S146: Genomic Evolution and Resistance to Pirtobrutinib in Covalent BTK-Inhibitor (Cbtki) Pre-Treated Chronic Lymphocytic Leukemia (Cll) Patients: Results From the Phase I/Ii Bruin Study

Brown, Jennifer R.; Desikan, Sai Prasad; Nguyen, Bastien; Won, Helen; Tantawy, Shady; McNeely, Samuel C.; Marella, Narasimha; Ebata, Kevin; Woyach, Jennifer A.; Patel, Krish; Tam, Constantine S.; Eyre, Toby A.; Cheah, Chan Y.; Shah, Nirav N.; Jurczak, Wojciech; Balbas, Minna; Nair, Binoj C.; Abada, Paolo; Wang, Chunxiao; Wang, Denise; Mato, Anthony R.; Gandhi, Varsha; Wierda, William G.

doi:10.1097/01.hs9.0000967496.62332.46

Cited by 2 publications

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“…This suggests that newer noncovalent BTKi might overcome the resistance observed with covalent BTKi even in the context of super-resistant mutants, pointing to the possibility to re-treat a resistant patient with another BTKi after relapse. In the phase 1/2 BRUIN study, pirtobrutinib allowed the clearance of C481 mutations of ibrutinib resistance while new BTK mutations such as L528W, V416L, A428D, D539G, and Y545N and gatekeeper mutations like T474I/F/L/Y were detected at pirtobrutinib resistance [ 110 ]. Further studies are necessary to determine which noncovalent BTKi resistance mutations are able to circumvent or not, as well as to determine their efficacy across a broader population in first-line settings to guide therapy choice and sequencing.…”

Section: Mechanisms Of Resistance To Target Therapy In Cllmentioning

confidence: 99%

Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia

Del Giudice,

Della Starza,

De Falco

et al. 2024

Cancers

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The recent evolution in chronic lymphocytic leukemia (CLL) targeted therapies led to a progressive change in the way clinicians manage the goals of treatment and evaluate the response to treatment in respect to the paradigm of the chemoimmunotherapy era. Continuous therapies with BTK inhibitors achieve prolonged and sustained control of the disease. On the other hand, venetoclax and anti-CD20 monoclonal antibodies or, more recently, ibrutinib plus venetoclax combinations, given for a fixed duration, achieve undetectable measurable residual disease (uMRD) in the vast majority of patients. On these grounds, a time-limited MRD-driven strategy, a previously unexplored scenario in CLL, is being attempted. On the other side of the spectrum, novel genetic and non-genetic mechanisms of resistance to targeted treatments are emerging. Here we review the response assessment criteria, the evolution and clinical application of MRD analysis and the mechanisms of resistance according to the novel treatment strategies within clinical trials. The extent to which this novel evidence will translate in the real-life management of CLL patients remains an open issue to be addressed.

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Section: Mechanisms Of Resistance To Target Therapy In Cllmentioning

confidence: 99%

Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia

Del Giudice,

Della Starza,

De Falco

et al. 2024

Cancers

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“…Recently Wang et al revealed the occurrence of 5 non-C481 mutations (V416L, A428D, M437R, T474I, and L528W) in patients initially responding to but ultimately relapsing on pirtobrutinib (Figure 3) [84]. These mutations cluster within the kinase domain of BTK [84] and result in sidechain point substitutions that impede the binding of both covalent and non-covalent BTK inhibitors [85,92]. Similar to the earlier described C481F/R/Y mutations, point mutations K430R, V416L, A428D, M437R, and L528W cause steric hindrance and structural clashing, preventing the binding of BTKis but also ATP, causing these mutations to be kinase deficient/dead.…”

Section: Non-covalent Btk Inhibitors In Cll and The Rise Of Non-c481 ...mentioning

confidence: 99%

“…Following the pirtobrutinib treatment, samples from patients who progressed were sequenced again and showed the clearance of C481S/Y/R/F mutations. Instead, new BTK mutations such as L528W, V416L, A428D, D539G, Y545N, and gatekeeper mutations like T474I/F/L/Y were detected (Figure 3) [92]. Future studies are necessary to determine which resistance mutations these ncBTKis can or cannot circumvent and their efficacy across a broader patient population.…”

Section: Non-covalent Btk Inhibitors In Cll and The Rise Of Non-c481 ...mentioning

confidence: 99%

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)

Chirino,

Montoya,

Safronenka

et al. 2023

Genes

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Bruton’s tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK’s active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.

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S146: Genomic Evolution and Resistance to Pirtobrutinib in Covalent BTK-Inhibitor (Cbtki) Pre-Treated Chronic Lymphocytic Leukemia (Cll) Patients: Results From the Phase I/Ii Bruin Study

Abstract: Background:Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, demonstrated broad efficacy in patients (pts) with CLL/SLL who were resistant to cBTKi. Mechanisms of resistance to pirtobrutinib have not been systematically analyzed to date.

Cited by 2 publications

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Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia

Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)

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