pretreated RR-CLL. Personalised approaches with these novel agents and combination strategies based on the understanding of resistance mechanisms have the potential to overcome the clinical challenge of what to do next for a patient who has already had a cBTKi and venetoclax.

show abstract

Lisaftoclax (APG-2575) Safety and Activity As Monotherapy or Combined with Acalabrutinib or Rituximab in Patients (pts) with Treatment-Naïve, Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): Initial Data from a Phase 2 Global Study

Cited by 11 publications

References 0 publications

Targeting BCL2 pathways in CLL: a story of resistance and ingenuity

Targeting BCL2 pathways in CLL: a story of resistance and ingenuity

Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About