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Booth RA, Ansari MT, Tricco AC, et al. Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Dec. (Evidence Reports/Technology Assessments, No. 196.)

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Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs.

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Executive Summary

Background

Thiopurine drugs are used to treat chronic autoimmune inflammatory conditions and hematological malignancies, and to prevent organ transplant rejection. The present study focuses on populations with autoimmune disease.

Thiopurine drugs are associated with various toxic adverse effects, including myelosuppression, hepatotoxicity, pancreatitis, and flu-like symptoms. One of the most serious dose-dependent reactions is severe myelosuppression that is thought to be caused by the active metabolite, deoxy-6-thioguanosine 5′ triphosphate (6-tGN). Excessive levels of 6-tGN may arise not only due to overdosing, but also because of decreased inactivation of the drug.

The most extensively characterized enzyme in the metabolism of thiopurines is thiopurine methyltransferase (TPMT). TPMT inactivates the active forms of two commonly used thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine (6-MP), by methylation. Multiple studies have shown that lower TPMT enzymatic activity is correlated with higher levels of the active drug metabolites and increased thiopurine toxicity. Genetic polymorphisms associated with lower TPMT enzymatic activity are similarly correlated.

Approximately 0.3 percent of the population with chronic autoimmune disease that could potentially benefit from thiopurine treatment is homozygous for a variant TPMT allele expressed as low or even absent TPMT activity. These patients are at greatest risk of myelosuppression. Approximately 15 percent of the patient population is heterozygous for variant alleles; they are likely to have intermediate TPMT enzymatic activity, with moderate risk of myelosuppression with thiopurine therapy. Four common variant alleles (TPMT*2, *3A, *3B, and *3C) account for 80 percent to 95 percent of individuals with below normal TPMT activity; however the frequency of these alleles varies among Caucasians, Asians, and Africans.

Until recently, the recommended starting dose of either AZA or 6-MP did not take into account patients with very low or absent TPMT activity. The initial doses range from 1.0 to 2.5 mg/kg/day for AZA, and 0.75 to 1.25 mg/kg/day for 6-MP. It has been proposed that patients with either intermediate or low to absent TPMT activity may benefit from lower initial doses.

Various clinical guidelines recommend measuring TPMT enzymatic activity or screening for TPMT alleles before starting patients on thiopurine drugs. However, the evidence base for these recommendations is unclear. It is also unclear whether one or both of the tests, TPMT genotyping or enzymatic activity (phenotyping) should be used to determine TPMT status before thiopurine treatment initiation. As such, there is a need to review the current literature regarding the assessment of TPMT status prior to administration of thiopurine drugs, to determine if pretreatment TPMT testing reduces drug-related toxicity. The population of interest was restricted to those with chronic autoimmune disease, as patients with malignancy or organ transplant frequently require concomitant treatments of similar toxicity profile.

This evidence report was commissioned by the Agency for Healthcare Research and Quality (AHRQ) to address the following of questions about TPMT genotypic and phenotypic testing methodology, their comparative diagnostic accuracy, effectiveness of pretreatment testing, association with drug toxicity, and costs involved.

Key Questions

KQ1. In terms of the analytical performance characteristics of enzymatic measurement of TPMT activity and determination of TPMT allelic polymorphisms:

  1. What are the preanalytical requirements for enzymatic measurement of TPMT and determination of TPMT allelic polymorphisms? (e.g. specimen types and collection procedures, lab transportation, interference of coadministered drugs, patient preparation and identification etc.)
  2. What are the within and between laboratory precision and reproducibility of the available methods of enzymatic measurement of TPMT and determination of TPMT allelic polymorphisms (proficiency testing)?
  3. What is the diagnostic sensitivity and specificity of TPMT allelic polymorphism measurement compared to the measurement of TPMT enzymatic activity in correctly identifying chronic autoimmune disease patients eligible for thiopurine therapy with low or absent TPMT enzymatic activity? How do effect modifiers (e.g. underlying disease prevalence and severity, different activity thresholds, Hardy-Weinberg equilibrium, number and types of alleles tested) explain any observed heterogeneity in sensitivity and specificity?
  4. Are there any postanalytical requirements specific to measurement of TPMT enzymatic activity or TPMT allelic polymorphism measurement? (e.g. timely reporting of data, reference intervals, immediate or reporting within a time-frame, highlighting of extreme results)

KQ2. Does the measurement of TPMT enzymatic activity or determination of TPMT allelic polymorphisms change the management of patients with chronic autoimmune disease when compared with no determination of TPMT status?

KQ3. In chronic autoimmune disease patients prescribed thiopurine-based drugs (AZA or 6-MP), does the assessment of TPMT status to guide therapy, when compared with no pretreatment assessment, lead to:

  1. reduction in rates of mortality, infection, hospitalization, withdrawal due to adverse events (WDAE), serious adverse events (SAE) and improvement in health-related quality of life?
  2. reduction in rates of myelotoxicity, liver toxicity, and pancreatitis?
  3. In the absence or inconclusiveness of evidence answering key question 3a and/or 3b above, is there an association between TPMT status (as determined by TPMT enzymatic activity and/or TPMT allelic determination) and/or the following amongst chronic autoimmune disease patients treated with thiopurines?
    1. the clinical outcomes of mortality, infections, hospitalization, WDAE, SAE and health-related quality of life?
    2. surrogate outcomes of myelotoxicity, liver toxicity, and pancreatitis?

KQ4. What are the costs of determining TPMT enzyme activity and/or genotyping for patients with chronic autoimmune disease being considered for thiopurine-based therapy (e.g., costs of testing, costs of care, and costs of treating drug-associated complications)?

Methods

Search Strategy

The following databases were searched: Ovid MEDLINE® 1950 to May Week 3 2010; The Cochrane Library® (CLIB 2009 3) including CENTRAL, CDSR, DARE, HTA, and NHSEED; BIOSIS® May 6 2009; EMBASE® 1980 to 2010 Week 21; Genetics Abstracts: May 7 2009; and Ovid Healthstar 1966 to April 2010. EconLitTM was searched May 7 2009 for the economic question (Key Question 4).

Study Selection

English language records of any study design in chronic autoimmune disease populations were included. Effectiveness studies of testing prior to treatment were restricted to comparative experimental or observational designs.

Outcomes included determinants of preanalytic variability and proficiency of TPMT genotypic and phenotypic (enzymatic activity) testing; diagnostic accuracy of genotypic testing compared with the enzymatic assay; clinical and laboratory measures of drug toxicity; and costs of both testing and drug-associated complications.

One reviewer screened abstracts to include studies, and a second reviewer independently verified exclusions. Two reviewers independently screened full-text reports, with conflicts resolved by consensus or third party adjudication. Data were extracted in standardized forms.

Risk of Bias Assessment

Standard criteria were used to assess risk of bias of individual studies, except for studies eligible for questions pertaining to TPMT testing methods (KQ 1a and 1b) and costs (KQ4), for which no assessment scales exist. Studies were assessed as good, fair or poor.

Evidence Synthesis

Evidence was synthesized qualitatively for key questions 1a, 1b and 4. Data synthesis was not possible for key questions 1d, 2, 3a and 3b due to scarcity of evidence. We therefore examined associations between thiopurine toxicity and TPMT genotype and phenotype (KQ3c). For key question 4, costing data were converted to U.S. dollars (2009) using purchasing power parities, inflated to reflect 2009 values using the consumer price index for U.S. medical care for all urban consumers.

Quantitative syntheses were undertaken with the underlying assumption that given similar doses of the drugs, differences in outcomes of thiopurine toxicity arise from differences in TPMT enzymatic activities. Because enzymatic activity or genotype are the main determinant of thiopurine toxicity, we assumed that the underlying autoimmune disease, method of genotyping or phenotyping (enzymatic activity testing), population demographics, and study design did not give rise to substantial diversity in effect estimates. We, therefore, pooled studies across these covariates to estimate diagnostic accuracy and strength of association with adverse events related to TPMT testing and status, respectively. Individual study estimates (odds ratios, or sensitivity and specificity) were pooled using DerSimonian and Laird’s random-effects model, with weighting by individual study variance and the estimated between-study heterogeneity. Data were pooled when two or more studies were in a given analysis for an outcome. Pooled estimates of diagnostic sensitivity and specificity, and odds ratios and their 95 percent confidence intervals (CIs) were calculated using CMA software (version 2.2.046). With small numbers of studies in most analyses, we could explore clinical and/or methodological diversity for very few of the preidentified covariates. When feasible, statistical heterogeneity was tested using Cochran’s Q, and reported when found to be substantial (p value for chi-squared test of heterogeneity below 0.10, and I2 above 50 percent).

For quantitative syntheses of evidence of genetic association studies for drug toxicity outcomes, a codominant model was used to pool estimates associated with noncarrier, heterozygous carrier and homozygous carrier states. Noncarrier state indicated absence of tested TPMT polymorphisms. Heterozygous carrier state indicated presence of one variant TPMT allele on one of the paired chromosomes; homozygous carrier state implied presence of one of the identical TPMT variant alleles on each one of the paired chromosomes, or presence of two different variant alleles each on one of the two paired chromosomes (the latter is also called a compound heterozygous state). Similarly, three categories of enzymatic activities were defined (high/normal, intermediate and low/absent). We compared each state with the other two genotypic or phenotypic states. The TPMT enzymatic activity assay was considered to be the reference, for the index test of genotyping of the different single nucleotide polymorphisms (SNPs). With a dichotomous index test, i.e. the presence or absence of variant alleles, investigation of implicit or explicit cut-off threshold effects was ruled out by design. Therefore, we pooled for the outcomes of test sensitivity and specificity for each set of variant TPMT alleles tested.

Rating the Strength of Evidence

Evidence of comparative effectiveness of TPMT pretesting versus no testing for the critical and important outcomes of mortality (critical), serious adverse events (critical), myelotoxicity (important), and health-related quality of life (important) was rated across the domains of risk of bias, consistency, directness and precision as high, moderate, low or insufficient.

Laboratory Survey

To augment the limited published literature to answer key questions 1a, 1b, 1c, and 1d, further data regarding the preanalytical and postanalytical requirements and performance characteristics of TPMT laboratory analyses were collected. With advice from the Technical Expert Panel, the review team decided to survey English speaking laboratories that provide TPMT analytical services. Seven laboratories were contacted. An 11-item questionnaire addressing TPMT analytical methods (e.g., sample type and handling), preanalytical requirements (e.g., specimen stability), quality control procedures, and reporting of results was administered via Survey MonkeyTM.

Results

We screened 1790 titles or abstracts and 538 full text records. One hundred and fifteen unique studies and their 21 companion reports were included. One randomized controlled trial was included; all other studies were of observational design. The majority (greater than 75 percent) of studies were rated as fair, while a substantial (37 percent) percentage of diagnostic studies were of poor design. No evidence was found to answer Key Question 1d. Sparse evidence answered Key Questions 2, 3a and 3b. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included populations.

Six of the seven laboratories invited to participate in the survey returned responses; three from Canada and three from the United Kingdom. Among the responses, yearly TPMT testing volumes ranged from 50 to 1500 allelic determinations and 600 to 19,000 enzymatic determinations.

KQ 1a. Preanalytical Requirements for TPMT Enzymatic Activity and allelic Polymorphisms Measurements

Storage conditions and study designs varied widely across 13 studies assessing the influence of storage on TPMT activity. Temperatures ranging from −85°C to room temperature, and time periods ranging from a few hours to 16 months were studied. TPMT is a stable enzyme and its activity remained constant during storage at room temperature for five days or at −20°C for three months. Storage at −80°C resulted in 15 percent of TPMT activity decrease after 16 months. All surveyed laboratories analyzed specimens of blood with EDTA anticoagulant, stored for up to eight days, at 4oC or room temperature before analysis. Other factors noted prior to testing, such as gender, age, and race did not significantly affect the TPMT enzyme activity.

Nineteen different drugs studied to date in patients being treated for autoimmune conditions had no clinically relevant inhibiting effect on TPMT activity (see the main Results section for a list of drugs). Studies showing potentially clinically significant effects were conducted in vitro, and therefore their in vivo influence on TPMT activity remains unknown.

Research suggests that younger red blood cells (RBCs) have higher TPMT activity than older RBCs, but these differences are not clinically relevant and can be avoided if the TPMT activity is expressed per grams of hemoglobin or per milliliter of packed RBCs. However, these two reporting units are not identical and results are not directly comparable.

Two studies investigated the effect of comorbid conditions on TPMT activity, including inflammatory bowel disease, autoimmune hepatitis, multiple sclerosis, myasthenia gravis, pemphigus and chronic renal failure. They reported clinically insignificant differences in TPMT activity for all diseases, except for patients with the chronic renal failure. These patients’ TPMT activity predialysis was 50 percent higher than healthy controls, but postdialysis levels dropped to levels comparable with the controls’.

No evidence was reported for patient preparation or identification. Also, no evidence was found regarding preanalytical factors influencing TPMT genotyping. However, since preanalytical requirements are commonly understood for genetic testing, previously published guidelines can be used. The Clinical and Laboratory Standards Institute (CLSI) has published guidelines covering all preanalytical requirements for collection, transportation, preparation and storage of specimens for genetic testing.

KQ 1b. Within and Between Laboratory Precision and Reproducibility of Enzymatic Measurement of TPMT and Determination of TPMT Allelic Polymorphisms

Enzymatic assays measure the S-methylation of 6-MP by TPMT to form 6-methylmercaptopurine. Initially, 6-methylmercaptopurine was measured using a radiolabel method, which was later replaced by high performance liquid chromatography (HPLC). Alternatively, 6-thioguanine (6-TG) may be used as a substrate in HPLC-based methods, which measure 6-methyl-TG. All methods used to measure the TPMT activity are highly precise and accurate. The radiolabel method reported by eight studies had interassay and intra-assay variation coefficients from 0.51 to 8.4 percent and from 0.72 to 6.8 percent, respectively. The HPLC based methods produced inter-assay and intra-assay coefficients of variation ranging from 0.2 to nine percent and from zero to 9.5 percent respectively, in 16 studies. Among surveyed laboratories, enzymatic analysis repeatability ranged from three to 10 percent within runs, and from five to 20 percent between runs.

We found only three studies that investigated TPMT genotyping test performance. Matrix-assisted laser desorption/ionization, with a time-of-flight (MALDI-TOF) mass spectrometry multiplex assay and TaqMan® 5′ nuclease assays were compared with denaturating HPLC, and 100 percent concordance was observed for 586 and 50 genotypes, respectively. The MALDI-TOF study also measured reproducibility to be in 100 percent agreement, when 10 percent of randomly selected samples of the study population were genotyped in duplicate. A novel microchip platform was compared with TaqMan® and with a conventional restriction fragment length polymorphism (RFLP) assay, resulting in 100 percent concordance.

KQ 1c. Diagnostic Sensitivity and Specificity of TPMT Allelic Polymorphism Measurement, Compared to the Measurement of TPMT Enzymatic Activity

A total of 16 studies, mostly of cross-sectional and prospective observational design, contributed to quantitative syntheses. Studies did not specifically examine diagnostic accuracy of genetic testing with the TPMT enzymatic activity test as the reference standard, so we designated the activity test to be the reference standard and genotyping to be the index test. The pooled sensitivity of the carrier genotype (i.e. homozygous plus heterozygous patients) to correctly identify all those patients with subnormal (intermediate, or low to absent) enzymatic activity was imprecise and ranged from 70.70 to 82.10 percent across the different subgroups of alleles tested (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). The pooled sensitivity of a homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was based on two studies with few homozygotes (87.10, 95 percent CI 44.30 to 98.30 percent). Meta-regression analysis did not identify any significant effect modifiers. Compared with the reference standard of TPMT enzymatic activity, the specificity of TPMT genotyping to correctly identify patients with normal/high enzymatic activities, or normal/high and intermediate enzymatic activities, was very high (greater than 90 percent) across all combinations of alleles tested.

There was insufficient data to determine the optimum combination of TPMT alleles for testing. Approximately 80 percent of the studies tested at least the TPMT *3A, *3B, and *3C or TPMT *2, *3A, and 3C variant alleles, irrespective of testing additional polymorphisms.

Among the surveyed laboratories, reported concordance between enzymatic analysis genotyping ranged from 60 percent to 100 percent.

KQ 2. Knowledge of TPMT Status and Change in Management

Evidence from one randomized controlled trial in 333 patients with chronic inflammatory conditions of whom only one patient was homozygous for a variant allele suggests that physician azathioprine prescribing practice may not entirely be guided by pharmacogenetic testing. Cautious prescribing is adopted by physicians regardless of pre treatment genotyping results. No significant differences could be observed between the prethiopurine tested and nontested groups in azathioprine starting doses or mean doses at the end of the study period, however, heterozygotes received lower doses compared with noncarriers in the group pretested before therapy.

KQ 3a and 3b. Knowledge of TPMT Status to Guide Therapy

Table 1Rating the strength of evidence

Pretreatment genotyping to guide thiopurine treatment vs. thiopurine treatment without pretesting
OutcomeN of studiesN of SubjectsDomains pertaining to strength of evidenceOR (95% CI)Strength of evidence
Risk of BiasConsistencyDirectnessPrecision
Mortality1 RCT1333MediumUnknownDirectImprecise0.33 (0.03 to 3.18)Insufficient
Serious adverse events1 RCT1333MediumUnknownDirectImprecise0.48 (0.14 to 1.64)Insufficient
Health- related quality of life00-----Insufficient
Myelotoxicity00-----Insufficient
Applicability of evidenceThere is limited applicability of evidence for the outcomes of mortality and serious adverse events since there was just one homozygous carrier of TPMT variant allele in the entire sample of mostly IBD patients observed for just 4 months. Also, patients likelier to experience adverse events were excluded during the screening phase

Abbreviations: RCT = randomized controlled trial

Evidence comparing efficacy of prior TPMT status determination with no pretesting from one fair quality randomized controlled trial and a poor quality retrospective cohort study demonstrated no significant differences in the outcomes of leukopenia, neutropenia and pancreatitis, while significantly higher odds were observed for hepatitis in the group randomized to prior TPMT genotyping, odds ratio 2.54 (95 percent CI 1.08 to 5.97). Other intermediate outcomes were not reported.

KQ 3c. Association Between TPMT Status and Thiopurine Toxicity

TPMT enzymatic activity. Among 15 studies, mostly cross-sectional in design, quantitative syntheses demonstrated a dose response relationship associating subnormal TPMT enzymatic activities with leukopenia and myelotoxicity. In comparison with normal enzymatic activity, greater odds of leukopenia were noted with low enzymatic activity (OR 80.00, 95 percent CI 11.5 to 559), than intermediate activity (OR 2.96, 95 percent CI 1.18 to 7.42). Greater odds of myelotoxicity were also noted with low activity when compared with intermediate (OR 10.20, 95 percent CI 2.23 to 46.60) and normal (OR 13.60, 95 percent CI 3.52 to 52.80) TPMT enzymatic activities.

Pooling of the few small studies with events for the outcomes of withdrawal due to adverse events, anemia, hepatitis or elevated hepatic transaminases and pancreatitis, revealed no significant associations.

No evidence was available for the outcomes of mortality, hospitalization, serious adverse events, and health related quality of life. The sparse data available for the outcomes of infection, neutropenia and thrombocytopenia did not permit a meaningful synthesis.

TPMT genotype. Thirty studies contributed to quantitative syntheses. A dose response relationship was suggested between TPMT genotypic status and leukopenia. In studies testing TPMT *2, *3A, *3B, and * 3C, plus/minus additional genetic variants, homozygosity for a variant TPMT allele yielded the highest odds ratio for leukopenia (18.60, 95 percent CI 4.12 to 83.60) compared with noncarrier status, while heterozygous patients experienced lower, but still significantly increased odds (4.62, 95 percent CI 2.34 to 9.16) compared with noncarriers. However, with only 6 homozygous participants, direct comparison with heterozygous carriers did not yield statistically significant results.

For all other outcomes of mortality, hospitalization, serious adverse events (SAE), health related quality of life (HQOL), neutropenia, infection, withdrawal due to adverse events, myelotoxicity, anemia, thrombocytopenia, hepatitis or elevated hepatic transaminases, and pancreatitis, evidence was either absent, insufficient or lacked power to demonstrate significant differences between heterozygous and homozygous carriers in comparisons with noncarriers, and between themselves.

KQ 4. Costs of TPMT Testing, Costs of Care, and Costs of Treating Drug-Associated Complications

Eleven studies reported data on the costs of determining TPMT activity and/or genotyping for patients with chronic autoimmune disease being considered for thiopurine therapy. The studies were conducted in Canada, United States, New Zealand, Europe (Italy, Scotland, United Kingdom, Spain), and Korea. All data were converted into U.S. dollars (2009).

Eight studies reported 11 cost estimates for TPMT genotyping, which were obtained from public and private laboratories or hospitals. The cost of obtaining a test per patient ranged from $29.43 to $617.80, with the highest cost being reported by a private laboratory. Excluding the cost from the private laboratory, the average cost for the genotype test per patient was $89.94.

Four studies reported five cost estimates for the TPMT enzymatic analysis, which were also from laboratories or hospitals. The cost of obtaining a test per patient ranged from $46.36 to $320.98 and the source for the highest cost was not reported. Excluding the highest costing item, the average cost for the TPMT phenotype test per patient was $53.13.

Seven studies reported eight cost estimates for treating AZA related complications. The costs were obtained from hospitals and governmental agencies. The one-time cost of adverse events associated with AZA ranged from $1,366.82 to $7,110.02 USD (2009), with an average of $4,019.29. One study reported two cost estimates for the average cost per identified TPMT-deficient individual, with an average of $11,848.51.

Conclusions

There is currently insufficient evidence regarding effectiveness of determining TPMT status prior to thiopurine treatment in terms of improvement in clinical outcomes and incident myelotoxicity in comparison with routine monitoring of full blood counts and adverse events. It is also unclear whether pretesting guides appropriate prescribing. Indirect evidence confirmed previously known strong associations between lower levels of TPMT enzymatic activity and the presence of TPMT variant alleles with thiopurine related leukopenia. Sufficient preanalytical data were available to recommend preferred specimen collection, stability and storage conditions for determination of TPMT status. There was no clinically significant effect on TPMT activity of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). The available methods for determination of TPMT enzymatic activity showed good precision, with coefficients of variation generally below 10 percent. Based upon limited evidence, the reproducibility of TPMT allelic polymorphism determination is acceptable. However, the sensitivity of genetic testing to identify patients with low or intermediate TPMT enzymatic activity is imprecisely known. Thus, if knowledge of TPMT status is desired and there has been no recent transfusion of RBCs, with the current evidence enzymatic assay (phenotyping) rather than allelic polymorphism determination is preferred. Enzymatic assay will capture effects of other polymorphisms that are not detected by genotyping the common alleles; laboratories tend to use genotyping as a confirmatory test for low TPMT activity. The average cost of TPMT phenotyping was approximately half of the average cost of TPMT genotyping, but these costs may not be generalizable to all TPMT tests. More research has been conducted examining TPMT genotyping but the cost estimates are heterogeneous, likely due to different methodological choices.

Remaining Issues

There is insufficient evidence examining the effectiveness of TPMT pretreatment enzymatic or genetic testing, to minimize thiopurine related toxicity in patients with chronic autoimmune diseases. As a priority, well powered, good quality, randomized controlled studies need to be conducted, in diverse and representative patient populations, to compare the effectiveness of TPMT genotyping and phenotyping with one another, and with no TPMT testing. These studies should be large enough to include a sizable number of patients homozygous for the variant alleles and should be pragmatic in conduct, mimicking routine clinical practice. Outcomes would include both treatment efficacy and harms associated with thiopurine therapy. Another objective would be to establish the optimum initial dose adjustment for a given TPMT status. These studies should ensure that outcomes are truly assessed without prior knowledge of results of TPMT testing and administered drug dose, by employing appropriate blinding procedures. The recently concluded pragmatic TARGET study by Newman and associates was under-powered to detect differences in clinically important outcomes, largely because it faced recruitment problems. In future such recruitment problems may be mitigated by educating the public and clinicians that the evidence base for pretreatment TPMT testing is lacking and that it is unclear whether pretreatment testing does more good (i.e. reduction in thiopurine related toxicity) than harm (i.e. reduction in thiopurine efficacy because of overzealous dose reductions based on prior testing).

Until such experimental high quality evidence becomes available, alternative evidence may be sought in prospectively designed observational studies that estimate health related quality of life, drug prescription patterns, and myelotoxicity related mortality as important outcomes associated with and with no pretreatment TPMT testing. With availability of empiric evidence from such studies, decision-analytic modeling that comprehensively consider alternative strategies such as regular blood cell count and liver enzyme testing, metabolite monitoring, and dose adjustments for concomitant medications that impact the TPMT enzymatic pathway can help guide practice until evidence becomes available from well powered pragmatic trials. Subsequent models might also need to consider new information as technologies develop and knowledge evolves.

TPMT genotyping should test for the most common TPMT polymorphisms in the population of interest. There is little direct evidence identifying the optimum set of alleles to be tested, and this may need to be established for specific populations if TPMT genotyping turns out to be effective in future studies.

TPMT activity analyses are reported on one of two bases: per milliliter of packed red blood cells; or per gram of hemoglobin. These are not readily or exactly comparable. Common reporting units are needed, as well as cutoffs for low/absent, intermediate, normal TPMT enzymatic activity, and high enzymatic activities.

Future studies should clearly report numbers of uninterpretable or equivocal test results.

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