Pharmacogenetics of Response to Glucocorticosteroids in Adults with Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2609-2609
Author(s):  
Krzysztof Jamroziak ◽  
Ewa Balcerczak ◽  
Zofia Szemraj ◽  
Aleksandra Salagacka ◽  
Olga Grzybowska-Izydorczyk ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Glucocorticoid Receptor ◽  
Induction Chemotherapy ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Prognostic Impact ◽  
Functional Polymorphisms ◽  
Glucocorticoid Receptor Gene

Abstract Glucocorticoids are crucial components of standard chemotherapy regimens used for the treatment of adult acute lymphoblastic leukemia (ALL). However, little is known on significance of the inherited genetic background for response to steroids in adult ALL. We hypothesized that functional single nucleotide polymorphisms (SNPs) in genes important for steroid pharmacokinetics and pharmacodynamics may contribute to sensitivity or resistance to steroids. In this study we investigated whether analysis of common functional SNP in drug transporter P-glycoprotein gene (MDR1 or ABCB1), phase I cytochrome P450A metabolizing enzymes genes (CYP3A4 and CYP3A5) and glucocorticoid receptor gene NR3C1 can be useful to predict response to induction chemotherapy and survival of adult ALL patients. Sixty-two uniformly treated adult ALL patients were investigated for 6 common SNPs affecting steroid pathway including MDR1 exon 26 C3435T, CYP3A4*1B, CYP3A5*3, CYP3A5*6, NR3C1 bcl I and NR3C1 N363S polymorphisms. Genotypes were identified using direct sequencing or restriction fragment length polymorphism (RFLP) method. In the genotyped cohort 60% patients achieved complete remission after first induction chemotherapy. The analysis of the prognostic impact of the genotyped SNPs on treatment response showed that carriers of the glucocorticoid receptor NR3C1 gene 363S allele had a significantly greater probability of achievement of complete remission as compared to the non-carriers, odds ratio(OR)=1.23, 95% confidence interval (95%CI) = 1.02 −1.47, p=0.042). None of the analyzed polymorphic variants showed significant impact on probability of progression-free and overall survival of the included patients. In conclusion, we found that glucocorticoid receptor NR3C1 gene N363S polymorphism contributes to the response to steroids in patients with adult ALL. Inherited functional polymorphisms in pharmacokinetic pathways of anti-leukemic drugs should be considered as determinants of response potentially useful for individualization of chemotherapy of adult ALL of in the future.

Polymorphisms in glucocorticoid receptor gene and the outcome of childhood acute lymphoblastic leukemia (ALL)

2010 ◽  
Vol 34 (4) ◽  
pp. 492-497 ◽  
Author(s):  
Malgorzata Labuda ◽  
Annabel Gahier ◽  
Vincent Gagné ◽  
Albert Moghrabi ◽  
Daniel Sinnett ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor Gene

Pharmacogenetic Analysis of Polymorphisms in Pharmacological Pathway of Vincristine, Doxorubicine and Dexamethasone (VAD Regimen) To Predict Response in Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 104-104 ◽  
Author(s):  
Krzysztof Jamroziak ◽  
Ewa Balcerczak ◽  
Mariusz Panczyk ◽  
Sylwester Piaskowski ◽  
Agnieszka Janus ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Glucocorticoid Receptor ◽  
Partial Remission ◽  
Multi Drug Resistance ◽  
Prognostic Impact ◽  
Metabolizing Enzymes ◽  
Glycoprotein Gene ◽  
Functional Polymorphisms ◽  
P Glycoprotein ◽  
Glucocorticoid Receptor Gene

Abstract Combination of vincristine, doxorubicin and dexamethasone (VAD regimen) is a widely-used, effective and economic initial treatment of multiple myeloma (MM). However, between 30 and 50% of MM patients do not respond to VAD, and exposure to VAD may induce multi-drug resistance. Therefore, in the era of emerging novel therapies for MM, there is a need for pre-treatment identification of potential responders to VAD. Importantly, all three VAD components have common steps in their pathways of transport and metabolism, thus even modest inherited alteration caused by single nucleotide polymorphisms (SNP) may influence VAD efficacy an toxicity. The aim of this study was to investigate whether analysis of common functional SNP in drug transporter P-glycoprotein gene (MDR1 or ABCB1), phase I cytochrome P450A metabolizing enzymes genes (CYP3A4 and CYP3A5), phase II glutathione S-transferase P metabolizing enzyme gene (GSTP1) as well as in glucocorticoid receptor gene NR3C1 can be useful to predict response to VAD in MM. Fifty-two uniformly treated MM patients were investigated for 8 common SNPs including MDR1 exon 12 C1236T, MDR1 exon 21 G2677T/A, MDR1 exon 26 C3435T, CYP3A4*1B, CYP3A5*3, GSTP1 A313G as well as NR3C1 bcl I and NR3C1 N363S polymorphisms. Genotypes were identified using direct sequencing or RFLP methods. The response to VAD was estimated after administration of 3 courses of VAD, and patients who achieved complete or partial remission of MM were assigned as responders to VAD. In the cohort of included MM patients there were 39/52 (75%) responders to VAD. The analysis of the prognostic impact of the genotyped SNPs showed that carriers of P-glycoprotein gene MDR1 2677G allele had a significantly greater probability of achievement of the response to VAD as compared to the non-carriers, odds ratio(OR)=8.0, 95% confidence interval (95%CI)= 1.2–52.9, Fisher exact test p=0.031). Moreover, the predictive effect of MDR1 2677G allele was further increased by the presence of glucocorticoid receptor NR3C1 gene 363N allele. The carriers of both MDR1 2677G and NR3C1 363N alleles had 8.4-fold greater probability to achieve complete or partial remission with 3 courses of VAD (OR=8.40, 95% CI=1.8–40.0, p=0.008). Taken together, these data support the hypothesis that analysis of common functional polymorphisms in drug transporters, metabolizing enzymes and receptors may be useful for individualization of the initial therapy of MM. Particularly MDR1 G2677T/A and NR3C1 N363S SNPs can be considered as determinants of response to VAD therapy.

Prognostic Impact of Different High Risk Features in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in First Complete Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2303-2303
Author(s):  
Theis Terwey ◽  
Philipp Hemmati ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
Renate Arnold
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Prognostic Impact ◽  
Very High ◽  
First Complete Remission

Abstract Abstract 2303 Poster Board II-280 Introduction: In acute lymphoblastic leukemia (ALL) specific clinical and biological features confer high relapse risk and inferior overall survival (OS) after treatment with conventional chemotherapy alone. The differential prognostic impact of these high risk features after treatment with allogeneic hematopoietic stem cell transplantation (HCT) has not been well studied. Patients and Methods: 79 adult ALL patients in first complete remission (CR) received allogeneic HCT at our center between 1995 and 2008. All patients were high or very high risk according to German Multicenter Study Group for Adult ALL (GMALL) criteria. Median age was 36 years (range: 17-68). Patients received high-dose conditioning consisting of 12 Gy total body irradiation ± etoposide ± cyclophosphamide (n=69, 87%) or reduced intensity conditioning (RIC) consisting of fludarabine/busulfan/ATG (n=10, 13%) and HSCT from related (n=34, 43%) or unrelated (n=45, 57%) donors. Bone marrow (n=17, 22%) or peripheral blood stem cells (n=62, 78%) were given. Graft-versus-host-disease prophylaxis was CSA/MTX for high-dose conditioning or CSA/MMF for RIC. Results: Patients were classified as high risk or very high risk due to Philadelphia chromosome-positive disease (Ph+) (n=30, 38%), leukocytosis>30/nl at diagnosis in B-ALL (n=25, 23%), late response to induction therapy in B-ALL (>week 4) (n=13, 16%), early or mature T-ALL (n=13, 16%), pro-B-ALL/t(4;11) (n=8, 10%), persistence of minimal residual disease (MRD) (>week 16) (n=8, 10%) or complex aberrant karyotype (n=6, 8%). 57 patients (72%) presented with one high risk feature, whereas 20 patients (25%) and 2 patients (3%) presented with two or three features, respectively. Currently, after a median follow-up of 56 months (7-169) 49 patients (62%) remain alive. Projected OS of the whole cohort at 1, 2 and 5 years was 78%, 70% and 55% and leukemia-free survival was 77%, 66% and 55%. Cumulative incidence of non-relapse mortality (NRM) and relapse mortality (RM) at 5 years was 23% and 18%, respectively. In multivariate Cox regression analysis, a non-significant trend for inferior OS was seen for patients with early or mature T-ALL (hazard ratio (HR): 2.03 (95%CI: 0.92-4.52), p=0.082), whereas no differential effect on OS, NRM or RM was seen for any other high risk feature (Table 1). In additional analyses, inferior OS (HR 1.81 (95%CI: 1.02-3.29), p=0.043) and increased RM (HR 2.17 (95%CI 1.16-4.05), p=0.015) was observed for patients with more than one high risk feature. Conclusions: In summary, this single center study on allogeneic HCT in high risk ALL found a negative prognostic trend for early or mature T cell immunophenotype. No differential prognostic impact on OS, NRM and RM was seen for other high risk features as defined by GMALL criteria, however this conclusion is limited by the low patient number in some of the subgroups. Overall survival for the whole cohort was 55% at 5 years, with inferior OS and higher RM being observed in patients with more than one high risk feature. Disclosures: No relevant conflicts of interest to declare.

Adolescents and Young Adults with Acute Lymphoblastic Leukemia Have Better Outcomes When Treated with Pediatric-Inspired Regimens - Systematic Review and Meta-Analysis of Comparative Trials

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2591-2591
Author(s):  
Ron Ram ◽  
Ofir Wolach ◽  
Liat Vidal ◽  
Anat Gafter-Gvili ◽  
Ofer Shpilberg ◽  
...  
Keyword(s):  
Systematic Review ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
All Cause Mortality ◽  
Comparative Trials

Abstract Abstract 2591 Background: Survival of adults with acute lymphoblastic leukemia (ALL) is inferior to pediatric patients. Therefore, strategies to improve long-term results in this population are warranted. Objectives: This study aims to evaluate the efficacy and safety of pediatric-inspired regimens given to adolescents and young adults (AYA) with ALL. Methods: Systematic review and meta-analysis of comparative trials of AYA patients with ALL given induction chemotherapy with either pediatric-inspired regimens or conventional adult chemotherapy was conducted. Cochrane Library, MEDLINE and conference proceedings were searched (up-to May, 2011). Outcomes assessed were: all-cause mortality, number of patients achieving complete remission after induction chemotherapy and toxicity of the regimen (evaluated by non-relapse mortality). Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Results: Our search yielded 11 trials, including 2489 patients. The age of AYA patients ranged between 10 and 57 years. Studies were published between the years 2003 and 2009. AYA patients given pediatric-inspired regimens had a statistically significant lower all cause mortality at 3 years (RR 0.58; 95% CI 0.51–0.79, 7 trials) beyond 3 years (RR 0.58; 95% CI 0.51–0.65, 8 trials) and at the end of study period (RR 0.59; 95% CI 0.52–0.66, 9 trials, Figure). Sensitivity analysis for all cause mortality including studies in which the two cohorts were well compared in either age or disease risk also showed decreased all cause mortality in patients given pediatric-inspired regimen (RR 0.53; 95% CI 0.41–0.70, I2=50%, 4 trials). However, this superiority in survival for pediatric-inspired regimens was not maintained when studies including only patients older than 20 years were analyzed (RR 0.49; 95% CI 0.23–1.06, I2=67%, 2 trials). Complete remission rate after induction chemotherapy was superior in patients given pediatric-inspired regimens when compared to patients given conventional adult chemotherapy (RR 1.05; 95% CI 1.01–1.10, I2=55%, 7 trials) with comparable non-relapse mortality in both groups (RR 0.53; 95% CI 0.19–1.48, I2=56%, 4 trials). Conclusions: For patients up to the age of 20 years, pediatric-inspired regimens are superior to conventional adult chemotherapy in terms of ACM and complete remission rate with similar non relapse mortality. Randomized controlled trials to further investigate the feasibility of this approach in adult ALL patients are warranted. Disclosures: No relevant conflicts of interest to declare.

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