TP53 GENE MUTATIONS IMPACT ON OVERALL SURVIVAL OF PATIENTS TREATED WITH LOW-DOSE CLOFARABINE AS A SECOND LINE THERAPY DUE TO THEIR RESISTANCE TO AZACITIDINE
(Abstract release date: 05/19/16)
EHA Library. Braun T. 06/09/16; 132779; E1230
Disclosure(s): Nothing to disclose.
Dr. Thomas Braun
Contributions
Contributions
Abstract
Abstract: E1230
Type: Eposter Presentation
Background
Patients with higher risk Myelodysplastic Syndromes (IPSS-INT2 and High; HR-MDS) failing treatment with hypomethylating agents (azacitidine and decitabine; HMA) have a very poor outcome with a median survival of 5 months. No standard treatment is defined in this setting. We have recently conducted a dose escalation trial of clofarabine, at a starting daily dose of 5 mg/m2, among patients with HR-MDS or AML evolving from MDS if failing prior azacitidine therapy (NCT01063257; Braun et al., ASH 2011). Among MDS/AML associated mutations, TP53 gene mutations confer a poor patients overall survival and a short response duration to HMA (Takahashi et al., Oncotarget 2016).
Aims
We analyzed these MDS/AML mutations in respect to drug response and overall survival in this second line therapy trial.
Methods
Twenty-seven patients with a median age of 71 years (62-90) were included after informed consent from December 2009 to July 2012. All were due to receive clofarabine at a dose ranging from 5 to 10/m2 either for 5 consecutive days or 5 doses over 10 days, for a maximum of 8 cycles. All study patients were analyzed by next generation sequencing for evidence of mutations in the following genes: TET2, ASXL1, RUNX1, DNMT3a, TP53, IDH1/2, NRAS/KRAS, CBL, ETV6, EZH2, FLT3-ITD, NPM, JAK2, MPL515, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1 and ZRSR2. Gene mutations identified by NGS were checked by Sanger sequencing if necessary.
Results
Twenty patients (74%) had HR-MDS including 1 patient with Chronic Myelomonocytic Leukemia-2 and 7 (26%) patients had AML evolving from MDS (16F/11M). Fifteen (56%) patients had adverse karyotype including 9 patients with complex cytogenetics. Among 8 (29%) patients, a TP53 mutation could be detected, which was isolated in 4 cases and associated with a complex karyotype in 7/8 cases. Distribution of the other gene mutations detected in this cohort were as follows: ASXL1 (26%), DNMT3a (22%), RUNX1 (15%), TET2 (15%), SRSF2 (15%), U2AF1 (11%), SF3B1 (11%), EZH2 (7%), IDH2 (7%), ETV6 (7%), NRAS (3.5%), ZRSR2 (3.5%), FLT3-ITD (3.5%), PTPN11 (3.5%) and SETBP1 (3.5%). Four (15%) patients had no gene mutation detected, 8 (29%) patients had 2 and 6 (22%) patients had at least 3 or more mutations detected. Only the detection of TP53 mutations had a significant impact on overall survival with a median survival of 4.7 versus 8.4 months of TP53 mutated patients and unmutated patients respectively (p=0.0022). The two other most frequent mutations of the ASXL1 and DNMT3a genes in this population, did no impact overall survival even among patients unmutated for TP53. As expected, adverse karyotype was significantly associated with shorter overall survival (8 months versus 4.4 months; p=0.017). When excluding patiens with TP53 mutations, survival of patients with unfavorable cytogenetics was not significantly shorter when compared to patients with intermediate or favorable cytogenetics (7.2 months versus 10.9 months; p=0.31). Eight (32%) of 25 patients evaluable for response achieved response according to IWG 2006 criteria after 1 or 2 cycles of clofarabine (1 CR, 4 mCR+HI, 2 mCR and 1 HI) and 10 (40%) patients had stable disease. Overall survival was 11.1 months (CI 0.68-3.9) versus 6.7 months (CI 0.25-1.46) in responders and non-responders to clofarabine respectively (p=0.18). In this phase I low-dose clofarabine trial, TP53 mutations were detected among 7/19 non-responders and 1/8 responding patients (p=0.36) to clofarabine. Interestingly, 6 of the 8 patients mutated for TP53 had obtained a prior response to azacitidine before relapse. Mutations of ASXL1 (p=0.63) and DNMT3a (p=1) had no impact on response to clofarabine.
Conclusion
Presence of TP53 mutations, detected here in about 50% of patients with an unfavorable karyotype, appears to be the most powerful adverse prognostic factor for overall survival in this MDS/AML population selected by its resistance to azacitidine.
Session topic: E-poster
Keyword(s): Hypomethylation, Myelodysplasia, P53, Treatment
Type: Eposter Presentation
Background
Patients with higher risk Myelodysplastic Syndromes (IPSS-INT2 and High; HR-MDS) failing treatment with hypomethylating agents (azacitidine and decitabine; HMA) have a very poor outcome with a median survival of 5 months. No standard treatment is defined in this setting. We have recently conducted a dose escalation trial of clofarabine, at a starting daily dose of 5 mg/m2, among patients with HR-MDS or AML evolving from MDS if failing prior azacitidine therapy (NCT01063257; Braun et al., ASH 2011). Among MDS/AML associated mutations, TP53 gene mutations confer a poor patients overall survival and a short response duration to HMA (Takahashi et al., Oncotarget 2016).
Aims
We analyzed these MDS/AML mutations in respect to drug response and overall survival in this second line therapy trial.
Methods
Twenty-seven patients with a median age of 71 years (62-90) were included after informed consent from December 2009 to July 2012. All were due to receive clofarabine at a dose ranging from 5 to 10/m2 either for 5 consecutive days or 5 doses over 10 days, for a maximum of 8 cycles. All study patients were analyzed by next generation sequencing for evidence of mutations in the following genes: TET2, ASXL1, RUNX1, DNMT3a, TP53, IDH1/2, NRAS/KRAS, CBL, ETV6, EZH2, FLT3-ITD, NPM, JAK2, MPL515, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1 and ZRSR2. Gene mutations identified by NGS were checked by Sanger sequencing if necessary.
Results
Twenty patients (74%) had HR-MDS including 1 patient with Chronic Myelomonocytic Leukemia-2 and 7 (26%) patients had AML evolving from MDS (16F/11M). Fifteen (56%) patients had adverse karyotype including 9 patients with complex cytogenetics. Among 8 (29%) patients, a TP53 mutation could be detected, which was isolated in 4 cases and associated with a complex karyotype in 7/8 cases. Distribution of the other gene mutations detected in this cohort were as follows: ASXL1 (26%), DNMT3a (22%), RUNX1 (15%), TET2 (15%), SRSF2 (15%), U2AF1 (11%), SF3B1 (11%), EZH2 (7%), IDH2 (7%), ETV6 (7%), NRAS (3.5%), ZRSR2 (3.5%), FLT3-ITD (3.5%), PTPN11 (3.5%) and SETBP1 (3.5%). Four (15%) patients had no gene mutation detected, 8 (29%) patients had 2 and 6 (22%) patients had at least 3 or more mutations detected. Only the detection of TP53 mutations had a significant impact on overall survival with a median survival of 4.7 versus 8.4 months of TP53 mutated patients and unmutated patients respectively (p=0.0022). The two other most frequent mutations of the ASXL1 and DNMT3a genes in this population, did no impact overall survival even among patients unmutated for TP53. As expected, adverse karyotype was significantly associated with shorter overall survival (8 months versus 4.4 months; p=0.017). When excluding patiens with TP53 mutations, survival of patients with unfavorable cytogenetics was not significantly shorter when compared to patients with intermediate or favorable cytogenetics (7.2 months versus 10.9 months; p=0.31). Eight (32%) of 25 patients evaluable for response achieved response according to IWG 2006 criteria after 1 or 2 cycles of clofarabine (1 CR, 4 mCR+HI, 2 mCR and 1 HI) and 10 (40%) patients had stable disease. Overall survival was 11.1 months (CI 0.68-3.9) versus 6.7 months (CI 0.25-1.46) in responders and non-responders to clofarabine respectively (p=0.18). In this phase I low-dose clofarabine trial, TP53 mutations were detected among 7/19 non-responders and 1/8 responding patients (p=0.36) to clofarabine. Interestingly, 6 of the 8 patients mutated for TP53 had obtained a prior response to azacitidine before relapse. Mutations of ASXL1 (p=0.63) and DNMT3a (p=1) had no impact on response to clofarabine.
Conclusion
Presence of TP53 mutations, detected here in about 50% of patients with an unfavorable karyotype, appears to be the most powerful adverse prognostic factor for overall survival in this MDS/AML population selected by its resistance to azacitidine.
Session topic: E-poster
Keyword(s): Hypomethylation, Myelodysplasia, P53, Treatment
Abstract: E1230
Type: Eposter Presentation
Background
Patients with higher risk Myelodysplastic Syndromes (IPSS-INT2 and High; HR-MDS) failing treatment with hypomethylating agents (azacitidine and decitabine; HMA) have a very poor outcome with a median survival of 5 months. No standard treatment is defined in this setting. We have recently conducted a dose escalation trial of clofarabine, at a starting daily dose of 5 mg/m2, among patients with HR-MDS or AML evolving from MDS if failing prior azacitidine therapy (NCT01063257; Braun et al., ASH 2011). Among MDS/AML associated mutations, TP53 gene mutations confer a poor patients overall survival and a short response duration to HMA (Takahashi et al., Oncotarget 2016).
Aims
We analyzed these MDS/AML mutations in respect to drug response and overall survival in this second line therapy trial.
Methods
Twenty-seven patients with a median age of 71 years (62-90) were included after informed consent from December 2009 to July 2012. All were due to receive clofarabine at a dose ranging from 5 to 10/m2 either for 5 consecutive days or 5 doses over 10 days, for a maximum of 8 cycles. All study patients were analyzed by next generation sequencing for evidence of mutations in the following genes: TET2, ASXL1, RUNX1, DNMT3a, TP53, IDH1/2, NRAS/KRAS, CBL, ETV6, EZH2, FLT3-ITD, NPM, JAK2, MPL515, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1 and ZRSR2. Gene mutations identified by NGS were checked by Sanger sequencing if necessary.
Results
Twenty patients (74%) had HR-MDS including 1 patient with Chronic Myelomonocytic Leukemia-2 and 7 (26%) patients had AML evolving from MDS (16F/11M). Fifteen (56%) patients had adverse karyotype including 9 patients with complex cytogenetics. Among 8 (29%) patients, a TP53 mutation could be detected, which was isolated in 4 cases and associated with a complex karyotype in 7/8 cases. Distribution of the other gene mutations detected in this cohort were as follows: ASXL1 (26%), DNMT3a (22%), RUNX1 (15%), TET2 (15%), SRSF2 (15%), U2AF1 (11%), SF3B1 (11%), EZH2 (7%), IDH2 (7%), ETV6 (7%), NRAS (3.5%), ZRSR2 (3.5%), FLT3-ITD (3.5%), PTPN11 (3.5%) and SETBP1 (3.5%). Four (15%) patients had no gene mutation detected, 8 (29%) patients had 2 and 6 (22%) patients had at least 3 or more mutations detected. Only the detection of TP53 mutations had a significant impact on overall survival with a median survival of 4.7 versus 8.4 months of TP53 mutated patients and unmutated patients respectively (p=0.0022). The two other most frequent mutations of the ASXL1 and DNMT3a genes in this population, did no impact overall survival even among patients unmutated for TP53. As expected, adverse karyotype was significantly associated with shorter overall survival (8 months versus 4.4 months; p=0.017). When excluding patiens with TP53 mutations, survival of patients with unfavorable cytogenetics was not significantly shorter when compared to patients with intermediate or favorable cytogenetics (7.2 months versus 10.9 months; p=0.31). Eight (32%) of 25 patients evaluable for response achieved response according to IWG 2006 criteria after 1 or 2 cycles of clofarabine (1 CR, 4 mCR+HI, 2 mCR and 1 HI) and 10 (40%) patients had stable disease. Overall survival was 11.1 months (CI 0.68-3.9) versus 6.7 months (CI 0.25-1.46) in responders and non-responders to clofarabine respectively (p=0.18). In this phase I low-dose clofarabine trial, TP53 mutations were detected among 7/19 non-responders and 1/8 responding patients (p=0.36) to clofarabine. Interestingly, 6 of the 8 patients mutated for TP53 had obtained a prior response to azacitidine before relapse. Mutations of ASXL1 (p=0.63) and DNMT3a (p=1) had no impact on response to clofarabine.
Conclusion
Presence of TP53 mutations, detected here in about 50% of patients with an unfavorable karyotype, appears to be the most powerful adverse prognostic factor for overall survival in this MDS/AML population selected by its resistance to azacitidine.
Session topic: E-poster
Keyword(s): Hypomethylation, Myelodysplasia, P53, Treatment
Type: Eposter Presentation
Background
Patients with higher risk Myelodysplastic Syndromes (IPSS-INT2 and High; HR-MDS) failing treatment with hypomethylating agents (azacitidine and decitabine; HMA) have a very poor outcome with a median survival of 5 months. No standard treatment is defined in this setting. We have recently conducted a dose escalation trial of clofarabine, at a starting daily dose of 5 mg/m2, among patients with HR-MDS or AML evolving from MDS if failing prior azacitidine therapy (NCT01063257; Braun et al., ASH 2011). Among MDS/AML associated mutations, TP53 gene mutations confer a poor patients overall survival and a short response duration to HMA (Takahashi et al., Oncotarget 2016).
Aims
We analyzed these MDS/AML mutations in respect to drug response and overall survival in this second line therapy trial.
Methods
Twenty-seven patients with a median age of 71 years (62-90) were included after informed consent from December 2009 to July 2012. All were due to receive clofarabine at a dose ranging from 5 to 10/m2 either for 5 consecutive days or 5 doses over 10 days, for a maximum of 8 cycles. All study patients were analyzed by next generation sequencing for evidence of mutations in the following genes: TET2, ASXL1, RUNX1, DNMT3a, TP53, IDH1/2, NRAS/KRAS, CBL, ETV6, EZH2, FLT3-ITD, NPM, JAK2, MPL515, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1 and ZRSR2. Gene mutations identified by NGS were checked by Sanger sequencing if necessary.
Results
Twenty patients (74%) had HR-MDS including 1 patient with Chronic Myelomonocytic Leukemia-2 and 7 (26%) patients had AML evolving from MDS (16F/11M). Fifteen (56%) patients had adverse karyotype including 9 patients with complex cytogenetics. Among 8 (29%) patients, a TP53 mutation could be detected, which was isolated in 4 cases and associated with a complex karyotype in 7/8 cases. Distribution of the other gene mutations detected in this cohort were as follows: ASXL1 (26%), DNMT3a (22%), RUNX1 (15%), TET2 (15%), SRSF2 (15%), U2AF1 (11%), SF3B1 (11%), EZH2 (7%), IDH2 (7%), ETV6 (7%), NRAS (3.5%), ZRSR2 (3.5%), FLT3-ITD (3.5%), PTPN11 (3.5%) and SETBP1 (3.5%). Four (15%) patients had no gene mutation detected, 8 (29%) patients had 2 and 6 (22%) patients had at least 3 or more mutations detected. Only the detection of TP53 mutations had a significant impact on overall survival with a median survival of 4.7 versus 8.4 months of TP53 mutated patients and unmutated patients respectively (p=0.0022). The two other most frequent mutations of the ASXL1 and DNMT3a genes in this population, did no impact overall survival even among patients unmutated for TP53. As expected, adverse karyotype was significantly associated with shorter overall survival (8 months versus 4.4 months; p=0.017). When excluding patiens with TP53 mutations, survival of patients with unfavorable cytogenetics was not significantly shorter when compared to patients with intermediate or favorable cytogenetics (7.2 months versus 10.9 months; p=0.31). Eight (32%) of 25 patients evaluable for response achieved response according to IWG 2006 criteria after 1 or 2 cycles of clofarabine (1 CR, 4 mCR+HI, 2 mCR and 1 HI) and 10 (40%) patients had stable disease. Overall survival was 11.1 months (CI 0.68-3.9) versus 6.7 months (CI 0.25-1.46) in responders and non-responders to clofarabine respectively (p=0.18). In this phase I low-dose clofarabine trial, TP53 mutations were detected among 7/19 non-responders and 1/8 responding patients (p=0.36) to clofarabine. Interestingly, 6 of the 8 patients mutated for TP53 had obtained a prior response to azacitidine before relapse. Mutations of ASXL1 (p=0.63) and DNMT3a (p=1) had no impact on response to clofarabine.
Conclusion
Presence of TP53 mutations, detected here in about 50% of patients with an unfavorable karyotype, appears to be the most powerful adverse prognostic factor for overall survival in this MDS/AML population selected by its resistance to azacitidine.
Session topic: E-poster
Keyword(s): Hypomethylation, Myelodysplasia, P53, Treatment
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