Author(s): Mohammad Salem Hareedy [*] aff1 aff2 , Ehab S El Desoky aff1 , Jean-Baptiste Woillard aff2 aff3 aff4 , Romany Helmy Thabet aff1 , Amany Mohamad Ali aff5 , Pierre Marquet aff2 aff3 aff4 , Nicolas Picard aff2 aff3 aff5
6-mercaptopurine; childhood acute lymphoblastic leukemia; leukopenia; neutropenia; pharmacogenetics; relapse
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer (nearly a third of all childhood cancers). The prognosis for ALL has improved owing to the development and proper usage of multiple chemotherapeutic drugs that lead to a survival of about 80% [1 ].
6-mercaptopurine (6-MP) is one of the backbone drugs used for maintenance therapy in ALL [2 ]. It is a prodrug devoid of intrinsic activity and needs activation inside the cells through multienzymatic reactions to 6-thio-guanine nucleotides (6-TGNs) which participate in the antileukemic effect of 6-MP through incorporation in the DNA of leukemic cells. The different metabolites of 6-MP can also contribute to toxicity [3 ]. See Figure 1.
ALL relapse and hematological toxicity are major clinical problems in patients maintained on 6-MP treatment and both can be fatal [4 ].
The activity of the enzymes TPMT and inosine triphosphate pyrophosphatase (ITPase), which are involved in the metabolic pathways of thiopurine drugs like 6-MP and AZA, presents wide interindividual variability, partly due to genetic polymorphisms [5 ].
Pharmacogenetic association studies between TPMT SNPs and the clinical outcome of treatment with thiopurine drugs (6-MP and AZA) focused on four variant alleles (TPMT*3A, TPMT*3C, TPMT*2 and TPMT*3B) [6 ], while two important SNPs in the inosine triphosphatase (ITPA ) gene, coding for ITPase, namely rs1127354 (c.94C[greater than]A) and rs7270101 (IVS2+21A[greater than]C) were found to be related to the thiopurine related adverse effects [7,8 ] and also showed excellent phenotype-genotype correlation with decreased ITPase activity [9 ].
Some patients from different ethnic groups treated with thiopurine drugs showed an increased risk of hematological toxicity and other forms of adverse drug reactions if they carried at least one of these TPMT or ITPA SNPs [8,10,11 ]. Therefore, genotype-based dose adjustment of these drugs may improve patient outcome [5 ].
Several others enzymes or transporters are involved in the 6-MP pathway: inosine 5′-monophosphate dehydrogenase 1 (IMPDH1) catalyzes the conversion of 6-thioinsosine monophosphate (6-TIMP) into 6-thioxanthosine monophosphate (6-TXMP), which in turn lead to the formation of 6-TGNs. Solute carriers (SLC) 28A2, 28A3, 29A1 and 29A2 are involved in 6-MP uptake, and ATP-binding cassette (ABCC4 and ABCC5) transporters are involved in the efflux of 6-MP active metabolites [12 ]. ABCC4 is also involved in the efflux of 6-MP itself [13 ]. Little data is available regarding the impact of SNPs in these important proteins on 6-MP outcomes.
The aim of the present study was to identify genetic factors associated with both hematological toxicity (i.e., neutropenia, agranulocytosis and/or leukopenia) and therapeutic failure (i.e., ALL relapse) in patients with ALL maintained on 6-MP in Upper (southern) Egypt. Important pharmacogenes involved in the 6-MP activation and elimination pathways, (including TPMT and ITPA ) were considered and candidate polymorphisms were carefully selected based on...