OUTCOME OF PATIENTS WITH REFRACTORY OR RELAPSED AML WITH IDH1 AND IDH2 MUTATIONS AFTER CONVENTIONAL SALVAGE THERAPY: A STUDY OF THE GERMAN-AUSTRIAN AML STUDY GROUP (AMLSG)
(Abstract release date: 05/19/16)
EHA Library. Paschka P. 06/12/16; 135303; S809
Dr. Peter Paschka
Contributions
Contributions
Abstract
Abstract: S809
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C13
Background
Somatic mutations affecting isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 15% to 20% of patients (pts) with acute myeloid leukemia (AML). The incidence of these mutations increases with age, which is mainly attributed to IDH2 mutations. The mutated enzymes emerge as promising therapeutic targets given their abnormal function to produce the oncometabolite 2-hydroxyglutarate. First selective inhibitors of mutant IDH1 and IDH2 proteins are in early clinical development, however, it is currently unknown how results from single-agent inhibitor therapy compare to those of conventional salvage therapy.
Aims
The primary objective of this study was to assess the outcome of patients with refractory or relapsed AML with IDH1/2 mutations.
Methods
A total of 2825 adults with AML [median age: 55 years (yrs), range 18-84 yrs] who entered eight prospective first-line AMLSG trials of intensive conventional induction and consolidation therapy were included in the study. Refractory disease (RD) was defined as failure to achieve complete remission (CR) after two cycles of induction. Mutational status of IDH1 and IDH2 was assessed at the time of initial diagnosis using a combination of denaturing-high-performance liquid chromatography followed by direct DNA-sequencing.
Results
Overall, IDH1/2 mutations were identified in 530 (18.8%) of 2825 pts; IDH1 mutations in 7.5% (212/2822) and IDH2 mutations in 11.5% (326/2825) of pts; 8 pts had a mutation in both IDH1 and IDH2. All but one IDH1 mutation involved codon R132. Among the IDH2 mutated cases, IDH2R140 and IDH2R172 mutations were detected in 246 (75%) and 75 (23%) pts, respectively; there were 5 cases with IDH2 mutations involving other codons. In IDH1/2 mutated AML the CR rate after induction therapy was 62% (327/530) (IDH1: 64%; IDH2: 61%). A total of 138 pts, including those who only received one induction cycle, were refractory to the primary induction; among the pts receiving two induction cycles 82 had RD (IDH1, n=31; IDH2, n=50; IDH1+IDH2, n=1). Two hundred and eight IDH1/2 mutated pts relapsed (IDH1, n=112; IDH2, n=92; IDH1+IDH2, n=4). Median overall survival (OS) in pts with RD (measured from the date of RD) and relapse (RE; measured from the time of RE) was 1.03 yrs and 0.79 yr, respectively; in IDH1 mutated AML 0.53 yr and 0.63 yr, respectively, and in IDH2 mutated AML 1.22 yrs and 1.09 yrs, respectively. The median OS in all IDH1/2 mutated pts with RD/RE was 0.81 yr; pts with IDH2 mutations had a longer (P=.003) survival, which was mainly attributed to the cases carrying IDH2R172 mutations. Of the 82 pts with RD, 39 (48%) received allogeneic hematopoietic-cell transplantation (alloHCT); the median survival time with alloHCT was 1.80 yrs compared to 0.53 yr in those who did not undergo alloHCT. Of the 208 relapsed patients, 153 received intensive chemotherapy or alloHCT, and 89 (58%) of the 153 pts subsequently achieved a CR/CRi. Seventy-four relapsed pts received alloHCT. Median survival after relapse of pts receiving alloHCT was 1.50 yrs compared to 0.63 yr in those not receiving an alloHCT.
Conclusion
IDH1/2 mutations represent a frequent (in this study ~19%) molecular alteration in AML. A substantial proportion of AML pts with IDH1/2 mutations have RD or relapse. Median survival with conventional salvage treatment in these pts was 0.81 yr, with IDH2 mutated pts and those receiving alloHCT having significantly longer survival. Our results represent a benchmark for clinical trials evaluating IDH inhibitors in this clinical setting.
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Acute myeloid leukemia, Refractory, Relapse
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C13
Background
Somatic mutations affecting isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 15% to 20% of patients (pts) with acute myeloid leukemia (AML). The incidence of these mutations increases with age, which is mainly attributed to IDH2 mutations. The mutated enzymes emerge as promising therapeutic targets given their abnormal function to produce the oncometabolite 2-hydroxyglutarate. First selective inhibitors of mutant IDH1 and IDH2 proteins are in early clinical development, however, it is currently unknown how results from single-agent inhibitor therapy compare to those of conventional salvage therapy.
Aims
The primary objective of this study was to assess the outcome of patients with refractory or relapsed AML with IDH1/2 mutations.
Methods
A total of 2825 adults with AML [median age: 55 years (yrs), range 18-84 yrs] who entered eight prospective first-line AMLSG trials of intensive conventional induction and consolidation therapy were included in the study. Refractory disease (RD) was defined as failure to achieve complete remission (CR) after two cycles of induction. Mutational status of IDH1 and IDH2 was assessed at the time of initial diagnosis using a combination of denaturing-high-performance liquid chromatography followed by direct DNA-sequencing.
Results
Overall, IDH1/2 mutations were identified in 530 (18.8%) of 2825 pts; IDH1 mutations in 7.5% (212/2822) and IDH2 mutations in 11.5% (326/2825) of pts; 8 pts had a mutation in both IDH1 and IDH2. All but one IDH1 mutation involved codon R132. Among the IDH2 mutated cases, IDH2R140 and IDH2R172 mutations were detected in 246 (75%) and 75 (23%) pts, respectively; there were 5 cases with IDH2 mutations involving other codons. In IDH1/2 mutated AML the CR rate after induction therapy was 62% (327/530) (IDH1: 64%; IDH2: 61%). A total of 138 pts, including those who only received one induction cycle, were refractory to the primary induction; among the pts receiving two induction cycles 82 had RD (IDH1, n=31; IDH2, n=50; IDH1+IDH2, n=1). Two hundred and eight IDH1/2 mutated pts relapsed (IDH1, n=112; IDH2, n=92; IDH1+IDH2, n=4). Median overall survival (OS) in pts with RD (measured from the date of RD) and relapse (RE; measured from the time of RE) was 1.03 yrs and 0.79 yr, respectively; in IDH1 mutated AML 0.53 yr and 0.63 yr, respectively, and in IDH2 mutated AML 1.22 yrs and 1.09 yrs, respectively. The median OS in all IDH1/2 mutated pts with RD/RE was 0.81 yr; pts with IDH2 mutations had a longer (P=.003) survival, which was mainly attributed to the cases carrying IDH2R172 mutations. Of the 82 pts with RD, 39 (48%) received allogeneic hematopoietic-cell transplantation (alloHCT); the median survival time with alloHCT was 1.80 yrs compared to 0.53 yr in those who did not undergo alloHCT. Of the 208 relapsed patients, 153 received intensive chemotherapy or alloHCT, and 89 (58%) of the 153 pts subsequently achieved a CR/CRi. Seventy-four relapsed pts received alloHCT. Median survival after relapse of pts receiving alloHCT was 1.50 yrs compared to 0.63 yr in those not receiving an alloHCT.
Conclusion
IDH1/2 mutations represent a frequent (in this study ~19%) molecular alteration in AML. A substantial proportion of AML pts with IDH1/2 mutations have RD or relapse. Median survival with conventional salvage treatment in these pts was 0.81 yr, with IDH2 mutated pts and those receiving alloHCT having significantly longer survival. Our results represent a benchmark for clinical trials evaluating IDH inhibitors in this clinical setting.
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Acute myeloid leukemia, Refractory, Relapse
Abstract: S809
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C13
Background
Somatic mutations affecting isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 15% to 20% of patients (pts) with acute myeloid leukemia (AML). The incidence of these mutations increases with age, which is mainly attributed to IDH2 mutations. The mutated enzymes emerge as promising therapeutic targets given their abnormal function to produce the oncometabolite 2-hydroxyglutarate. First selective inhibitors of mutant IDH1 and IDH2 proteins are in early clinical development, however, it is currently unknown how results from single-agent inhibitor therapy compare to those of conventional salvage therapy.
Aims
The primary objective of this study was to assess the outcome of patients with refractory or relapsed AML with IDH1/2 mutations.
Methods
A total of 2825 adults with AML [median age: 55 years (yrs), range 18-84 yrs] who entered eight prospective first-line AMLSG trials of intensive conventional induction and consolidation therapy were included in the study. Refractory disease (RD) was defined as failure to achieve complete remission (CR) after two cycles of induction. Mutational status of IDH1 and IDH2 was assessed at the time of initial diagnosis using a combination of denaturing-high-performance liquid chromatography followed by direct DNA-sequencing.
Results
Overall, IDH1/2 mutations were identified in 530 (18.8%) of 2825 pts; IDH1 mutations in 7.5% (212/2822) and IDH2 mutations in 11.5% (326/2825) of pts; 8 pts had a mutation in both IDH1 and IDH2. All but one IDH1 mutation involved codon R132. Among the IDH2 mutated cases, IDH2R140 and IDH2R172 mutations were detected in 246 (75%) and 75 (23%) pts, respectively; there were 5 cases with IDH2 mutations involving other codons. In IDH1/2 mutated AML the CR rate after induction therapy was 62% (327/530) (IDH1: 64%; IDH2: 61%). A total of 138 pts, including those who only received one induction cycle, were refractory to the primary induction; among the pts receiving two induction cycles 82 had RD (IDH1, n=31; IDH2, n=50; IDH1+IDH2, n=1). Two hundred and eight IDH1/2 mutated pts relapsed (IDH1, n=112; IDH2, n=92; IDH1+IDH2, n=4). Median overall survival (OS) in pts with RD (measured from the date of RD) and relapse (RE; measured from the time of RE) was 1.03 yrs and 0.79 yr, respectively; in IDH1 mutated AML 0.53 yr and 0.63 yr, respectively, and in IDH2 mutated AML 1.22 yrs and 1.09 yrs, respectively. The median OS in all IDH1/2 mutated pts with RD/RE was 0.81 yr; pts with IDH2 mutations had a longer (P=.003) survival, which was mainly attributed to the cases carrying IDH2R172 mutations. Of the 82 pts with RD, 39 (48%) received allogeneic hematopoietic-cell transplantation (alloHCT); the median survival time with alloHCT was 1.80 yrs compared to 0.53 yr in those who did not undergo alloHCT. Of the 208 relapsed patients, 153 received intensive chemotherapy or alloHCT, and 89 (58%) of the 153 pts subsequently achieved a CR/CRi. Seventy-four relapsed pts received alloHCT. Median survival after relapse of pts receiving alloHCT was 1.50 yrs compared to 0.63 yr in those not receiving an alloHCT.
Conclusion
IDH1/2 mutations represent a frequent (in this study ~19%) molecular alteration in AML. A substantial proportion of AML pts with IDH1/2 mutations have RD or relapse. Median survival with conventional salvage treatment in these pts was 0.81 yr, with IDH2 mutated pts and those receiving alloHCT having significantly longer survival. Our results represent a benchmark for clinical trials evaluating IDH inhibitors in this clinical setting.
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Acute myeloid leukemia, Refractory, Relapse
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C13
Background
Somatic mutations affecting isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 15% to 20% of patients (pts) with acute myeloid leukemia (AML). The incidence of these mutations increases with age, which is mainly attributed to IDH2 mutations. The mutated enzymes emerge as promising therapeutic targets given their abnormal function to produce the oncometabolite 2-hydroxyglutarate. First selective inhibitors of mutant IDH1 and IDH2 proteins are in early clinical development, however, it is currently unknown how results from single-agent inhibitor therapy compare to those of conventional salvage therapy.
Aims
The primary objective of this study was to assess the outcome of patients with refractory or relapsed AML with IDH1/2 mutations.
Methods
A total of 2825 adults with AML [median age: 55 years (yrs), range 18-84 yrs] who entered eight prospective first-line AMLSG trials of intensive conventional induction and consolidation therapy were included in the study. Refractory disease (RD) was defined as failure to achieve complete remission (CR) after two cycles of induction. Mutational status of IDH1 and IDH2 was assessed at the time of initial diagnosis using a combination of denaturing-high-performance liquid chromatography followed by direct DNA-sequencing.
Results
Overall, IDH1/2 mutations were identified in 530 (18.8%) of 2825 pts; IDH1 mutations in 7.5% (212/2822) and IDH2 mutations in 11.5% (326/2825) of pts; 8 pts had a mutation in both IDH1 and IDH2. All but one IDH1 mutation involved codon R132. Among the IDH2 mutated cases, IDH2R140 and IDH2R172 mutations were detected in 246 (75%) and 75 (23%) pts, respectively; there were 5 cases with IDH2 mutations involving other codons. In IDH1/2 mutated AML the CR rate after induction therapy was 62% (327/530) (IDH1: 64%; IDH2: 61%). A total of 138 pts, including those who only received one induction cycle, were refractory to the primary induction; among the pts receiving two induction cycles 82 had RD (IDH1, n=31; IDH2, n=50; IDH1+IDH2, n=1). Two hundred and eight IDH1/2 mutated pts relapsed (IDH1, n=112; IDH2, n=92; IDH1+IDH2, n=4). Median overall survival (OS) in pts with RD (measured from the date of RD) and relapse (RE; measured from the time of RE) was 1.03 yrs and 0.79 yr, respectively; in IDH1 mutated AML 0.53 yr and 0.63 yr, respectively, and in IDH2 mutated AML 1.22 yrs and 1.09 yrs, respectively. The median OS in all IDH1/2 mutated pts with RD/RE was 0.81 yr; pts with IDH2 mutations had a longer (P=.003) survival, which was mainly attributed to the cases carrying IDH2R172 mutations. Of the 82 pts with RD, 39 (48%) received allogeneic hematopoietic-cell transplantation (alloHCT); the median survival time with alloHCT was 1.80 yrs compared to 0.53 yr in those who did not undergo alloHCT. Of the 208 relapsed patients, 153 received intensive chemotherapy or alloHCT, and 89 (58%) of the 153 pts subsequently achieved a CR/CRi. Seventy-four relapsed pts received alloHCT. Median survival after relapse of pts receiving alloHCT was 1.50 yrs compared to 0.63 yr in those not receiving an alloHCT.
Conclusion
IDH1/2 mutations represent a frequent (in this study ~19%) molecular alteration in AML. A substantial proportion of AML pts with IDH1/2 mutations have RD or relapse. Median survival with conventional salvage treatment in these pts was 0.81 yr, with IDH2 mutated pts and those receiving alloHCT having significantly longer survival. Our results represent a benchmark for clinical trials evaluating IDH inhibitors in this clinical setting.
Session topic: Treatment in Specific AML Subgroups
Keyword(s): Acute myeloid leukemia, Refractory, Relapse
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