Thiopurine-methyltransferase genotyping prior to thiopurine therapy

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; OUBIÑA, M

Documento de Evaluación de tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Thiopurines are a drug class that includes azathioprine, 6-mercaptopurine and thioguanine. These are indicated for pathologies such as acute lymphoblastic leukemia, some autoimmune diseases and in patients with solid organ transplants.The enzyme thiopurine S-methyltransferase (TPMT) is involved in the thiopurine metabolism, thus avoiding the accumulation of toxic metabolites, responsible for adverse effects such as myelosuppression. When the enzymatic activity is reduced, it is likely that this adverse effect occurs.The TPMT activity may be impaired by mutations. The corresponding gene is co-dominantly inherited and the enzymatic activity deficit depends on the presence of one or both mutated alleles.When receiving thiopurines, Individuals with normal enzymatic activity present a 7% risk of myelosuppression, while in hetezygous individuals, this risk is 35% (OR 4.62; 95%CI 2.34 to 9.16). In homozygous individuals, for the mutated allele, risk is almost 100% (OR 18.6; 95%CI 4.12 to 83.6).The prevalence of such abnormal alleles varies according to different populations. In the case of Argentina, the joint prevalence of heterozygous and homozygous individuals is 8.2%.At present, the usual approach to prevent myelosuppression is to start treatment at standard doses and then to perform periodic tests, readjusting the dose or opting for an alternative treatment. In the case of a heterozygous individual, the dose should be reduced by 50% and in the case of a homozygous individual, it should be reduced by 90% or else, opt for another treatment.The use of the TPTM enzyme genotyping prior to thiopurine administration is proposed to predict the risk of experiencing myelosuppression by adjusting the dose in the presence of mutated alleles.TechnologyGenotyping consists on identifying specific mutations by polymerase chain reaction (PCR), in a blood sample. It has 70 to 82% sensitivity and 100% specificity.PurposeTo assess the evidence available on the efficacy, safety, and other coverage policy related aspects on the use of TPMT enzyme allele genotyping prior to thiopurine therapy.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsFor this report, one RCT, one health technology assessment, two clinical practice guidelines and seven economic evaluations were included.The RCT included 333 with bowel inflammatory disease who showed no differences in the frequency of adverse events in the genotyping arm (28%) versus the arm receiving standard of care (27%), OR 1.1 (95%CI 0.66 to 1.8).One health technology assessment published in 2010 by the American Research and Quality Agency evaluating the TPMT enzyme deficit determination prior to thiopurine therapy in patients with autoimmune disease, was included. This evaluation concludes that currently there is not enough evidence to show that this technology is associated to a reduction in the rate of adverse events.As regards the economic evaluations surveyed, six evaluations consider it a cost-effective technology within the framework of treating patients with autoimmune diseases or inflammatory bowel disease in health systems such as those of the United Kingdom and the United States. One economic evaluation did not consider it cost-effective, taking into account patients with acute lymphoblastic leukemia in the Canadian health system.One clinical practice guideline published in 2011 by the US National Health Institute´s Clinical Pharmacogenetics Implementation Consortium and the London Guy´s & St. Thomas´ Department of Purines Research and Gastroenterology published in 2004 was included. Both recommend measuring the TPMT enzyme deficit prior to treatment, the first measurement by genotyping and the second one by phenotyping.The cost of TPMT enzyme genotyping is approximately AR$ 2,500 (Argentine pesos/August 2013), approximately U$S 430 (US dollars).ConclusionsThe quality of the evidence found is poor. At present, there are no studies showing that this technology decreases the rate of adverse events, hospitalizations or mortality. There is conflict about recommending this technology, taking into account that each source considers the efficacy of genotyping versus standard approach to prevent myelosuppression in different pathologies and with varying prognoses.