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Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation
Author(s) -
KanagalShamanna Rashmi,
Jain Preetesh,
Patel Keyur P.,
Routbort Mark,
BuesoRamos Carlos,
Alhalouli Tahani,
Khoury Joseph D.,
Luthra Rajyalakshmi,
Ferrajoli Alessandra,
Keating Michael,
Jain Nitin,
Burger Jan,
Estrov Zeev,
Wierda William,
Kantarjian Hagop M.,
Medeiros L. Jeffrey
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31831
Subject(s) - bruton's tyrosine kinase , ibrutinib , chronic lymphocytic leukemia , cancer research , medicine , somatic evolution in cancer , mutation , tyrosine kinase , leukemia , immunology , cancer , genetics , biology , gene , receptor
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.