MYD88 (L265P) MUTATION IS ASSOCIATED WITH AN UNFAVORABLE OUTCOME OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
(Abstract release date: 05/19/16)
EHA Library. Hattori K. 06/09/16; 132504; E955
Mr. Keiichiro Hattori
Contributions
Contributions
Abstract
Abstract: E955
Type: Eposter Presentation
Background
Primary central nervous system lymphomas (PCNSL) typically show an immunophenotype resembling that of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Somatic mutations in MyD88, CD79B, and CARD11 were shown to activate the NFκB signaling pathway in ABC-DLBCL. These mutations are reported to be strongly over-represented in PCNSL. Nonetheless, clinical relevance of these mutations remains unclear. On the other hand, the several specific clinical parameters, such as MSKCC and IELSG prognostic score systems, were reported to predict the treatment outcome of PCNSL patients. Recently advanced genetic knowledge, however, is not incorporated in any of these proposals.
Aims
We conducted this study to elucidate the impact of gene mutations on clinical outcome of PCNSL.
Methods
We analyzed 42 immuno-competent patients suffering from newly diagnosed PCNSL who were aged over 60 years, or aged 55-60 years if they had poor performance status, and in whom enough material for DNA extraction was available. They were treated with modified version of the EORTC protocol, consisted of systemic administration of intermediate-dose methotrexate (MTX), lomustine, procarbazine, and methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine (Taoka K., et al., Int J Hematol 2010; Lee SY., et al., Oncol Res Treat 2014), at the University of Tsukuba Hospital between March, 2005 and May, 2015.Targeted deep sequencing was performed by using Ion Ampliseq technology for 12 genes, including MyD88, CD79B, PIM1, TBL1XR1, BTG2, PRDM1, TNFAIP3, CARD11, B2M, TOX, TMEM30A, and PRKCD.All candidate mutations were validated by genomic PCR followed by Sanger sequencing. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and compared by the peto-peto generalized Wilcoxon test.
Results
At least one mutation was detected in 38/42 cases (90.4 %). Frequencies of mutations of 12 genes were similar to those of the previous reports (MyD88, 79%; CD79B, 52%; PIM1, 69%; TBL1XR1, 24%; BTG2, 29%; PRDM1, 24%; TNFAIP3, 12%; CARD11, 19%; B2M, 11.9%; TOX, 11.9%; TMEM30A, 4.8%; PRKCD, 4.8%). The median follow-up time was 26 months (range, 1–105 months), with OS at 3 years of 46% and PFS at 3 years of 26%.By univariate analysis, age>75 (P=0.0105) and altered mentation (P=0.0202) were significantly associated with inferior OS. Regarding PFS, CrCl>90 (P=0.0286) and altered mentation (P=0.0473) were significant factors. In addition, MyD88 L265P mutation showed a tendency to be associated with inferior OS and PFS, although statistically non-significant (OS:P=0.127, PFS: P=0.0872, Figure1). When adjusted to a multivariate Cox regression analysis, MyD88 L265P mutation remained as a significant risk factor for death (hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.0–8.3, P=0.0470), together with altered mentation (HR, 4.7; 95% CI, 1.5-14.7, P=0.0072). Regarding PFS, only MYD88 L265P mutation (P=0.0303) was significantly associated with a higher risk of progression.
Conclusion
This is the first study that provides evidence that elderly PCNSL patients with MyD88 L265P mutation show an unfavorable prognosis. Given that MyD88 L265P mutation was reported to be also associated with an unfavorable outcome of DLBCL, not otherwise specified and cutaneous DLBCL of leg type, dysregulated cellular program by this mutation may be an important determinant for the prognosis of DLBCL in general.These findings open new perspectives in the utility of MyD88 L265P mutation in the clinical sequencing settings of PCNSL.
Session topic: E-poster
Keyword(s): CNS lymphoma, Somatic mutation
Type: Eposter Presentation
Background
Primary central nervous system lymphomas (PCNSL) typically show an immunophenotype resembling that of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Somatic mutations in MyD88, CD79B, and CARD11 were shown to activate the NFκB signaling pathway in ABC-DLBCL. These mutations are reported to be strongly over-represented in PCNSL. Nonetheless, clinical relevance of these mutations remains unclear. On the other hand, the several specific clinical parameters, such as MSKCC and IELSG prognostic score systems, were reported to predict the treatment outcome of PCNSL patients. Recently advanced genetic knowledge, however, is not incorporated in any of these proposals.
Aims
We conducted this study to elucidate the impact of gene mutations on clinical outcome of PCNSL.
Methods
We analyzed 42 immuno-competent patients suffering from newly diagnosed PCNSL who were aged over 60 years, or aged 55-60 years if they had poor performance status, and in whom enough material for DNA extraction was available. They were treated with modified version of the EORTC protocol, consisted of systemic administration of intermediate-dose methotrexate (MTX), lomustine, procarbazine, and methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine (Taoka K., et al., Int J Hematol 2010; Lee SY., et al., Oncol Res Treat 2014), at the University of Tsukuba Hospital between March, 2005 and May, 2015.Targeted deep sequencing was performed by using Ion Ampliseq technology for 12 genes, including MyD88, CD79B, PIM1, TBL1XR1, BTG2, PRDM1, TNFAIP3, CARD11, B2M, TOX, TMEM30A, and PRKCD.All candidate mutations were validated by genomic PCR followed by Sanger sequencing. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and compared by the peto-peto generalized Wilcoxon test.
Results
At least one mutation was detected in 38/42 cases (90.4 %). Frequencies of mutations of 12 genes were similar to those of the previous reports (MyD88, 79%; CD79B, 52%; PIM1, 69%; TBL1XR1, 24%; BTG2, 29%; PRDM1, 24%; TNFAIP3, 12%; CARD11, 19%; B2M, 11.9%; TOX, 11.9%; TMEM30A, 4.8%; PRKCD, 4.8%). The median follow-up time was 26 months (range, 1–105 months), with OS at 3 years of 46% and PFS at 3 years of 26%.By univariate analysis, age>75 (P=0.0105) and altered mentation (P=0.0202) were significantly associated with inferior OS. Regarding PFS, CrCl>90 (P=0.0286) and altered mentation (P=0.0473) were significant factors. In addition, MyD88 L265P mutation showed a tendency to be associated with inferior OS and PFS, although statistically non-significant (OS:P=0.127, PFS: P=0.0872, Figure1). When adjusted to a multivariate Cox regression analysis, MyD88 L265P mutation remained as a significant risk factor for death (hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.0–8.3, P=0.0470), together with altered mentation (HR, 4.7; 95% CI, 1.5-14.7, P=0.0072). Regarding PFS, only MYD88 L265P mutation (P=0.0303) was significantly associated with a higher risk of progression.
Conclusion
This is the first study that provides evidence that elderly PCNSL patients with MyD88 L265P mutation show an unfavorable prognosis. Given that MyD88 L265P mutation was reported to be also associated with an unfavorable outcome of DLBCL, not otherwise specified and cutaneous DLBCL of leg type, dysregulated cellular program by this mutation may be an important determinant for the prognosis of DLBCL in general.These findings open new perspectives in the utility of MyD88 L265P mutation in the clinical sequencing settings of PCNSL.
Session topic: E-poster
Keyword(s): CNS lymphoma, Somatic mutation
Abstract: E955
Type: Eposter Presentation
Background
Primary central nervous system lymphomas (PCNSL) typically show an immunophenotype resembling that of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Somatic mutations in MyD88, CD79B, and CARD11 were shown to activate the NFκB signaling pathway in ABC-DLBCL. These mutations are reported to be strongly over-represented in PCNSL. Nonetheless, clinical relevance of these mutations remains unclear. On the other hand, the several specific clinical parameters, such as MSKCC and IELSG prognostic score systems, were reported to predict the treatment outcome of PCNSL patients. Recently advanced genetic knowledge, however, is not incorporated in any of these proposals.
Aims
We conducted this study to elucidate the impact of gene mutations on clinical outcome of PCNSL.
Methods
We analyzed 42 immuno-competent patients suffering from newly diagnosed PCNSL who were aged over 60 years, or aged 55-60 years if they had poor performance status, and in whom enough material for DNA extraction was available. They were treated with modified version of the EORTC protocol, consisted of systemic administration of intermediate-dose methotrexate (MTX), lomustine, procarbazine, and methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine (Taoka K., et al., Int J Hematol 2010; Lee SY., et al., Oncol Res Treat 2014), at the University of Tsukuba Hospital between March, 2005 and May, 2015.Targeted deep sequencing was performed by using Ion Ampliseq technology for 12 genes, including MyD88, CD79B, PIM1, TBL1XR1, BTG2, PRDM1, TNFAIP3, CARD11, B2M, TOX, TMEM30A, and PRKCD.All candidate mutations were validated by genomic PCR followed by Sanger sequencing. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and compared by the peto-peto generalized Wilcoxon test.
Results
At least one mutation was detected in 38/42 cases (90.4 %). Frequencies of mutations of 12 genes were similar to those of the previous reports (MyD88, 79%; CD79B, 52%; PIM1, 69%; TBL1XR1, 24%; BTG2, 29%; PRDM1, 24%; TNFAIP3, 12%; CARD11, 19%; B2M, 11.9%; TOX, 11.9%; TMEM30A, 4.8%; PRKCD, 4.8%). The median follow-up time was 26 months (range, 1–105 months), with OS at 3 years of 46% and PFS at 3 years of 26%.By univariate analysis, age>75 (P=0.0105) and altered mentation (P=0.0202) were significantly associated with inferior OS. Regarding PFS, CrCl>90 (P=0.0286) and altered mentation (P=0.0473) were significant factors. In addition, MyD88 L265P mutation showed a tendency to be associated with inferior OS and PFS, although statistically non-significant (OS:P=0.127, PFS: P=0.0872, Figure1). When adjusted to a multivariate Cox regression analysis, MyD88 L265P mutation remained as a significant risk factor for death (hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.0–8.3, P=0.0470), together with altered mentation (HR, 4.7; 95% CI, 1.5-14.7, P=0.0072). Regarding PFS, only MYD88 L265P mutation (P=0.0303) was significantly associated with a higher risk of progression.
Conclusion
This is the first study that provides evidence that elderly PCNSL patients with MyD88 L265P mutation show an unfavorable prognosis. Given that MyD88 L265P mutation was reported to be also associated with an unfavorable outcome of DLBCL, not otherwise specified and cutaneous DLBCL of leg type, dysregulated cellular program by this mutation may be an important determinant for the prognosis of DLBCL in general.These findings open new perspectives in the utility of MyD88 L265P mutation in the clinical sequencing settings of PCNSL.
Session topic: E-poster
Keyword(s): CNS lymphoma, Somatic mutation
Type: Eposter Presentation
Background
Primary central nervous system lymphomas (PCNSL) typically show an immunophenotype resembling that of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Somatic mutations in MyD88, CD79B, and CARD11 were shown to activate the NFκB signaling pathway in ABC-DLBCL. These mutations are reported to be strongly over-represented in PCNSL. Nonetheless, clinical relevance of these mutations remains unclear. On the other hand, the several specific clinical parameters, such as MSKCC and IELSG prognostic score systems, were reported to predict the treatment outcome of PCNSL patients. Recently advanced genetic knowledge, however, is not incorporated in any of these proposals.
Aims
We conducted this study to elucidate the impact of gene mutations on clinical outcome of PCNSL.
Methods
We analyzed 42 immuno-competent patients suffering from newly diagnosed PCNSL who were aged over 60 years, or aged 55-60 years if they had poor performance status, and in whom enough material for DNA extraction was available. They were treated with modified version of the EORTC protocol, consisted of systemic administration of intermediate-dose methotrexate (MTX), lomustine, procarbazine, and methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine (Taoka K., et al., Int J Hematol 2010; Lee SY., et al., Oncol Res Treat 2014), at the University of Tsukuba Hospital between March, 2005 and May, 2015.Targeted deep sequencing was performed by using Ion Ampliseq technology for 12 genes, including MyD88, CD79B, PIM1, TBL1XR1, BTG2, PRDM1, TNFAIP3, CARD11, B2M, TOX, TMEM30A, and PRKCD.All candidate mutations were validated by genomic PCR followed by Sanger sequencing. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and compared by the peto-peto generalized Wilcoxon test.
Results
At least one mutation was detected in 38/42 cases (90.4 %). Frequencies of mutations of 12 genes were similar to those of the previous reports (MyD88, 79%; CD79B, 52%; PIM1, 69%; TBL1XR1, 24%; BTG2, 29%; PRDM1, 24%; TNFAIP3, 12%; CARD11, 19%; B2M, 11.9%; TOX, 11.9%; TMEM30A, 4.8%; PRKCD, 4.8%). The median follow-up time was 26 months (range, 1–105 months), with OS at 3 years of 46% and PFS at 3 years of 26%.By univariate analysis, age>75 (P=0.0105) and altered mentation (P=0.0202) were significantly associated with inferior OS. Regarding PFS, CrCl>90 (P=0.0286) and altered mentation (P=0.0473) were significant factors. In addition, MyD88 L265P mutation showed a tendency to be associated with inferior OS and PFS, although statistically non-significant (OS:P=0.127, PFS: P=0.0872, Figure1). When adjusted to a multivariate Cox regression analysis, MyD88 L265P mutation remained as a significant risk factor for death (hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.0–8.3, P=0.0470), together with altered mentation (HR, 4.7; 95% CI, 1.5-14.7, P=0.0072). Regarding PFS, only MYD88 L265P mutation (P=0.0303) was significantly associated with a higher risk of progression.
Conclusion
This is the first study that provides evidence that elderly PCNSL patients with MyD88 L265P mutation show an unfavorable prognosis. Given that MyD88 L265P mutation was reported to be also associated with an unfavorable outcome of DLBCL, not otherwise specified and cutaneous DLBCL of leg type, dysregulated cellular program by this mutation may be an important determinant for the prognosis of DLBCL in general.These findings open new perspectives in the utility of MyD88 L265P mutation in the clinical sequencing settings of PCNSL.
Session topic: E-poster
Keyword(s): CNS lymphoma, Somatic mutation
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