Table C-25KQ 3c: Association between TPMT genotype and thiopurine toxicity – summary data

First Author, yearTPMT alleles testedOutcomes and definitionNon-carriersHomozygotesHeterozygotesHomozygotes vs. non-carriersHeterozygotes vs. non-carriersHomozygotes vs. heterozygotes
n with eventsn without eventsn with eventsn without eventsn with eventsn without eventsOdds Ratio (95% CI)
Ansari, 200828TPMT *3A, *3B, *3CWDAE

NA
66122NRNR1546.93 (2.21, 21.74)
Hepatitis

NR
8180NRNR0190.54 (0.03, 9.8)
Pancreatitis

NR
8180NRNR0190.54 (0.03, 9.8)
Leukopenia

WBC < 3500/mm3 or neutrophils < 1500/mm3
2186NRNR51433.21 (5.9, 186.88)
Hindorf, 200632TPMT *2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, *8, 10, *14, *15Hepatitis

All types of hepatotoxic reactions
152542063.33 (0.54, 20.45)0.13 (0.01, 2.41)23.4 (0.89, 613.02)
Pancreatitis

NR
132724061.04 (0.17, 6.42)0.16 (0.01, 2.99)7.22 (0.28, 189.2)
Myelotoxicity

Included all types of haematological toxicity (anaemia, leucopoenia, neutropenia, thrombocytopenia)
221833330.82 (0.15, 4.56)0.82 (0.15, 4.56)1 (0.1, 9.61)
Winter, 200744TPMT *2, *3A, *3B, * 3CHepatitis

deranged liver function tests
8111001101.39 (0.16, 12.24)
Pancreatitis

NR
1118000113.43 (0.13, 89.24)
Leukopenia

WBC < 3000/mm3
9110001101.22 (0.14, 10.65)
De Ridder, 200659TPMT*2, *3A, *3B, *3CHepatitis

Hepatotoxicity by serum alanine transaminase levels greater than twice the upper normal limit (50 IU/L) and resolution after withdrawal of AZA
0670302
Pancreatitis

Severe abdominal pain and hyperamylasemi a and resolution after withdrawal of AZA
46303022.02 (0.09, 45.36)2.82 (0.12, 68.1)
Leukopenia

Leucocyte count < 2.5x109 cells
16603116.33 (0.22, 185.33)66 (2.2, 1984.33)0.14 (0, 5.95)
Black, 199857TPMT *3A, TPMT*2Leukopenia

Low leukocyte count
0610051451 (16.35, 12442.54)
Hepatitis

Abnormal liver function test
65500151.83 (0.18, 18.41)
Ishioka, 199964TPMT*1, *2, *3A, *3B, * 3CLeukopenia

WBC<4000/mm3 & 75% before administration
429003045.89 (2.02, 1044.27)
Derijks, 200460TPMT *2, *3A, *3B, * 3CHepatitis

Hepatotoxicity - ALT>80 U/L, AST>80 U/L, bilirubins > 40 μmol/L
11901044.33 (0.12, 159.53)1.44 (0.05, 41.62)
Pancreatitis

Pancreatitis - amylase > 220 U/L, lipase > 120 U/L (elevations>2times normal upper limit)
31701041.67 (0.06, 49.95)0.56 (0.02, 12.82)
Leukopenia

Myelotoxicity (leukocyte count < 4.0 × 109/L, platelet count < 100 × 109/L)
119102239 (1.06, 1435.74)19 (1.15, 314.99)3 (0.08, 115.35)
Gearry, 200462TPMT*1, *2, *3A, 3CHepatitis

Hepatitis: elevation of serum liver transaminases greater than twice the upper limit of normal
18115010132.08 (0.08, 53.04)0.23 (0.01, 4.06)
Pancreatitis

Pancreatitis: severe abdominal pain associated with an elevation of serum amylase greater than three times the upper limit of normal
5128012117.79 (0.28, 213.81)4.65 (0.81, 26.83)1.53 (0.05, 49.8)
Leukopenia

WBC < 3000/mm3 or neutrophils < 2000/mm3
213110112157.8 (5.08, 4904.53)5.46 (0.46, 64.67)25 (0.67, 934.5)
Joji, 200366TPMT *1, *2, *3A, *3B, * 3CLeukopenia

WBC<3000/mm3
121300205.4 (0.24, 123.81)
Myelotoxicity

Pancytopenia
12400023.27 (0.1, 103.43)
Hibi, 200363TPMT *2, 3B, *3A, *3CLeukopenia

WBC < 3000/mm3
569106137.91 (1.38, 1044.73)82.8 (8.27, 828.71)0.69 (0.02, 26.91)
Corominas, 200358TPMT *2, *3A, *3B, *3C, *7, *8WDAE

NA
332003216 (1.87, 136.7)
Dubinsky, 200061TPMT *3A, *3B, *3CLeukopenia

WBC<4000/mm3
127200170.86 (0.1, 7.6)
Bezier, 200856TPMT*2, *3A, *3B, *3CAny infection (including sepsis)

Grade 1 (minor) to grade 4 (sepsis with hypotension)
92200020.47 (0.02, 10.83)
WDAE

NA
151600111.07 (0.06, 18.62)
Leukopenia

WBC <3.9 x 109/L
82300020.55 (0.02, 12.73)
Neutropenia

WMC <1.9 x 109/L
42700021.22 (0.05, 29.86)
Anemia

<109 g/L
72400020.65 (0.03, 15.16)
Reuther, 200371TPMT *3A, *3B, *3CHepatitis

Alanine transaminase levels twice the upper normal level (40 U/L)
0620004
Leukopenia

WBC less than 3x109/L
0620004
Stocco, 200541TPMT *2, *3A, *3B, *3CHepatitis

ALT, GGT or alkaline phosphatase more than twice normal levels
65900050.83 (0.04, 16.82)
Pancreatitis

Severe abdominal pain, accompanied by serum amylase level of greater than twice normal levels
46100051.24 (0.06, 26.21)
Myelotoxicity

Leucopoenia (WBC < 3000mm3) and/or thrombocytopenia (platelets < 100,000mm3)
75800050.71 (0.04, 14.15)
Zelinkova, 200678TPMT *1, *2, *3A, *3B, *3CLeukopenia

WBC < 3x10^9/L resolving after discontinuation or dose reduction
82301032081.35 (3.08, 2147.05)4.31 (1.06, 17.55)17.57 (0.59, 524.14)
Hepatitis

Hepatotoxicity - serum alanine transaminase levels greater than twice the upper normal limit (45 U/L) and resolution after withdrawal or dose reduction
9229002222.31 (0.47, 11.38)
Okada, 200537TPMT *2, *3A, *3B, *3CLeukopenia

WBC < 2300/mm3
21400117 (0.3, 162.21)
Stocco, 200774TPMT *2, *3A, *3B, *3CPancreatitis

Severe abdominal pain accompanied by serum amylase level more than twice the normal limit
65900142.46 (0.24, 25.69)
Hepatitis

NR
36400032.63 (0.11, 61.59)
Leukopenia

NR
26500033.74 (0.15, 93.79)
Thrombocytopenia

NR
16600036.33 (0.22, 185.33)
Tamori, 200775TPMT *2, *3A, *3B, *3CMyelotoxicity

Thrombocytopenia, granulocytopenia and neutropenia
17100015 (0.39, 576.73)
Marinaki, 200469TPMT *2, *3A, *3CHepatitis

Serum alanine transaminase levels greater than twice upper normal limit (50 IU/L) and resolution after withdrawal of AZA
3110001162.29 (0.22, 23.39)
Pancreatitis

Severe abdominal pain and serum amylase > 800 U/L
7106001160.95 (0.11, 8.21)
Neutropenia

Neutrophil count of <2x109 cells
10103001160.64 (0.08, 5.37)
von Ahsen, 200543TPMT *2, *3A, *3B, *3CHepatitis

Aspartate or alanine aminotransferase 2 times the upper limit of reference interval
36300051.65 (0.08, 36.2)
Pancreatitis

Upper abdominal pain with pancreatic amylase or lipase 2 times the upper limit of the reference interval
165001416.25 (0.85, 310.48)
Myelotoxicity

Myelosuppression - leukocyte counts < 2.5x109/L or platelet counts <100x109/L
0660005
Jun, 200567TPMT *2, *3A, *3B, *3C, 3D, *6Hepatitis

>= Two fold elevation of upper normal limit
18600073.84 (0.14, 102.83)
Leukopenia

WBC < 4000 mm3 and <75% before administration
167100160.74 (0.08, 6.58)
Stocco, 200442TPMT *2, *3A, *3B, * 3CAny infection (including sepsis)

Infection documented clinically or microbiologically
33700041.19 (0.05, 26.97)
Hepatitis

ALT, GGT or alkaline phosphatase more than twice their normal levels
23800041.71 (0.07, 41.54)
Pancreatitis

Severe abdominal pain, accompanied by a serum amylase level of greater than twice their normal levels
23800041.71 (0.07, 41.54)
Myelotoxicity

WBC count < 3000 cells/mm3, and platelets < 100,000/mm3
132700040.23 (0.01, 4.52)
Snow, 199539NRHepatitis

9 (Raised AST and ALT)
12000051.24 (0.04, 34.93)
Leukopenia

NR
120002313.33 (0.91, 196.38)
Tani, 200976TPMT*2, *3A, *3B, *3CWDAE

NA
185801011.05 (0.04, 27)1.05 (0.04, 27)
Leukopenia

<3000/mm3
76901013.09 (0.12, 82.76)3.09 (0.12, 82.76)
Thrombocytopenia

<100000/mm3
175010116.78 (0.47, 605.23)16.78 (0.47, 605.23)
Any infection (including sepsis)

NR
47201015.37 (0.19, 151.44)5.37 (0.19, 151.44)
Palmieri, 200770TPMT *3A, *3B, *3CPancreatitis

Upper abdominal pain with pancreatic amylase and lipase greater than twice the normal upper limit
16377020274.58 (0.21, 99.18)0.42 (0.02, 7.12)
Leukopenia

WBC <3.0 x 109/L
1737620423107.57 (4.97, 2326.61)3.85 (1.2, 12.37)26.11 (1.06, 640.27)
Hepatitis

Serum alanine transaminase increase greater than twice the upper normal limit and resolution after withdrawal or dose reduction
11382021266.65 (0.3, 146.57)1.34 (0.17, 10.75)3.53 (0.11, 111.68)
Jae Hak, 200865TPMT *1, *2, *3A, *3B, *3CLeukopenia

WBC<3.0 x 109/L
11316600523.67 (0.7, 19.26)
Schmeling, 200772TPMT *2, *3A, *3B, *3CLeukopenia

WBC <3.0x 10^9/L
448002212 (1.32, 109.34)
Hepatitis

LFT >100U/L
124000040.36 (0.02, 7.16)
Lopez, 200668TPMT*2, *3A, *3B, *3C, *3DPancreatitis

NR
525000140.24 (0.03, 2.23)
Seddik, 200373TPMT *2, *3A, *3B, *3CLeukopenia

WBC <3.0 x 109/L
66300152.1 (0.21, 21.04)
van Dieren, 200577NRHepatitis

NR
877010103.04 (0.11, 80.61)0.43 (0.02, 8.08)
Leukopenia

NR
679102836.69 (1.35, 993.86)3.29 (0.57, 19.09)10.2 (0.31, 336.95)
Thrombocytopenia

NR
08510010513 (7.4, 35584.39)63 (0.87, 4537.84)
Stassen, 200940TPMT *2, *3A, *3B, *3CLeukopenia

NR
346700341.48 (0.31, 6.98)
Thrombocytopenia

NR
89300070.73 (0.04, 13.98)
Anemia

NR
307000341.75 (0.37, 8.30)
Newman, 201045TPMT *2, *3A, *3B, *3CMortality31470101514.05 (0.48, 409.13)1.36 (0.07, 27.55)
WDAE015001015
SAE71431001557.4 (2.15, 1531.14)0.62 (0.03, 11.33)93 (1.31, 6606.26)
Hepatitis8142010155.59 (0.21, 147.71)0.54 (0.03, 9.83)
Pancreatitis41460101510.85 (0.39, 304.77)1.05 (0.05, 20.43)
Neutropenia015010015903 (13.05, 62488.75)93 (1.31, 6606.26)
Kolorz 200979TPMT *2, *3A, *3B, *3CLeukopenia1664005210 (1.77, 56.35)

Abbreviations: ALT = Alanine transaminase; AZA = azathioprine; GGT = Gamma-glutamyl transferase; L = liter; LFT = liver function test; mm = millimetre; NR = not reported; TPMT = thiopurine methyltransferase; WBC = white blood cell count; U = Unit of enzymatic activity = nanomole of product per hour; WDAE = withdrawal due to adverse events; SAE = serious adverse event

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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