Appeal type: Experimental/Investigational
Decision: Upheld Decision of Health Plan

Physician 1: The patient is a 19-year-old male who consulted his gastroenterologist for a second opinion regarding his diagnosis and treatment of Crohns disease. The disease is said to involve the terminal ileum by small bowel x-ray. The patient had previously been found to have perianal swelling, though the only note regarding the physical examination indicates a rectal exam was deferred. At the time of the second opinion the patient was taking Asacol, Flagyl, Imuran (azathioprine), and prednisone. The gastroenterologist recommended the patient undergo Prometheus-PRO-Predict TPMT Genetics testing. The Health Plan has declined coverage for this test on the basis that there is insufficient scientific evidence demonstrating how 6-MP genotype analysis will impact the patients management or clinical outcomes. At issue in this case is the clinical utility of TPMT testing. In the case of this patient, his gastroenterologist has requested a specific commercial and proprietary package of tests including TPMT genetics. Sometimes TPMT activity is tested directly in other laboratories. The ability to make these determinations is not in question, but their utility is the subject of controversy. The controversy is the subject of some debate and was addressed at the American Gastroenterological Associations meeting on inflammatory bowel disease in San Diego, California in January 2005. The use of thiopurine methyl transferase (TPMT) activity measurements of TPMT genetics in routine clinical practice has been reviewed (Bonis and MacDermott). The reviewers noted it is important to emphasize that patients with normal TPMT status can still have severe toxicity. The reviewers stated, Thus, a normal screening test does not preclude toxicity. Furthermore, those with high TPMT activity may be predisposed to forming potentially hepatotoxic levels of 6-MP possibly increasing the risk for hepatotoxicity with an aggressive dosing regimen. It was the conclusion of the reviewers that the safety and efficacy of these approaches are unproven. Those who believe that TPMT activity or genetic testing is useful argue with using larger starting doses of either mercaptopurine or azathioprine. The majority, who argue that testing is not helpful, point to the fact that testing does not guarantee safety. Therefore, they start with smaller doses, follow liver tests and CBC, and increase the dose slowly. This patient is already taking azathioprine without toxicity. If he had absent TPMT activity that would have been manifest at this point. There is no argument made that a very rapid dose escalation to very high levels is required or desirable. Therefore, genetic testing for TPMT would not change the way that azathioprine would be administered, namely, with slowly escalating doses and careful monitoring of the patients liver tests and CBC. Therefore, I have determined that the requested test is not likely to be more beneficial for evaluation of the patients medical condition than any available standard therapy. The Health Plans denial should be upheld. Physician 2: The patient is a 19-year-old male with a history of Crohns disease. He is taking Asacol, Flagyl, Imuran and prednisone. He is having four to five bowel movements a day and some abdominal pain that is resolved by having a bowel movement. A TPMT test has been recommended by the patients provider to see if a further increase in Imuran is warranted. The Health Plan has denied coverage for the requested test on the basis it is considered investigational for evaluation of the patients medical condition. The Health Plans denial should be upheld. Use of TPMT is not the community standard. None of the major GI societies endorse this type of testing. An article by Reuther, et al. indicates large prospective studies with patient entry as the start of Aza therapy (Imuran) are needed in order to explore the applicability of TPMT testing. The current dose of 50mg of Imuran is typically a starting point and increases from this level could be safely administered by monitoring the patients CBC, liver function tests, and serum amylase and lipase. Therefore, I have determined that the requested test is not likely to be more beneficial for evaluation of the patients medical condition than any available standard therapy. The Health Plans denial should be upheld. Physician 3: The patient is a 19-year-old male with Crohns disease who has been treated with multiple medications including, Asacol, Flagyl, azathioprine, and prednisone. Despite combinations of these medications, the patient continues to have four to five watery bowel movements a day. The patient had a small bowel series, which revealed terminal ileal disease and a possible fistula. The patients gastroenterologist has recommended 6-MP and genotype analysis of the TPMT gene. The Health Plan has denied coverage for the proposed testing on the basis it is considered experimental. This patient has not responded to combination regimens of mercaptopurine (Asacol) Flagyl, azathioprine and prednisone, and continues to be symptomatic. His small bowel series demonstrates significant small bowel disease and a possible fistula. The patient needs to be tried on a higher dose of azathioprine before the treating physician decides to consider alternative therapies such as Remicade. The importance of metabolite monitoring and TPMT activity was first discovered through the research initialized in childhood acute lymphoblastic leukemia. A number of studies have demonstrated that many patients who initially failed to respond to low dose azathioprine therapy and then underwent dose escalation responded well once they achieved erythrocyte 6-TG levels greater than 250. Although there is no formal consensus among experts, most would agree that metabolite monitoring is most informative in cases in which the patients are failing a standard dose or even high dose therapy. Levels of TG can help differentiate between noncompliance, underdosing, drug resistance, and refractory cases. In cases of noncompliance or underdosing, clinicians can safely dose escalate or reintroduce the drugs. In cases of drug resistance or refractory cases, clinicians can consider alternative therapies. The patient is likely to benefit from monitoring of 6TG levels during dose-escalation to see if optimization of therapy with azathioprine improves his response before considering alternative therapies. Accordingly, I have determined that the requested test is likely to be more beneficial for evaluation of the patients medical condition than any available standard therapy. The Health Plans denial should be overturned.