NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systems-based approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in pre-dose metabolite profiles between groups of subjects are used to predict post-dose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21st century healthcare

Association of ITPA Genotype with Event-Free Survival and Relapse Rates in Children with Acute Lymphoblastic Leukemia Undergoing Maintenance Therapy

<div><p>Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicities and relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional <i>ITPA</i> alleles (94C>A and/or IVS2+21A>C variant) was associated with longer event-free survival compared to patients with the wild-type <i>ITPA</i> genotype (p = 0.033). Furthermore, patients carrying at least one non-functional <i>ITPA</i> allele were shown to be at a lower risk of suffering early (p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the <i>ITPA</i> genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL.</p></div

Influence of <i>ITPA</i> genotype on the incidence of relapses grouped according to time to relapse.

<p>Pie chart slices represent the percent of patients with different <i>ITPA</i> genotypes; wild-type <i>ITPA</i>: 94CC/IVS2+21AA ITPA genotype combination, variant <i>ITPA</i>: 94CA/IVS2+21AA, 94CA/IVS2+21AC, 94CA/IVS2+21CC, 94CC/IVS2+21AC, 94CC/IVS2+21CC ITPA genotype combinations. Very early relapse, <18 months after diagnosis; early relapse,>18 months after diagnosis and <6 months after the end of treatment; late relapse,>6 months after discontinuation of therapy (multinomial regression model adjusted to treatment protocol group, age group at diagnosis and gender; reference category  =  no relapse; p = 0.003).</p

Frequency of the analyzed polymorphisms in patients with childhood ALL.

†<p>PACSIN2 rs2413739 could not be determined in 3 patients.</p><p>Abbreviations: TPMT, Thiopurine S-methyltransferase; MTHFR, methylenetetrahydrofolate reductase; MTRR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; BHMT, betaine—homocysteine S-methyltransferase; GNMT, glycine N-methyltransferase; PACSIN2, protein kinase C and casein kinase substrate in neurons protein; ITPA, Inosine triphosphate pyrophosphatase.</p><p>Frequency of the analyzed polymorphisms in patients with childhood ALL.</p

Clinical characteristics of relapsed patients (N = 102).

<p>Abbreviations: POG, Pediatric Oncology Group; BFM, Berlin-Frankfurt-Muenster; EMD, extramedullary disease.</p>1<p>less than18 months from diagnosis.</p>2<p>more than 18 months after diagnosis and less than 6 months after the end of treatment.</p>3<p>more than 6 months after the end of treatment.</p>4<p>Bone marrow with or without extramedullary disease.</p>5<p>CNS/testes/Other (spinal channel, liver, iris, mesenterium, lymph nodes neck, labia major).</p><p>Clinical characteristics of relapsed patients (N = 102).</p

Clinical characteristics of patients with childhood ALL (N = 308).

<p>Abbreviations: POG, Pediatric Oncology Group; BFM, Berlin-Frankfurt-Muenster.</p><p>Clinical characteristics of patients with childhood ALL (N = 308).</p

Overall and event-free survival rates in patients with childhood ALL, according to treatment protocol and risk group stratification.

1<p>Risk group was not determined for 80 patients (those who were treated under POG protocol).</p><p>Abbreviations: POG, Pediatric Oncology Group; BFM, Berlin-Frankfurt-Muenster.</p><p>Overall and event-free survival rates in patients with childhood ALL, according to treatment protocol and risk group stratification.</p