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In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.
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PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for over five decades. Recent pharmacogenomics-based 10-SNP ara-C score (ACS10) showed low ACS10 (£0) to be associated with poor outcome in AML patients treated with standard chemotherapy. Here, we evaluated ACS10 score in the context of three different induction 1 regimens in pediatric AML patients. EXPERIMENTAL DESIGN: ACS10 score groups (low,£0 or high,>0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose cytarabine (LDAC arm, n=91), AML02+AML08 high-dose cytarabine (HDAC arm, n=194) and AML08 clofarabine+ cytarabine (Clo/Ara-C arm, n=105) induction 1 regimens. RESULTS: Within the low-ACS10 score (£0) group, significantly improved EFS and OS was observed among patients treated with Clo/Ara-C as compared to LDAC (EFS, HR=0.45, 95% CI, 0.23-0.88, p=0.020; OS, HR=0.44, 95% CI, 0.19-0.99, p=0.048). In contrast, within the high-ACS10 score group (score >0) augmentation with Clo/Ara-C was not favorable as compared to LDAC (Clo/Ara-C vs. LDAC, EFS, HR=1.95, 95% CI: 1.05-3.63, p=0.035; OS HR=2.17, 95%CI: 1.05-4.49; p=0.037). Personalization models predicted 9% improvement in outcome in ACS10 score-based tailored induction (Clo/Ara-C for low and LDAC for high-ACS10 groups) as compared to non-personalized approaches (p<0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcome in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.
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Acute myeloid leukemia (AML) is a clonal hematopoietic disease that arises from chromosomal and genetic aberrations in myeloid precursor cells. AML is one of the most common types of acute leukemia in adults; however, it is relatively rare overall, comprising about 1% of all cancers. In the last decade or so, numerous genome-wide association studies (GWAS) have been conducted to screen between hundreds of thousands and millions of variants across many human genomes to discover genetic polymorphisms associated with a particular disease or phenotype. In oncology, GWAS has been performed in almost every commonly occurring cancer. Despite the increasing number of studies published regarding other malignancies, there is a paucity of GWAS studies for AML. In this review article, we will summarize the current status of GWAS in AML.
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Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance, and, consequently, clinical response in AML. Despite this, the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within the SAMHD1 gene for association with clinical outcome in 400 pediatric patients with newly diagnosed AML from 2 clinical trials, AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least 1 clinical outcome: minimal residual disease after induction I, event-free survival (EFS), or overall survival (OS) in the 2 cohorts. In an independent cohort of patients from the COG-AAML1031 trial (n = 854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, all the SNPs remained independent predictors of clinical outcome. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.
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Leucemia Mieloide Aguda , Proteína 1 que Contiene Dominios SAM y HD , Niño , Humanos , Trifosfato de Arabinofuranosil Citosina/metabolismo , Trifosfato de Arabinofuranosil Citosina/uso terapéutico , Citarabina/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleótido Simple , Proteína 1 que Contiene Dominios SAM y HD/genéticaRESUMEN
BACKGROUND AND PURPOSE: To implement a sports pharmacy advanced pharmacy practice experience (SP-APPE) utilizing medicinal chemistry as a foundational approach. EDUCATIONAL ACTIVITY AND SETTING: A student-pharmacist and medicinal chemistry faculty member collaborated to reboot a SP-APPE. Approached from a medicinal chemistry perspective and tailored to the infrastructure of the university, three fourth-year student-pharmacists piloted the SP-APPE (fall 2017 to fall 2018). Various performance enhancing drugs (PEDs) and supplements were investigated. Student-pharmacists evaluated general knowledge of PEDs along with the perceived value of pharmacists in sports among student-athletes, athletic personnel, and pre-APPE students. FINDINGS: By demonstrating how legitimate medications were chemically similar to substances banned by sports governing agencies, comparing chemical structures/pharmacophores of PEDs to those of various prescription drugs, and comprehending athletes' misuse of PEDs, student-pharmacists educated student-athletes and athletic personnel on pertinent topics spanning pharmacy and sports (e.g., marijuana, medication sharing, deciphering supplement labels). Laboratory analytical methods that detect PEDs and educational points regarding potential adverse health risks posed by PED usage were also reviewed. Survey participants (approximately 75%, n = 134) perceived pharmacists as valuable to student-athletes and athletic personnel. Student-pharmacists indicated that medicinal chemistry knowledge was strengthened by completing the APPE and relevant to their pharmacy careers. SUMMARY: Based on medicinal chemistry principles, the SP-APPE provided a venue for student-pharmacists to interact with athletics, assist with drug information education, and identify drugs or supplements as chemically related to those banned by sports governing agencies. Confident in medicinal chemistry concepts, student-pharmacists translated their expertise to benefit the patient/student-athlete.
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Educación en Farmacia , Farmacia , Deportes , Estudiantes de Farmacia , Química Farmacéutica , Humanos , FarmacéuticosRESUMEN
There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic interindividual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel, including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx." This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings.