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- Jardin, Fabrice, et al.
(författare)
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Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.
- 2016
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 91:9, s. 923-30
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Tidskriftsartikel (refereegranskat)abstract
- Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.
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| 3. |
- Hayden, Patrick J., et al.
(författare)
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Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWP
- 2020
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Ingår i: European Journal of Haematology. - : WILEY. - 0902-4441 .- 1600-0609.
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. Methods A retrospective analysis of the EBMT database (1991-2012) was performed. Results A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P amp;lt; .001) but not after 2002 (HR = 1.2, P = .276). Conclusion From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.
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| 5. |
- Schmid, Christoph, et al.
(författare)
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Outcome and risk factor analysis of molecular subgroups in cytogenetically normal AML treated by allogeneic transplantation.
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 126:17, s. 2062-2069
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Tidskriftsartikel (refereegranskat)abstract
- Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) is limited. Therefore, we performed a retrospective registry analysis on 702 adults with CN-AML undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD). Double negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. 2y-OS from HSCT was 81±5% in NPM1(mut)/FLT3(wt) (n=68), 75±3% in NPM1(wt)/FLT3(wt) (n=290), 66±3% in NPM1(mut)/FLT3-ITD (n=269) and 54±7% in NPM1(wt)/FLT3-ITD (n=75; p=0.003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) (n=13, 2y-OS:100%), and with a triple negative genotype (n=138, 2y-OS:77±3%). In a Cox-model of predefined factors, older age, presence of FLT3-ITD and >1 course of chemotherapy to reach CR were associated with inferior outcome. 2y-OS/LFS were 88±3%/79±4% in patients without any, 77±2%/73±3% with one, and 53±4%/50±4 with>=2 risk factors (p=0.002 for LFS, p=0.003 for OS). Hence, FLT3-ITD proofed to be the decisive molecular marker for outcome after HSCT for CN-AML in CR1, regardless of NPM1 mutational status, variations of transplant protocols, or development of GvHD. Age, FLT3-ITD and response to induction chemotherapy allow for a prognostic risk classification.
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