Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need

Zygmunciak, Przemysław; Robak, Tadeusz; Puła, Bartosz

doi:10.3390/ijms25031589

Cited by 9 publications

(1 citation statement)

References 122 publications

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“…PROTACs constitute specialized molecules consisting of two linked domains, one that binds to the targeted protein and the other to E3 ubiquitin ligase. Such binding results in the degradation of the targeted protein by the proteasome [74][75][76]. Several BTK degraders, including NX-2127, NX-5948, BGB-16673, ABBV-101, and AC676, were recently under investigation in CLL patients [77][78][79][80][81].…”

Section: Overcoming Resistance To Btkimentioning

confidence: 99%

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

Wiśniewski,

Puła

2024

IJMS

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Bruton’s Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

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Section: Overcoming Resistance To Btkimentioning

confidence: 99%

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

Wiśniewski,

Puła

2024

IJMS

Self Cite

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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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Extramedullary and extranodal manifestations in chronic lymphocytic leukemia – an update

Robak,

Puła,

Braun

et al. 2024

Ann Hematol

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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common leukemia characterized by clonal expansion of mature CD5+/CD23 + B cells in the blood, bone marrow (BM) and lymphoid tissues. CLL can undergo extramedullary and extranodal infiltration, with one study noting an incidence of only 0.3 per 100,000 people, and in 17.6% of CLL patients in another report. The most common extranodal sites of leukemic involvement are the skin and central nervous system; however, other organs, including liver, lungs, kidney, gastrointestinal tract, bone, prostate and heart, are occasionally involved. The prognostic significance of extra-medullary CLL is still under debate, but the prognosis in such patients seems to be better in the era of novel targeted drugs. Following a diagnosis of extranodal CLL, survival appears to depend on the site of infiltration. This review presents an overview of CLL in patients with extramedullary and extranodal leukemic lesions, focusing on its epidemiology, pathogenesis, prognosis, clinical characteristics and treatment results.

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Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need

Cited by 9 publications

References 122 publications

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

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

Extramedullary and extranodal manifestations in chronic lymphocytic leukemia – an update

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