Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Kadri, Sabah; Lee, Jimmy; Fitzpatrick, Carrie; Galanina, Natalie; Sukhanova, Madina; Venkataraman, Girish; Sharma, Shruti; Long, Brad S.; Petras, Kristin; Theissen, Megan; Ming, Mei; Kobzev, Yuri; Kang, Wenjun; A, Guo; Wang, Y. Lynn; Niu, Nifang; Weiner, Howard; Thirman, Michael J.; Stock, Wendy; Smith, Sonali M.; Nabhan, Chadi; Segal, Jeremy P.; Lü, Ping; Wang, Y. Lynn

doi:10.1182/bloodadvances.2016003632

Cited by 109 publications

(150 citation statements)

References 44 publications

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“…The frequency of BTK and PLCG2 mutations in RT is different than the frequency of such mutations in patients who have progressive CLL on ibrutinib without transformation. In the peripheral blood, BTK and PLCG2 mutations are found in about 80% of patients with progressive CLL (Table 1) but only about 40% of patients with RT [5, 11]. Likely due to the greater difficulty in obtaining transformed tissue, the molecular details of the Richter’s tissue remain largely unexplored to date.…”

Section: Reasons For Discontinuation Of Ibrutinib Therapymentioning

confidence: 99%

“…Likely due to the greater difficulty in obtaining transformed tissue, the molecular details of the Richter’s tissue remain largely unexplored to date. However, one study has reported that three out of six cases of RT displayed BTK mutations in the nodal tissue [11]. The different BTK/PLCG2 mutational frequency in RT suggests an underlying biology that is distinct from simple progression of CLL without transformation (discussed below).…”

Section: Reasons For Discontinuation Of Ibrutinib Therapymentioning

confidence: 99%

“…BTK and PLCG2 mutations are not strictly necessary for resistance to ibrutinib, as not all patients who relapse, either with RT or with CLL simple progression, have detectable BTK or PLCG2 mutations (Table 1) [5, 11, 18]. Other genetic alterations have been proposed to cause ibrutinib resistance in the approximately 20% of CLL patients with acquired resistance in the absence of BTK or PLCG2 mutations.…”

Section: Btk and Plcg2 Mutations Are Not Necessary For Acquired Resismentioning

confidence: 99%

“…In the case of BTK and PLCG2 mutations in ibrutinib-resistant disease, this characteristic is clearly demonstrated. Nearly all reported BTK mutations in the dozens of cases reported in the literature have occurred at the cysteine 481 hotspot [5, 8, 10], except for a few additional cases reported with mutations at T316, T474, and L528 [6, 11, 34]. While the reported PLCG2 mutations are more varied, and involve amino acid residues P664, R665, S707, L845, D993, D1140, and M1141 [5, 7, 10], they seem to cluster within particular domains [35], rather than being randomly distributed throughout the protein.…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

“…A deletion in the short arm of chromosome 8, del(8p), was identified in three out of five patients with acquired resistance to ibrutinib in the absence of any BTK mutations [18]. Additionally, two separate investigators have reported a total of three ibrutinib-resistant patients (including one without any BTK mutation) with non-overlapping mutations in the gene PCLO [11, 18]. Nevertheless, the demonstration of genetic alterations or mutations within the same gene in more than one patient is not proof that such mutations are sufficient for resistance.…”

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

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AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Lampson

Brown

2018

Expert Review of Hematology

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Introduction: Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in ≈80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it. Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse. Expert Commentary: While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.

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Section: Reasons For Discontinuation Of Ibrutinib Therapymentioning

confidence: 99%

Section: Reasons For Discontinuation Of Ibrutinib Therapymentioning

confidence: 99%

Section: Btk and Plcg2 Mutations Are Not Necessary For Acquired Resismentioning

confidence: 99%

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

Section: Characteristics Of Mutations That Are Sufficient For Acquirementioning

confidence: 99%

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AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Lampson

Brown

2018

Expert Review of Hematology

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Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib

et al. 2022

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Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010–2019. After a median follow‐up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow‐up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60–10.00], p = .003), higher LDH (HR 1.80 for 2‐fold increase [1.33–2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15–7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post‐progression. In a subset analysis of 50 patients who obtained a PET‐CT at progression, the median SUVmax for patients who would develop RT was 15.2 (n = 30, range: 4.0–46.3) versus those patients who did not develop RT with a SUVmax of 7.7 (n = 20, range: 2.3–27.2) (p = .0030). Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis.

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Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

Kanagal‐Shamanna

Jain

Patel

et al. 2018

Cancer

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Background In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/phospholipase C gamma 2 (PLCG2) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited. Methods Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution. Results The study group included 29 patients with BTKi‐resistant CLL, 23 patients with disease progression, and 6 patients with Richter transformation (RT). The median times to disease progression and RT were 33.3 months and 13.3 months, respectively. In 11 patients, sequencing was possible at both baseline (prior to treatment with BTKi) and at time of disease progression/RT. Of these patients, 4 demonstrated BTK mutations at the time of disease progression/RT; patients without BTK mutations frequently acquired mutations associated with disease progression/RT in TP53, SF3B1, and CARD11, whereas additional mutations were rare in patients with BTK‐mutated CLL. Sequencing of all 29 patients at the time of disease progression/RT identified BTK mutations at a frequency of 66%, including a novel V537I mutation. Among patients with disease progression, BTK mutations were observed in 16 patients (70%). The median time to disease progression was shorter in patients without BTK mutations compared with those with BTK‐mutated CLL. Among patients with RT, SF3B1 mutations were more frequent than BTK mutations (67% vs 50%). Following BTKi discontinuation, we sequential mutation analysis was performed in 2 patients with RT and 3 patients with disease progression in the setting of persistent disease. Both patients with RT demonstrated disappearance of BTK and expansion of TP53 mutations. All 3 patients with disease progression received venetoclax and demonstrated suppression of BTK mutations. Conclusions Longitudinal, targeted, multigene deep sequencing is informative for the clinical monitoring of mutational evolution in patients with CLL who are receiving BTKi.

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Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

Cited by 109 publications

References 44 publications

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib

Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation

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