Genomic evolution of ibrutinib‐resistant clones in Waldenström macroglobulinaemia

Jiménez, Cristina; Chan, Gloria; Liu, Xu; Tsakmaklis, Nickolas; Kofides, Amanda; Demos, Maria; Chen, Jiaji; Liu, Xia; Munshi, Manit; Yang, Guang; Castillo, Jorge J.; Wiestner, Adrian; Treon, Steven P.; Hunter, Zachary

doi:10.1111/bjh.16463

Cited by 26 publications

(27 citation statements)

References 15 publications

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“…The C481 mutants are not exclusively seen during ibrutinib treatment, they are also found in patients treated with other irreversible BTKi that target C481, namely acalabrutinib ( 57 ) and zanubrutinib ( 58 ). Furthermore, resistance mutations not only appear in CLL, but also in MCL ( 59 ), marginal zone leukemia (MZL) ( 60 ) and Waldenström’s macroglobulinemia ( 14 , 61 ).…”

Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

“…Furthermore, apart from the BCR-signaling components which are affected, there are additional resistance mutations. Those located to the short arm of chromosome 8 have been suggested to impair apoptosis by causing haploinsufficiency for the TRAIL receptor ( 61 , 66 ), whereas other mutations affect additional genes ( 61 , 67 ). Del (8p) was found in a sizable number of ibrutinib-resistant CLL cases, resulting in deletion and haploinsufficiency of tumor necrosis factor-related apoptosis-inducing ligand-receptor (TRAIL-R) ( 66 , 68 ).…”

Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

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Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

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Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

Section: Resistance Mutations Predominantly Affect Btkmentioning

confidence: 99%

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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“…Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% CI [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI 34-not reached).…”

Section: Ibrutinib Is Highly Active and Produces Long-term Responses In Patients Withmentioning

confidence: 99%

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy

et al. 2021

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Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5). Following discontinuation of ibrutinib, a rapid increase in serum IgM level was observed in 60% (29/48) of evaluable patients, of whom 10 acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% CI 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (OR 0.20, 95% CI 0.05-0.73) and salvage therapy 07 days after discontinuing ibrutinib (OR 4.12, 95% CI 1.07-18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI 26-75%). Response to salvage therapy was associated with better OS after ibrutinib (HR 0.08, 95% CI 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTKC481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

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“…In Waldenström’s macroglobulinemia (WM), mutations in CARD11 also lead to ibrutinib resistance, and in WM patients the ibrutinib resistance may be accompanied by 6q and 8p chromosome region deletions that expand from pre-existing clones or emerge during treatment ( 71 , 94 ). These chromosomal regions contain important signaling pathway regulators.…”

Section: Genetic Mechanisms Of Ibrutinib Resistancementioning

confidence: 99%

“…The 6q region loss involves negative regulators of MYD88/NFκB ( TNFAIP3, HIVEP2, TRAF3IP2, IRAK1BP1 ), an inhibitor of BTK (IBTK), and regulators of apoptosis ( FOXO3, BCLAF1, PERP ). The genes deleted on 8p include DOK2, a TLR/ MYD88 signaling inhibitor, BLK, another target of ibrutinib that is important for B cell proliferation and differentiation, and TNFRSF10A/B, a gene encoding for TRAIL receptor ( 94 , 95 ). Common mutations in WM are WHIM-like mutations in CXCR4 and L265P mutations in MYD88, a mediator of Tolllike receptor signaling ( 110 ).…”

Section: Genetic Mechanisms Of Ibrutinib Resistancementioning

confidence: 99%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

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Genomic evolution of ibrutinib‐resistant clones in Waldenström macroglobulinaemia

Cited by 26 publications

References 15 publications

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

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