Clinical impact of SNP of P53 genes pathway on the adult AML patients.

INTRODUCTION: Acute myeloid leukemia (AML) is a highly heterogeneous disease, with biologically and prognostically different subtypes. AIM: To study the impact of p53, p21, and mdm2 gene polymorphisms on the clinical outcome in adult AML patients treated at the National Cancer Institute (NCI) - Cairo University. METHODS: Forty-eight adult AML patients presented to the Medical Oncology Department, NCI, from April 2010 till November 2011. Clinical data and bone marrow samples were obtained. Molecular genetic analysis involving P53, MDM2, and P21 single-nucleotide gene polymorphisms was done using polymerase chain reaction-restriction fragment length polymorphism coupled analysis. RESULTS: The mean age was 35.7 years. After a median follow-up period of 12 months, 28 patients (58.4%) achieved complete remission (CR) and the overall survival (OS) was 8.7 months. Patients with homozygous Arg/arg at codon 72 of P53 had a better median OS months than Arg/Pro and Pro/Pro (13.4 vs. 8.4 vs. 1.5 months, respectively; P = 0.045). P53/p21 combination had a better median OS and disease-free survival (DFS) of 12.1 and 13.7 months for wild type cases (GG + Ser/ser) and 20.3 and 20.7 months for patients with either variant genes (GC + Ser/arg) compared with 1.1 and 1.9 months for patients with both variant genes (CC + arg/arg), (P = 0.037 and 0.004). The presence of wild genotype of either P21 or MDM2 may abolish the effect of P53 homozygous variant genotype on the OS. Neither p21nor mdm2 polymorphism alone showed an impact on OS or DFS. CR was not affected by any of the three gene polymorphisms. CONCLUSION: The p53 pathway gene polymorphisms may affect the OS of adult AML patients.

Prognostic significance of WT1 expression at diagnosis and end of induction in Egyptian adult acute myeloid leukemia patients.

BACKGROUND: Wilms' tumor (WT1) gene overexpression has been reported in the majority of acute myeloid leukemia (AML) patients at diagnosis and has been evaluated as prognostic and minimal residual disease (MRD) marker. PATIENTS AND METHODS: WT1 overexpression was evaluated in 68 adult AML patients at diagnosis and at the end of induction using quantitative real-time polymerase chain reaction (PCR). RESULTS: No significant associations were encountered between WT1 overexpression at diagnosis and other prognostic factors. Complete remission (CR) was achieved in 74% of the patients with WT1 overexpression compared to 80% of patients with normal levels (P = 0.5). No significant associations were encountered between WT1 overexpression at diagnosis and disease-free survival (DFS) or overall survival (OS) (P = 0.6 and 0.3, respectively). At the end of induction, the median duration of DFS in patients achieving ≥ 2 log reduction was not reached compared to only 5 months (range: 2.1-7.9 months) in those attaining <2 log reduction (P = 0.2). The median duration of OS in patients achieving ≥ 2 log reduction was 13 months (range: 0-33.3 months) compared to 7.5 months (5.4-9.6 months) in those attaining <2 log reduction (P = 0.2). The survival at 1 year in patients achieving ≥ 2 log was double the group with <2 log reduction (67% compared to 33%). CONCLUSION: Our results, although not reaching the level of significance, probably due to the small sample size, still suggest that the early assessment of WT1 transcript level at the end of induction in patients in CR may have a prognostic significance on clinical outcome and may thus be a useful marker for risk stratification especially in patients lacking disease-specific marker.

Glutathione S-transferase GSTM1 and GSTT1 polymorphisms in adult acute myeloid leukemia; its impact on toxicity and response to chemotherapy.

BACKGROUND AND PURPOSE: Heterogeneity in patient' s response to chemotherapy is consistently observed across populations. Pharmacogenomics, the study of inherited differences in drug disposition and effects, is emerging as a tool to predict efficacy and toxicity of drugs. Glutathione S-transferases (GST) are involved in the metabolism and detoxification of environmental carcinogens and some classes of chemotherapeutics. Polymorphism of GSTM1 and GSTT1, in the form of homozygous deletion, is encountered in varying frequencies in normal population. It has been associated with altered response and toxicity from cytotoxic chemotherapy. In this study, we investigated the impact of these polymorphisms on response and side effects of chemotherapy in adult acute myeloid leukaemia (AML) patients. Correlations between these genetic polymorphisms and other prognostic factors were also investigated. PATIENTS AND METHODS: We genotyped GSTM1 and GSTT1 in 98 adult AML patients using multiplex PCR. Induction therapy included Doxorubicin and Cytosine arabinoside (3+7) regimen. Treatment outcomes were compared in those with or without GSTM1 and GSTT1 genes. RESULTS: The frequencies of GSTM1 null and GSTT1 null genotypes were 56% and 14%, respectively. Six percent (6%) were double null. The rate of toxic death during induction was 3/7 (43%) and 17/56 (30%) in GSTT1 null and GSTT1 present patients, respectively, p=0.67. This constituted 75% and 42% of total deaths in each group, respectively, p=0.31. Differences were not statistically significant. On the other hand, the rate of complete remission (CR) in patients with GSTM1 present compared to those with GSTM1 null genotype was 12/27 (48%) versus 23/36 (64%), p=0.21. GSTT1 null genotype was significantly associated with lymphoid marker (mainly CD7) expression (p=0.03), known with its adverse effect on prognosis. Overall survival and disease-free survival were similar in patients with and without the genes. No significant associations were encountered between GST genotypes and treatment outcomes. CONCLUSION: Our data suggest possible association, though not significant, between GSTT1 null genotype and toxic death during induction and between GSTM1 present genotype and lower rate of CR. Studies on larger numbers are needed focusing on selection of anticancer agents to avoid adverse reactions and therapeutic failure, with special emphasis on drug toxicity and dose adjustment.

Prognostic factors of Hodgkin's lymphoma and their impact on response to chemotherapy and survival.

OBJECTIVE: The aim of this study was to compare the standard prognostic factors of Hodgkin's lymphoma (HL) in relation to response to first line chemotherapy, disease free survival (DFS) and overall survival (OS). PATIENTS AND METHODS: The study was performed on a group of 100 adult patients diagnosed as HL and who were treated and followed-up in the years 1999 to 2001, in the Medical Oncology Department at National Cancer Institute (NCI), Cairo. The first line chemotherapy was COPP in 40%, ABVD in 35% and COPP/ABV hybrid in 25%. Patients were classified into early stage disease: Stages I, IIA and IIB without poor risk factors, n=43 and advanced stage disease: Stages III, IV and IIB with poor risk factors, n=57 analysis of the prognostic factors for early versus advanced-stage disease was done by univariate and multivariate regression analysis. RESULTS: Complete remission (CR) was attained in 69% of the patients after first line chemotherapy; being 87.8 % and 54.7% for early and advanced disease, respectively, (p=0.0001). The CR rates after different chemotherapy regimens were 81.8%, 90% and 90% for the ABVD, COPP and COPP/ABV hybrid regimens in the early-disease group; respectively; in contrast to the corresponding figures of 54.5%, 50% and 61.5% in the advanced- stage group. The DFS at 4 years, was 94 %, 55% and 54.5% for the patients treated with ABVD, COPP and COPP/ABV hybrid, respectively (p=0.2). The DFS and OS in this series of patients were 61.3% and 53.7%, being 69.8% and 70.7% for the early and 45.1% and 38.9% for the advanced-disease, respectively The OS of the whole group was significantly related to age (p=0.04), sex (p=0.005), early versus advanced disease (p=0.0001) and B symptoms (p=0.0006). CONCLUSIONS: The adequate response and DFS of the early compared to the advanced-stage disease supported the evolving role of risk adapted chemotherapy for HL. The prognostic factors proved to be of significant impact in our series. The results of this study pointed to the need for an improved treatment strategy in this potentially curable disease,especially for the advanced disease.