DIFFERENTIATION RESPONSE TO GILTERITINIB (ASP2215) IN RELAPSED/REFRACTORY FLT3 MUTATED ACUTE MYELOID LEUKEMIA PATIENTS IS ASSOCIATED WITH CO-MUTATIONS IN NPM1 AND DNMT3A
(Abstract release date: 05/19/16)
EHA Library. Canaani J. 06/10/16; 133176; P188
Dr. Jonathan Canaani
Contributions
Contributions
Abstract
Abstract: P188
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
FLT3 inhibitors show substantial clinical activity in relapsed/refractory FLT3-ITD mutated acute myeloid leukemia (AML). A subset of patients show a clinical response manifest by terminal differentiation of bone marrow blasts into granulocytes that contain FLT3-ITD. From clinical trials of the FLT3 inhibitor quizartinib (AC220), we observed this differentiation response predominantly among patients with a normal karyotype and mutated NPM1 and/or DNMT3A (Nybakken, et al. Leukemia 2015).
Aims
To confirm whether observations from quizartinib trials reflect a common response pattern to FLT3 inhibitor treatment.
Methods
We performed analysis of the local institutional cohort of patients enrolled on a phase 1/2 study of gilteritinib (ASP2215) for relapsed/refractory AML (NCT02014558). All subjects were screened for 33 AML-associated mutations at study entry by next generation sequencing and all available histomorphologic, and cytogenetic material underwent an independent pathologist’s blinded review.
Results
We restricted our analysis to the 25 FLT3-mutated subjects who received single-agent gilteritinib at > 80 mg/day, as correlative pharmacodynamic data showed that this dose consistently generated continuous, potent FLT3 target inhibition (Levis MJ, et al. ASCO abstracts 2015). 2 subjects were withdrawn prior to the first treatment response assessment (refractory leukemia and lethal infection); 2 subjects had technically insufficient marrows. The remaining 21 subjects were evaluable for marrow response. Subjects had a median age of 61 years (range 22-86 years) and were relapsed or refractory after a median of 2 prior lines of chemotherapy (range 1-7). Subjects received gilteritinib at a median dose of 200 mg (range 80-300) for a median of 154 days (range 38-642). Baseline karyotype was normal in 9/20 (45%). 19/21 patients had FLT3-ITD mutation (3 had both FLT3-ITD and FLT3-TKD), and 2 had FLT3-TKD only. Gene mutations seen in >10% of subjects included NPM1 (13, 62%), DNMT3A (11, 52%), WT1 (8, 38%), TET2 (7, 33%), and IDH1/2 (4, 19%). All subjects treated for >28 days showed complete or near-total eradication of peripheral blood blasts. Thirteen subjects (62%) experienced a differentiation response defined by markedly left-shifted clonal granulocytic hyperplasia with persistent FLT3-ITD:WT allelic ratio, >50% reduction in overall blast percentage from baseline, and peripheral blood neutrophil recovery. 11/13 (85%) subjects with differentiation response had mutated NPM1, but only 6/12 (50%) had a normal karyotype. While 2/3 NPM1 mutated subjects with WT DNMT3A did experience differentiation response, 10/11 subjects with DNMT3A mutation also had NPM1 mutations, confounding our ability to associate differentiation response and DNMT3A mutation status alone.3/21 subjects demonstrated both undetectable leukemic blasts from the marrow along with marked allelic ratio reduction or elimination of detectable FLT3-ITD, suggesting alternate mechanisms of treatment response (e.g. cytotoxicity or clonal selection without differentiation). Additionally, 5/21 evaluable subjects showed minimal to no reduction in marrow blasts. Considering the 8 non-differentiation responses plus the sole patient with growing AML prior to day 28, only 2/9 (22%) had an NPM1 mutation, and 5/8 had abnormal karyotype.
Conclusion
Differentiation response to gilteritinib is strongly enriched among relapsed/refractory FLT3-mutated patients with NPM1 and DNMT3A mutations. Our data inform response interpretation and may promote future trial enrichment strategies.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Flt3-ITD, Tyrosine kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
FLT3 inhibitors show substantial clinical activity in relapsed/refractory FLT3-ITD mutated acute myeloid leukemia (AML). A subset of patients show a clinical response manifest by terminal differentiation of bone marrow blasts into granulocytes that contain FLT3-ITD. From clinical trials of the FLT3 inhibitor quizartinib (AC220), we observed this differentiation response predominantly among patients with a normal karyotype and mutated NPM1 and/or DNMT3A (Nybakken, et al. Leukemia 2015).
Aims
To confirm whether observations from quizartinib trials reflect a common response pattern to FLT3 inhibitor treatment.
Methods
We performed analysis of the local institutional cohort of patients enrolled on a phase 1/2 study of gilteritinib (ASP2215) for relapsed/refractory AML (NCT02014558). All subjects were screened for 33 AML-associated mutations at study entry by next generation sequencing and all available histomorphologic, and cytogenetic material underwent an independent pathologist’s blinded review.
Results
We restricted our analysis to the 25 FLT3-mutated subjects who received single-agent gilteritinib at > 80 mg/day, as correlative pharmacodynamic data showed that this dose consistently generated continuous, potent FLT3 target inhibition (Levis MJ, et al. ASCO abstracts 2015). 2 subjects were withdrawn prior to the first treatment response assessment (refractory leukemia and lethal infection); 2 subjects had technically insufficient marrows. The remaining 21 subjects were evaluable for marrow response. Subjects had a median age of 61 years (range 22-86 years) and were relapsed or refractory after a median of 2 prior lines of chemotherapy (range 1-7). Subjects received gilteritinib at a median dose of 200 mg (range 80-300) for a median of 154 days (range 38-642). Baseline karyotype was normal in 9/20 (45%). 19/21 patients had FLT3-ITD mutation (3 had both FLT3-ITD and FLT3-TKD), and 2 had FLT3-TKD only. Gene mutations seen in >10% of subjects included NPM1 (13, 62%), DNMT3A (11, 52%), WT1 (8, 38%), TET2 (7, 33%), and IDH1/2 (4, 19%). All subjects treated for >28 days showed complete or near-total eradication of peripheral blood blasts. Thirteen subjects (62%) experienced a differentiation response defined by markedly left-shifted clonal granulocytic hyperplasia with persistent FLT3-ITD:WT allelic ratio, >50% reduction in overall blast percentage from baseline, and peripheral blood neutrophil recovery. 11/13 (85%) subjects with differentiation response had mutated NPM1, but only 6/12 (50%) had a normal karyotype. While 2/3 NPM1 mutated subjects with WT DNMT3A did experience differentiation response, 10/11 subjects with DNMT3A mutation also had NPM1 mutations, confounding our ability to associate differentiation response and DNMT3A mutation status alone.3/21 subjects demonstrated both undetectable leukemic blasts from the marrow along with marked allelic ratio reduction or elimination of detectable FLT3-ITD, suggesting alternate mechanisms of treatment response (e.g. cytotoxicity or clonal selection without differentiation). Additionally, 5/21 evaluable subjects showed minimal to no reduction in marrow blasts. Considering the 8 non-differentiation responses plus the sole patient with growing AML prior to day 28, only 2/9 (22%) had an NPM1 mutation, and 5/8 had abnormal karyotype.
Conclusion
Differentiation response to gilteritinib is strongly enriched among relapsed/refractory FLT3-mutated patients with NPM1 and DNMT3A mutations. Our data inform response interpretation and may promote future trial enrichment strategies.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Flt3-ITD, Tyrosine kinase inhibitor
Abstract: P188
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
FLT3 inhibitors show substantial clinical activity in relapsed/refractory FLT3-ITD mutated acute myeloid leukemia (AML). A subset of patients show a clinical response manifest by terminal differentiation of bone marrow blasts into granulocytes that contain FLT3-ITD. From clinical trials of the FLT3 inhibitor quizartinib (AC220), we observed this differentiation response predominantly among patients with a normal karyotype and mutated NPM1 and/or DNMT3A (Nybakken, et al. Leukemia 2015).
Aims
To confirm whether observations from quizartinib trials reflect a common response pattern to FLT3 inhibitor treatment.
Methods
We performed analysis of the local institutional cohort of patients enrolled on a phase 1/2 study of gilteritinib (ASP2215) for relapsed/refractory AML (NCT02014558). All subjects were screened for 33 AML-associated mutations at study entry by next generation sequencing and all available histomorphologic, and cytogenetic material underwent an independent pathologist’s blinded review.
Results
We restricted our analysis to the 25 FLT3-mutated subjects who received single-agent gilteritinib at > 80 mg/day, as correlative pharmacodynamic data showed that this dose consistently generated continuous, potent FLT3 target inhibition (Levis MJ, et al. ASCO abstracts 2015). 2 subjects were withdrawn prior to the first treatment response assessment (refractory leukemia and lethal infection); 2 subjects had technically insufficient marrows. The remaining 21 subjects were evaluable for marrow response. Subjects had a median age of 61 years (range 22-86 years) and were relapsed or refractory after a median of 2 prior lines of chemotherapy (range 1-7). Subjects received gilteritinib at a median dose of 200 mg (range 80-300) for a median of 154 days (range 38-642). Baseline karyotype was normal in 9/20 (45%). 19/21 patients had FLT3-ITD mutation (3 had both FLT3-ITD and FLT3-TKD), and 2 had FLT3-TKD only. Gene mutations seen in >10% of subjects included NPM1 (13, 62%), DNMT3A (11, 52%), WT1 (8, 38%), TET2 (7, 33%), and IDH1/2 (4, 19%). All subjects treated for >28 days showed complete or near-total eradication of peripheral blood blasts. Thirteen subjects (62%) experienced a differentiation response defined by markedly left-shifted clonal granulocytic hyperplasia with persistent FLT3-ITD:WT allelic ratio, >50% reduction in overall blast percentage from baseline, and peripheral blood neutrophil recovery. 11/13 (85%) subjects with differentiation response had mutated NPM1, but only 6/12 (50%) had a normal karyotype. While 2/3 NPM1 mutated subjects with WT DNMT3A did experience differentiation response, 10/11 subjects with DNMT3A mutation also had NPM1 mutations, confounding our ability to associate differentiation response and DNMT3A mutation status alone.3/21 subjects demonstrated both undetectable leukemic blasts from the marrow along with marked allelic ratio reduction or elimination of detectable FLT3-ITD, suggesting alternate mechanisms of treatment response (e.g. cytotoxicity or clonal selection without differentiation). Additionally, 5/21 evaluable subjects showed minimal to no reduction in marrow blasts. Considering the 8 non-differentiation responses plus the sole patient with growing AML prior to day 28, only 2/9 (22%) had an NPM1 mutation, and 5/8 had abnormal karyotype.
Conclusion
Differentiation response to gilteritinib is strongly enriched among relapsed/refractory FLT3-mutated patients with NPM1 and DNMT3A mutations. Our data inform response interpretation and may promote future trial enrichment strategies.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Flt3-ITD, Tyrosine kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
FLT3 inhibitors show substantial clinical activity in relapsed/refractory FLT3-ITD mutated acute myeloid leukemia (AML). A subset of patients show a clinical response manifest by terminal differentiation of bone marrow blasts into granulocytes that contain FLT3-ITD. From clinical trials of the FLT3 inhibitor quizartinib (AC220), we observed this differentiation response predominantly among patients with a normal karyotype and mutated NPM1 and/or DNMT3A (Nybakken, et al. Leukemia 2015).
Aims
To confirm whether observations from quizartinib trials reflect a common response pattern to FLT3 inhibitor treatment.
Methods
We performed analysis of the local institutional cohort of patients enrolled on a phase 1/2 study of gilteritinib (ASP2215) for relapsed/refractory AML (NCT02014558). All subjects were screened for 33 AML-associated mutations at study entry by next generation sequencing and all available histomorphologic, and cytogenetic material underwent an independent pathologist’s blinded review.
Results
We restricted our analysis to the 25 FLT3-mutated subjects who received single-agent gilteritinib at > 80 mg/day, as correlative pharmacodynamic data showed that this dose consistently generated continuous, potent FLT3 target inhibition (Levis MJ, et al. ASCO abstracts 2015). 2 subjects were withdrawn prior to the first treatment response assessment (refractory leukemia and lethal infection); 2 subjects had technically insufficient marrows. The remaining 21 subjects were evaluable for marrow response. Subjects had a median age of 61 years (range 22-86 years) and were relapsed or refractory after a median of 2 prior lines of chemotherapy (range 1-7). Subjects received gilteritinib at a median dose of 200 mg (range 80-300) for a median of 154 days (range 38-642). Baseline karyotype was normal in 9/20 (45%). 19/21 patients had FLT3-ITD mutation (3 had both FLT3-ITD and FLT3-TKD), and 2 had FLT3-TKD only. Gene mutations seen in >10% of subjects included NPM1 (13, 62%), DNMT3A (11, 52%), WT1 (8, 38%), TET2 (7, 33%), and IDH1/2 (4, 19%). All subjects treated for >28 days showed complete or near-total eradication of peripheral blood blasts. Thirteen subjects (62%) experienced a differentiation response defined by markedly left-shifted clonal granulocytic hyperplasia with persistent FLT3-ITD:WT allelic ratio, >50% reduction in overall blast percentage from baseline, and peripheral blood neutrophil recovery. 11/13 (85%) subjects with differentiation response had mutated NPM1, but only 6/12 (50%) had a normal karyotype. While 2/3 NPM1 mutated subjects with WT DNMT3A did experience differentiation response, 10/11 subjects with DNMT3A mutation also had NPM1 mutations, confounding our ability to associate differentiation response and DNMT3A mutation status alone.3/21 subjects demonstrated both undetectable leukemic blasts from the marrow along with marked allelic ratio reduction or elimination of detectable FLT3-ITD, suggesting alternate mechanisms of treatment response (e.g. cytotoxicity or clonal selection without differentiation). Additionally, 5/21 evaluable subjects showed minimal to no reduction in marrow blasts. Considering the 8 non-differentiation responses plus the sole patient with growing AML prior to day 28, only 2/9 (22%) had an NPM1 mutation, and 5/8 had abnormal karyotype.
Conclusion
Differentiation response to gilteritinib is strongly enriched among relapsed/refractory FLT3-mutated patients with NPM1 and DNMT3A mutations. Our data inform response interpretation and may promote future trial enrichment strategies.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): AML, Flt3-ITD, Tyrosine kinase inhibitor
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