ABSTRACT
Title
Pharmacogenomic markers of clinical efficacy in a dose-dense therapy regimen (R-CHOP14) in diffuse large B cell lymphoma: preliminary results
Authors
C. Napoli1, S. Nobili1, I. Landini1, G. Perrone1, B. Puccini2, G. Antognoli2, M. Doria3, M. Martelli4, E. Finolezzi4, L. Rigacci2, S. Di Lollo3, A. Bosi2, E. Mini1
1Chemotherapy Unit, Department of Pharmacology, 2Hematology Unit, Department of Medical and Surgical Critical Care, 3Pathological Anatomy Section, Department of Medical and Surgical Critical Care - University of Florence, Firenze; 4Department of Cellular Biotecnology and Haematology - University of Rome "La Sapienza", Roma
1Chemotherapy Unit, Department of Pharmacology, 2Hematology Unit, Department of Medical and Surgical Critical Care, 3Pathological Anatomy Section, Department of Medical and Surgical Critical Care - University of Florence, Firenze; 4Department of Cellular Biotecnology and Haematology - University of Rome "La Sapienza", Roma
Abstract
Background: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin’s lymphoma. Approximately half of patients (pts) will be cured of their disease by primary therapy, including the R-CHOP regimen (rituximab, doxorubicin, cyclophosphamide, vincristine, desamethasone). The remaining die of the disease, mainly because of the occurrence of tumor drug resistance. Many efforts have been made to explain the biochemical and molecular mechanisms involved in the resistance to the drugs used in the treatment of cancer pts, including those with DLBCL.
A dose-intense therapy regimen (e.g. R-CHOP14) may help to improve the treatment outcome of DLBCL pts
Aims: We have carried out a retrospective study aimed atcorrelating the mRNA expression levels of genes involved in metabolism, mechanisms of action and resistance to doxorubicin (i.e. MDR1, GSTP1, TOPO-2alpha, Bcl-2, PKC-beta2) that represents the backbone of the R-CHOP regimen with treatment outcome data of 32 pts at various stages of disease.
Methods: The expression of the 5 above mentioned genes were determined in formalin fixed paraffin-embedded samples from DLBCL using real time RT-PCR. The correlations between gene expression data and clinical/pathological characteristics as well as survival parameters have been evaluated by standard statistical tests.
Results: The case seriesincluded 19 males and 13 females, 6 pts had follicular lymphoma grade IIIb and 26 diffuse large B cell lymphoma, 11 presented symptoms at diagnosis. Eighteen pts showed abnormal LDH values, the IPI was intermediate-high risk or high risk in 8 pts. Twenty-eight pts (87.5%) obtained a complete remission and 4 (12.5%) a partial response.
The median overall survival (OS) as well as the median failure free survival (FFS) have not yet been reached after a median follow-up of 31.2 months.
The mRNA expression levels of TOPO-2alpha and GSTP1 were detectable in all samples, that of PKC-beta2 in 31 samples, that of MDR1 and bcl-2 in 16 and 12 samples, respectively.
The intragenic variation levels (ratio between the maximum and minimum levels of mRNA gene expression) ranged from 799 for bcl-2 to more than 100,000 for GSTP1.
No significant differences between FFS and mRNA expression levels of the study genes were observed.
An inverse relationship was observed between OS and TOPO-2amRNA expression (p=0.026): higher TOPO-2alpha gene expression was associated with shorter OS. Only a trend was observed between OS and PKC-beta2 or GSTP1 mRNA expression. No difference was observed between gene expression mRNA levels and clinical/pathological characteristics with the exception of the tumor histology for all genes (p < 0.05).
This preliminary data and others from related studies may help to identify gene profiles useful for selection pts eligible for intensified or personalized chemotherapy that can achieve greater efficacy than standard therapies.
Supported by a grant from Associazione Giacomo Onlus, Castiglioncello (LI)
A dose-intense therapy regimen (e.g. R-CHOP14) may help to improve the treatment outcome of DLBCL pts
Aims: We have carried out a retrospective study aimed atcorrelating the mRNA expression levels of genes involved in metabolism, mechanisms of action and resistance to doxorubicin (i.e. MDR1, GSTP1, TOPO-2alpha, Bcl-2, PKC-beta2) that represents the backbone of the R-CHOP regimen with treatment outcome data of 32 pts at various stages of disease.
Methods: The expression of the 5 above mentioned genes were determined in formalin fixed paraffin-embedded samples from DLBCL using real time RT-PCR. The correlations between gene expression data and clinical/pathological characteristics as well as survival parameters have been evaluated by standard statistical tests.
Results: The case seriesincluded 19 males and 13 females, 6 pts had follicular lymphoma grade IIIb and 26 diffuse large B cell lymphoma, 11 presented symptoms at diagnosis. Eighteen pts showed abnormal LDH values, the IPI was intermediate-high risk or high risk in 8 pts. Twenty-eight pts (87.5%) obtained a complete remission and 4 (12.5%) a partial response.
The median overall survival (OS) as well as the median failure free survival (FFS) have not yet been reached after a median follow-up of 31.2 months.
The mRNA expression levels of TOPO-2alpha and GSTP1 were detectable in all samples, that of PKC-beta2 in 31 samples, that of MDR1 and bcl-2 in 16 and 12 samples, respectively.
The intragenic variation levels (ratio between the maximum and minimum levels of mRNA gene expression) ranged from 799 for bcl-2 to more than 100,000 for GSTP1.
No significant differences between FFS and mRNA expression levels of the study genes were observed.
An inverse relationship was observed between OS and TOPO-2amRNA expression (p=0.026): higher TOPO-2alpha gene expression was associated with shorter OS. Only a trend was observed between OS and PKC-beta2 or GSTP1 mRNA expression. No difference was observed between gene expression mRNA levels and clinical/pathological characteristics with the exception of the tumor histology for all genes (p < 0.05).
This preliminary data and others from related studies may help to identify gene profiles useful for selection pts eligible for intensified or personalized chemotherapy that can achieve greater efficacy than standard therapies.
Supported by a grant from Associazione Giacomo Onlus, Castiglioncello (LI)