IDENTIFICATION OF A STRUCTURALLY NOVEL BTK MUTATION THAT DRIVES IBRUTINIB RESISTANCE IN CLL BUT NOT RICHTER TRANSFORMATION
(Abstract release date: 05/19/16)
EHA Library. Wang L. 06/09/16; 132583; E1034
Prof. Lynn Wang
Contributions
Contributions
Abstract
Abstract: E1034
Type: Eposter Presentation
Background
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. In addition, BTK mutations have been found in several Richter-transformed patients treated with ibr. In these patients, it is not clear whether BTK mutations are related to Richter transformation or ibr treatment or both.
Aims
As the use of ibr becomes more prevalent in CLL and other types of non-Hodgkin lymphoma (NHL), more patients are expected to develop resistance. Thus, a complete understanding of the mechanisms of ibr resistance is important for the development of strategies to prevent and treat ibrutinib resistance.
Methods
Serial samples were collected from a Richter transformed CLL patient who were treated with ibrutinib, responded and then relapsed. The samples were analyzed using Onco1K, a 1,200-gene next-gen sequencing panel with an average sequencing depth of 420x. The uncovered novel mutation was then validated with Sanger sequencing and characterized with structural modeling. The role of the mutation was further functionally defined with cell transfection followed by assays for cell-proliferation, BrdU-incorporation, and intracellular B-cell receptor signaling.
Results
A structurally novel mutation of Bruton tyrosine kinase was identified which was associated with CLL relapse but not Richter transformation. Functionally, cells carrying the mutant BTK show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S.
Conclusion
Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Genetic, Mutation
Type: Eposter Presentation
Background
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. In addition, BTK mutations have been found in several Richter-transformed patients treated with ibr. In these patients, it is not clear whether BTK mutations are related to Richter transformation or ibr treatment or both.
Aims
As the use of ibr becomes more prevalent in CLL and other types of non-Hodgkin lymphoma (NHL), more patients are expected to develop resistance. Thus, a complete understanding of the mechanisms of ibr resistance is important for the development of strategies to prevent and treat ibrutinib resistance.
Methods
Serial samples were collected from a Richter transformed CLL patient who were treated with ibrutinib, responded and then relapsed. The samples were analyzed using Onco1K, a 1,200-gene next-gen sequencing panel with an average sequencing depth of 420x. The uncovered novel mutation was then validated with Sanger sequencing and characterized with structural modeling. The role of the mutation was further functionally defined with cell transfection followed by assays for cell-proliferation, BrdU-incorporation, and intracellular B-cell receptor signaling.
Results
A structurally novel mutation of Bruton tyrosine kinase was identified which was associated with CLL relapse but not Richter transformation. Functionally, cells carrying the mutant BTK show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S.
Conclusion
Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Genetic, Mutation
Abstract: E1034
Type: Eposter Presentation
Background
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. In addition, BTK mutations have been found in several Richter-transformed patients treated with ibr. In these patients, it is not clear whether BTK mutations are related to Richter transformation or ibr treatment or both.
Aims
As the use of ibr becomes more prevalent in CLL and other types of non-Hodgkin lymphoma (NHL), more patients are expected to develop resistance. Thus, a complete understanding of the mechanisms of ibr resistance is important for the development of strategies to prevent and treat ibrutinib resistance.
Methods
Serial samples were collected from a Richter transformed CLL patient who were treated with ibrutinib, responded and then relapsed. The samples were analyzed using Onco1K, a 1,200-gene next-gen sequencing panel with an average sequencing depth of 420x. The uncovered novel mutation was then validated with Sanger sequencing and characterized with structural modeling. The role of the mutation was further functionally defined with cell transfection followed by assays for cell-proliferation, BrdU-incorporation, and intracellular B-cell receptor signaling.
Results
A structurally novel mutation of Bruton tyrosine kinase was identified which was associated with CLL relapse but not Richter transformation. Functionally, cells carrying the mutant BTK show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S.
Conclusion
Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Genetic, Mutation
Type: Eposter Presentation
Background
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. In addition, BTK mutations have been found in several Richter-transformed patients treated with ibr. In these patients, it is not clear whether BTK mutations are related to Richter transformation or ibr treatment or both.
Aims
As the use of ibr becomes more prevalent in CLL and other types of non-Hodgkin lymphoma (NHL), more patients are expected to develop resistance. Thus, a complete understanding of the mechanisms of ibr resistance is important for the development of strategies to prevent and treat ibrutinib resistance.
Methods
Serial samples were collected from a Richter transformed CLL patient who were treated with ibrutinib, responded and then relapsed. The samples were analyzed using Onco1K, a 1,200-gene next-gen sequencing panel with an average sequencing depth of 420x. The uncovered novel mutation was then validated with Sanger sequencing and characterized with structural modeling. The role of the mutation was further functionally defined with cell transfection followed by assays for cell-proliferation, BrdU-incorporation, and intracellular B-cell receptor signaling.
Results
A structurally novel mutation of Bruton tyrosine kinase was identified which was associated with CLL relapse but not Richter transformation. Functionally, cells carrying the mutant BTK show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S.
Conclusion
Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
Session topic: E-poster
Keyword(s): Chronic lymphocytic leukemia, Genetic, Mutation
{{ help_message }}
{{filter}}