Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

Quinquenel, Anne; Fornecker, Luc‐Matthieu; Letestu, Rémi; Ysebaert, Loïc; Fleury, Carole; Lazarian, Grégory; Dilhuydy, Marie-Sarah; Nollet, Delphine; Guièze, Romain; Feugier, Pierre; Roos‐Weil, Damien; Willems, Lise; Michallet, Anne‐Sophie; Delmer, Alain; Hormigos, Katia; Lévy, Vincent; Cymbalista, Florence; Baran‐Marszak, Fanny

doi:10.1182/blood.2019000854

Cited by 98 publications

(88 citation statements)

References 23 publications

(31 reference statements)

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“…29 Ahn et al 30 BTK-and PLCG2-mutations in a real-life setting, evaluated by next-generation sequencing, have been reported by the French Innovative Leukemia Organization, respectively in 57% and 13% patients who received ibrutinib. 31 This finding was significantly associated with subsequent CLL progression at a median of 8.5 months after sample collection. In the light of the above observations it would be important to consider future clinical trials aimed at evaluating the clinical impact of an early switch to another treatment in patients carrying BTK mutations and trials of agents capable of overcoming ibrutinib resistance caused by acquired BTK or PLCG2 mutations are already in progress.…”

Section: Resistance To Ibrutinibmentioning

confidence: 87%

“…BTK‐ and PLCG2‐mutations in a real‐life setting, evaluated by next‐generation sequencing, have been reported by the French Innovative Leukemia Organization, respectively in 57% and 13% patients who received ibrutinib . This finding was significantly associated with subsequent CLL progression at a median of 8.5 months after sample collection.…”

Section: Resistance To Ibrutinibmentioning

confidence: 93%

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Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Molica

Matutes

Tam

et al. 2019

Hematological Oncology

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A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first‐in‐class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib‐resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second‐generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high‐risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long‐term results of ongoing studies combining Ibrutinib with (chemo)‐immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

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Section: Resistance To Ibrutinibmentioning

confidence: 87%

Section: Resistance To Ibrutinibmentioning

confidence: 93%

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Molica

Matutes

Tam

et al. 2019

Hematological Oncology

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“…Genetic mechanisms of primary or acquired resistance to ibrutinib have been widely studied and recurrent mutations associated with resistance have been described in B cell malignancies ( Table 1 , Figure 1 ). Whole-exome sequencing revealed mutations in BCR-involved proteins BTK and PLCγ2 in ~80% of CLL patients with acquired resistance to ibrutinib ( 7 , 96 ), however, some studies have reported a much lower frequency of these mutations ( 97 , 98 ). The most common mutation in BTK is a C481S point mutation which interferes with the binding of ibrutinib to BTK ( 7 , 68 ).…”

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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“…In 2014, a study using whole-exome sequencing discovered acquired mutations within the BTK gene in 5/6 high-risk CLL patients relapsing on ibrutinib (10). A recent study on 30 CLL patients with residual lymphocytosis treated with ibrutinib for 3 years confirmed the presence of BTK mutations in 57% of CLL patients, and the presence of BTK mutations was associated with subsequent relapse (11). A number of studies have confirmed the presence of this mutation in CLL patients relapsing on ibrutinib and have shown that those mutations were not present prior to drug administration (12)(13)(14).…”

Section: Resistance-associated Mutations In Ibrutinib Treatmentmentioning

confidence: 99%

“…Moreover, different PLCG2 mutations are usually found in multiple subclones with low allelic burden (12,13,17). A recent study confirmed PLCG2 mutations in 13% of ibrutinib treated patients with residual lymphocytosis (11). However, the exact contribution of the PLCG2 to the clinical resistance of CLL patients remains not fully understood (22).…”

Section: Resistance-associated Mutations In Ibrutinib Treatmentmentioning

confidence: 99%

Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

et al. 2020

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Inhibitors of B-cell receptor signaling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide a state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No distinct unifying resistance-associated mutations or deregulated signaling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.

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Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study

Cited by 98 publications

References 23 publications

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

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

Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

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