Table C-20KQ 3c: Association between TPMT enzymatic activity and thiopurine toxicity – summary data

StudyOutcomes and definitionLow activityIntermediate activityNormal activityIntermediate vs. normalLow vs. intermediateLow vs. normal
n with eventsn without eventsn with eventsn without eventsn with eventsn without eventsOdds ratio (95% CI)
Ansari, 200229Neutropenia

Neutrophil count <2.0 X 109 cells
001919510.56 (0.61, 183.38)
Czaja, 200648WDAE

Included a range of side effects (thrombocytopenia, leukopenia, pancytopenia, nausea and vomiting, malaise and opportunistic infection) that treating physician deemed severe enough to end treatment
012109641.42 (0.27, 7.56)1.4 (0.04, 45.68)2.26 (0.09, 59.69)
Firooz, 200849WDAE

NR
00110131140.88 (0.1, 7.41)
Hepatitis

>3 fold increase of the upper limit of normal liver enzymes after 10 days
00110101171.17 (0.14, 10.09)
Pancreatitis

NR
0001111263.67 (0.14, 95.24)
Leukopenia

NR
0001111263.67 (0.14, 95.24)
Anemia

NR
0001111263.67 (0.14, 95.24)
Gisbert, 200650Pancreatitis

Abdominal pain present and serum amylase >3 times upper normal limit
00028113550.54 (0.03, 9.44)
Myelotoxicity

NR
00424133534.53 (1.37, 14.94)
Hepatitis

Transaminases two times higher than normal values
00004362
Hindorf, 200632Hepatitis

Included all types of hepatotoxic reactions
06441152981.94 (0.61, 6.12)0.71 (0.03, 14.78)1.48 (0.08, 27.51)
Pancreatitis

NR
06243133001.07 (0.23, 4.92)1.34 (0.06, 31.12)1.71 (0.09, 31.99)
Myelotoxicity

Included all types of haematological toxicity (anemia, leukopenia, neutropenia, thrombocytopenia)
33342222910.94 (0.27, 3.29)14 (1.93, 101.72)13.23 (2.52, 69.43)
Kader, 200051Leukopenia

WBC <4000/mm3
001111919 (0.62, 583.42)
Hepatitis

Aminotransferases >2 times normal
00112189 (0.39, 206.54)
Lennard, 198952Leukopenia

NR
410501133 (1.06, 1023.62)69 (2.35, 2028.86 )
Thrombocytopenia

NR
320501115.4 (0.56, 425.55)32.2 (1.23, 841.87)
Anemia

NR
410501133 (1.06, 1023.62)69 (2.35, 2028.86 )
Myelotoxicity

NR
320501115.4 (0.56, 425.55)32.2 (1.23, 841.87)
Okada, 200537Leukopenia

WBC <2300/mm3
00122133.25 (0.19, 54.78)
Schedel, 200653Myelotoxicity

Pancytopenia (not defined)
031271642.37 (0.14, 39.3)2.62 (0.09, 77.58)6.14 (0.21, 179.81)
Leukopenia

NR
2122606512.36 (0.57, 266.16)26 (1.58, 426.87)218.33 (6.99, 6815.05 )
Shah, 200854WDAE

NR
NRNR111181010.51 (0.06, 4.2)
Snow, 199539Hepatitis

Raised aspartate transaminase and alanine transaminase
00051201.24 (0.04, 34.93)
Leukopenia

NR
002312013.33 (0.91, 196.38)
Stassen, 200940Leukopenia

NR
003434671.48 (0.31, 6.98)
Thrombocytopenia

NR
00078930.73 (0.04, 13.98)
Anemia

NR
003430711.78 (0.37, 8.42)
Stocco, 200541Hepatitis

Alanine aminotransferase, gamma-glutamyl transferase or alkaline phosphatase >2 times normal levels
0003025
Pancreatitis

Severe abdominal pain accompanied by serum amylase level >2 times normal levels
00031242.33 (0.08, 69.29)
Myelotoxicity

Leukopenia (WBC <3000/mm3) and/or thrombocytopenia (platelets <100,000/mm3)
00033220.92 (0.04, 21.86)
Stolk, 199855Any infection

Upper airway infection
00170249.8 (0.36, 266.64)
Hepatitis

NR
00171233.29 (0.18, 59.6)
Myelotoxicity

Pancytopenia
00081230.92 (0.03, 24.87)
von Ahsen, 200543WDAE

Withdrawal from study for whatever reason
0014718323.56 (1.21, 10.42)
Hepatitis

Aspartate or alanine aminotransferase >=2 times upper limit of reference interval
001202481.2 (0.1, 14)
Pancreatitis

Upper abdominal pain accompanied by pancreatic amylase or lipase >=2 times upper limit of reference interval
001201492.45 (0.15, 41.11)
Myelotoxicity

Myelosuppression (leukocyte count <2.5x109/L or platelet count <100x109/L)
00021040
Winter, 200744Hepatitis

Deranged liver function tests
0111581050.88 (0.1, 7.5)3.44 (0.09, 127.7)4.14 (0.16, 109.52)
Pancreatitis

NR
01115011321.97 (0.86, 563.38)3.44 (0.09, 127.7)
Leukopenia

Mild leukopenia (WBC 2–3 x109/L) and severe leukopenia (WBC < 2 x109/L)
1011581050.88 (0.1, 7.5)31 (0.84, 1149.3)37.24 (1.41, 985.68)

Abbreviations: CI = confidence interval; n = number; NR = not reported; WBC = white blood cell count; WDAE = withdrawal due to adverse events

From: Appendix C, Evidence Tables

Cover of Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs
Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs.
Evidence Reports/Technology Assessments, No. 196.
Booth RA, Ansari MT, Tricco AC, et al.

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