SOHO State of the Art Updates and Next Questions: Updates on BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Easaw, Saumya; Ezzati, Shawyon; Coombs, Catherine C.

doi:10.1016/j.clml.2023.07.011

Cited by 5 publications

(2 citation statements)

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“…BTK inhibitors have become a cornerstone of CLL therapy, as B cell receptor (BCR) signaling is a key dependency of CLL cells that is required to sustain prosurvival signals from the microenvironment 19 . Several BTK inhibitors are available for the treatment of CLL and have demonstrated good long-term efficacy 20 . In the context of RT, preclinical models have demonstrated BCR signaling dependency that suggests sensitivity to BCR inhibitors 21 .…”

Section: Mainmentioning

confidence: 99%

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Al-Sawaf,

Ligtvoet,

Robrecht

et al. 2023

Nat Med

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In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45–82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2–72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study’s primary end point by rejecting the predefined null hypothesis of 40% (P = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8–16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4–91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956.

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Section: Mainmentioning

confidence: 99%

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Al-Sawaf,

Ligtvoet,

Robrecht

et al. 2023

Nat Med

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“…As is typical with kinase small-molecule drug discovery, the emergence of resistance mutations (e.g., C481S and T474M in BTK) is a critical concern for clinical efficacy and treatment. , These mutations impact the binding affinity and overall target engagement of inhibitors against BTK, especially mutation in the C481 position in the context of covalent inhibitors. Recent noncovalent BTK inhibitors such as pirtobrutinib and nemtabrutinib, including novel therapeutic protein degraders, hold promise for addressing some of the limitations of acquired resistance in relapsed and/or refractory patients previously treated with covalent BTK inhibitors. − Nevertheless, accurately predicting the effect of mutations in drug binding and pathogenesis could inform targeted approaches in drug discovery, as well as shed light on drug resistance mechanisms. With the advent of increased computer power, hardware technology, and algorithmic development, advanced computational approaches such as molecular dynamics and binding free energy calculations, are becoming routine in early stage drug discovery applications.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into the Impact of Mutations on the Binding Affinity of Targeted Covalent Inhibitors of BTK

Awoonor-Williams,

Abu-Saleh

2024

J. Phys. Chem. B

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Targeted covalent inhibitors (TCIs) have witnessed a significant resurgence in recent years, particularly in the kinase drug discovery field for treating diverse clinical indications. The inhibition of Bruton’s tyrosine kinase (BTK) for treating B-cell cancers is a classic example where TCIs such as ibrutinib have had breakthroughs in targeted therapy. However, selectivity remains challenging, and the emergence of resistance mutations is a critical concern for clinical efficacy. Computational methods that can accurately predict the impact of mutations on inhibitor binding affinity could prove helpful in informing targeted approachesproviding insights into drug resistance mechanisms. In addition, such systems could help guide the systematic evaluation and impact of mutations in disease models for optimal experimental design. Here, we have employed in silico physics-based methods to understand the effects of mutations on the binding affinity and conformational dynamics of select TCIs of BTK. The TCIs studied include ibrutinib, acalabrutinib, and zanubrutiniball of which are FDA-approved drugs for treating multiple forms of leukemia and lymphoma. Our results offer useful molecular insights into the structural determinants, thermodynamics, and conformational energies that impact ligand binding for this biological target of clinical relevance.

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Efficacy and Effectiveness Outcomes of Treatments for Double‐Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review

Zuber,

Akkala,

et al. 2024

Cancer Medicine

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BackgroundBruton's tyrosine kinase inhibitors (BTKi) and the B‐cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax‐treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as “double‐exposed,” and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double‐exposed CLL patients.MethodsPubMed, Embase, and Web of Science databases were searched until December 2023.ResultsWe retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T‐cell therapy.ConclusionThis study highlights the limited clinical data on efficacy outcomes for double‐exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

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SOHO State of the Art Updates and Next Questions: Updates on BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Cited by 5 publications

References 84 publications

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

Molecular Insights into the Impact of Mutations on the Binding Affinity of Targeted Covalent Inhibitors of BTK

Efficacy and Effectiveness Outcomes of Treatments for Double‐Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review

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