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

Targeting kinase-activating genetic lesions to improve therapy of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients' lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): t(9;22)(q34;q11.2) that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of B-immunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient's specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients' lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): t(9;22)(q34;q11.2) that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of B-immunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient's specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors

Pharmacogenomics education in medical and pharmacy schools: conclusions of a global survey

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005.status: publishe