Esteva Socias, Margalida

Universitat Autònoma de Barcelona. Facultat de Biociències

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Pharmacogenetics of childhood Acute Lymphoblastic Leukemia treated with Methotrexate Author: Margalida Esteva Socias.  Facultat de Biociències. Curs acadèmic 2014-2015.  Universitat Autònoma de Barcelona (Catalunya, Espanya) • Das A, Balan S, Banerjee M, Radhakrishnan K. Drug resistance in epilepsy and the ABCB1 gene: The clinical perspective. Indian J Hum Genet. 2011 May;17 Suppl 1:S12-21. doi: 10.4103/0971-6866.80353. • D'Angelo V, Ramaglia M, Iannotta A, et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol. 2011 Nov;68(5):1339-46. • GREGERS, Jannie. Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate. Supervised by Curt Peterson. Linköping University, Department of Clinical Pharmacology, 2012. ISBN 978-91-7519-929-0. • Schmeling H, Horneff G, Benseler SM, Fritzler MJ. Pharmacogenetics: can genes  determine treatment efficacy and safety in JIA? Nat Rev Rheumatol. 2014 Nov;10(11):682-90  • Despite some conflicting results, the mentioned polymorphisms in MTHFR, SLCO1B1, SLC19A1 and ABCB1 genes are considered to have an important potential for developing personalized medicine. However,  further evaluation of the genetic polymorphisms is needed in order to definitely  stablish their effect on MTX treatment in ALL patients. • MTX plasma concentration is though to be associated with an increase of toxicity. • Although positive associations between genetic polymorphisms and response to MTX treatment have been reported, we are still far from being able to apply pharmacogenetic tests in routine clinical practice.  Acute Lymphoblastic Leukemia (ALL) is a hematologic malignancy that affects blood cells and originates in the bone marrow, where haematopoiesis occurs. ALL is the most common form of childhood leukemia as well as the most common diagnosed childhood cancer (25-30%).   This form of blood cancer is characterised by an overproduction of immature white blood cells, called lymphoblasts. Due to their immaturity, these malignant cells are unable to function properly to prevent and fight infection. Tumor cells are the result of a multi-step process of carcinogenesis and are characterized by being carriers of genetic alterations. This means that, together with their continuing proliferation, they accumulate in the bone marrow and arrest the production of healthy cells.  BACKGROUND CONCLUDING REMARKS  Aims to determine how the genetic makeup of each individual influences the response to drugs. Polymorphisms can modulate the response to a drug or therapy  Pharmacogenetics SAME DIAGNOSIS SAME PERSCRIPTION DNA profiling SAME DIAGNOSIS DIFFERENT PERSCRIPTION Drug is toxic Drug is NOT toxic Drug is NOT toxic but NOT benefitial GENETIC VARIANTS Figure 2. Metabolic Pathway of MTX. (Adaptation of Schmeling H. et al., 2014)   Methotrexate (MTX) belongs to the class of chemotherapy drugs called antimetabolites. In particular, they have the ability to join the cellular metabolism causing the cells to lose their ability to divide. Specifically, MTX is a folic acid antagonist. Methotrexate Figure 1. Folic acid and methotrexate only differ in an amino and a methyl-group IDENTIFIED PROBLEMS The aim of the present poster is to review  the actual state of knowledge of pharmacogenetics and childhood Acute Lymphoblastic Leukemia focused on treatment with Metrotrexate  • Cytogenetic Location: 21q22.3 • Main transporter of MTX into cells      • Polymorphisms: G80A   SLC19A1 Figure 5. Kaplan-Meier analysis of SLC19A1 and outcome. (Gregers J. 2012) ↓ Uptake capacity for MTX Variant 80AA More efficient uptake MTX Remission 3 times higher Δ Toxicity Variant 80GG ↓Uptake MTX Majority of studies had been developed with relatively small number of patients.  It has not been established a unified protocol for ALL treatment with MTX and  research on the effect of each genetic variant.   Lack of consistency in quantifying the association between  genotype and  MTX response and toxicity. 1 2 3  • Cytogenetic Location: 7q21.12 • P-Glycoprotein            functional barrier      • Polymorphisms: C3435T and G1199A  ABCB1 Figure 3. P-Glycoprotein structure.  (Das A. et al. 2011) C3435T G1199A Affected outcome and protein function and expression 3435TT/CT ↓Protein expression Risk of relapse 40% pEFS 83% 3435CC ↑ALAT levels Risk of relapse 61% pEFS 78% 1199GG pEFS 83% 1199GA pEFS 68% 2,9-fold higher risk of relapse  CELL APOPTOSIS MTX Folic Acid ↓Folic Acid LEUCOVORIN CALCIUM Rescue 24h after MTX administration NORMAL CELLS Leucovorin acts protecting healthy cells from MTX effects while allowing the entry of MTX into tumor cells to kill them. TUMOR CELLS  • Cytogenetic Location: 1p36.3      • Polymorphisms: 677C>T MTHFR  Homocysteine                   Methionine Variant 677T Higher risk of relapse ↓DFS  Genotype 677TT 12-fold risk of developing toxicity Figure 4. Kaplan-Meier analysis of  disease-free survival and C677>T genotype [1 (CC+CT) versus 2 (TT)]. (D’Angelo V. et al., 2011)  • Cytogenetic Location: 12p      • Polymorphisms: rs4149081, rs11045879 and  rs4149056 SLCO1B1 Genotype rs4149081AA Genotype  rs11045879CC High-MTX plasma concentrations Clearance Toxicity rs4149056 T521C  V174A ↓ Transporting activity Weakening translocation of drugs from plasma to hepatocyte 521TC+CC Δ Hepatic toxicity ↓Clearance Δ MTX plasma concentration 

Pharmacogenetics of childhood acute lymphoblastic leukemia treated with methotrexate

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Pharmacogenetics of childhood acute lymphoblastic leukemia treated with methotrexate

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