Patient selection for azathioprine - typical courses of Crohn s disease

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1 Patient selection for azathioprine - typical courses of Crohn s disease remitting 44% steroid refractory 20% remitting 48% steroid refractory 21% 36% steroid dependent 31% steroid dependent Munkholm et al., Gut 1994; 35:360 Reinisch et al., Lancet 1995; 345:859

2 The evidence for thiopurines in Crohn s disease Induction of remission (Cochrane Metaanalysis) AZA 6-MP Candy 1995 Ewe 1993 Klein 1974 Rhodes 1971 Summers 1979 Willoughby 1971 subtotal 2.06 [1.25;3.39] Oren 1997 Present 1980 subtotal 3.34 [1.67;6.66] total 2.43 [1.62;3.64] 0, Peto Odds Ratio [95% CI]

3 Azathioprine / 6-Mercaptopurine in Crohn s disease Steroid sparing (Cochrane Metaanalysis) active Candy 1995 Ewe1993 Klein 1974 Present 1980 Willoughby 1971 total 3.69 [2.12;4.42] remission Rosenberg 1975 Willoughby 1971 total 5.22 [1.06;25.68] 0, Peto Odds Ratio [95% CI]

4 Azathioprine in Crohn disease Remission Maintenance (Cochrane Metaanalysis) AZA 2.5 mg/kg AZA 2.0 mg/kg AZA 1.0 mg/kg Candy 1995 Summers 1979 subtotal 4.13 [1.59;10.71] O Donoghue 1978 Rosenberg 1975 Willoughby 1971 subtotal 3.17 [1.33;7.59] Summers 1979 subtotal 1.2 [0.6;2.41] total 2.16 [1.35;3.47] 0, Peto Odds Ratio [95% CI]

5 Mucosal Healing : Azathioprine vs. Infliximab % Placebo 5 mg/kg 10 mg/kg Aza Accent I, D Haens 1999

6 Azathioprine metabolism after a dose hike 6-MMPR? TPMT AZA 6-MP 6-TIMP? 6-TGN? Remission

7 Target 6-TGN Level to Optimize Efficacy: >235 Frequency of Response 100% 80% 60% 40% 20% 0% n= % n=42 n= TGN QUARTILES 78% P< n= Dubinsky MC et al. Gastroenterol;118:2000

8 The Downside: Toxicity of 6-MP/AZA Allergic/non-dose dependent Pancreatitis GI intolerance Cutaneous Flu-like Dose-dependent Bone Marrow toxicity Hepatoxicity Malignancy

9 Azathioprine / 6-Mercaptopurine Side effects Present (n=396) % Goldstein (n=347) Pancreatitis Bone marrow Allergy 2 Hepatitis Infections Neoplasia

10 TPMT Pharmacogenetics Toxicity and Efficacy 6-MMPR TPMT AZA 6-MP 6-TIMP Myelosuppression 6-TGN

11 TPMT Phenotypic Distribution TPMT H TPMT H %of subjects TPMT L TPMT L TPMT L TPMT H (10%) 0 (1/200) Erythrocyte TPMT activity (U/ml) Weinshilboum: Am J Hum Genet, 1980

12 Crohn s Disease and Severe Myelosuppression during Azathioprine Therapy number % n=4 homozygous mutant TPMT genotype 20% n=8 n=29 heterozygous 70% wildtype Colombel et al., Gastroenterology 2000

13 Reducing the Risk of Myelosuppression through TPMT-Assay TPMT deficient , ,5 3, % 5% Present Connell 1 0 1,5 Present Connell Present 1989, Connell 1993 NNH

14 18 TPMT Polymorphisms Concordance rate of Phenotype/genotype 98.4% Schaeffeler et al. 2004

15 Azathioprine Therapy in IBD TPMT-Genotype and Stop of Treatment due to ADRs TPMT activity in RBC (nmol 6-methylthioguanine x g -1 x h -1 ) x x x x x x x x *1/*1 x x Schwab et al. Pharmacogenetics 2002 x 93 patients: leukopenia (n=2) leukopenia x *1/*3A TPMT genotype x 14 patients with ADRs: - pancreatitis - hepatoxicity - hematoxicity - abdominal pain - nausea, vormiting *1S/*3A x megaloblastic anemia *1/*3D pancytopenia x *3A/*3A

16 Methotrexate in Crohn s Disease Methotrexat 25 mg/wo. Placebo Methotrexat 15 mg/wo. 50 Remission (%) Wochen Remission induction Remission maintenance Feagan et al., NEJM 1995; 332:292 Feagan et al., NEJM 2000; 342:1627

17 Mycophenolate-Mofetil Ulcerative colitis (13) Crohn s disease (11) Remission (%) Monate Chronic active course, MMF 2g/day, remission induction with 60mg steroids Fellermann et al., Aliment Pharmacol Ther 2000; 14:171

18 No colectomy: Short term 80%, long term 50%

19 Gut, in press

20 72 Patients 6 months Azathioprine 2mg/kg vs ASA Success: Clinical + endoskopic remission and steroid weaning

21 If it were not for the great variability among individuals, medicine might as well be a science and not an art Sir William Osler 1892

22 N N N NH S O 2 N N N CH 3 Azathioprine Non-enzymatic Activation Why not use 6-Thioguanine? Methylmercaptopurine TPMT RNA TPMT 6-MP TPMT TPMT TPMT TPMT DNA

23 Major Enzymes of Thiopurine Drug Metabolism Hypoxanthine phosphoribosyltransferase (HPRT) deficient in Lesch Nyhan Syndrome widely distributed throughout the body highest activity in CNS higher in 6-MP treated leukemic children Xanthine oxidase (XO) highest activity in intestine and liver absent in circulating blood cells likely minimal intra- and inter-individual variability blocked by allopurinol Thiopurine Methyltransferase (TPMT)

24 Azathioprine Metabolism and Efficacy 6-MMPR TPMT AZA 6-MP 6-TIMP 6-TGN Remission

25 6-TGN and Efficacy *THERAPEUTIC EFFICACY MEDIAN 6-TGN MEDIAN 6-MMPR RESPONSE (106) FAILURE (72) p value < *Determined at each clinical evaluation point Dubinsky MC et al. Gastroenterol;118:2000

26 Gupta et al., 2001 P = 0.09 Little or no correlation between response and levels of 6-MP metabolites Lowry et al., 2001 Cuffari et al., 1996

27 6-Thioguanine-Nucleotide-Levels and Therapeutic Efficacy of Azathioprine 236 vs. 175 pmol Wright 2004

28 6-TGN Levels: Correlation with Clinical Efficacy Study n Setting Finding Cuffari (1996) 25 Adolescent CD 6-TGN correlates with clinical response Dubinsky (2000) 95 Pediatric IBD 6-TGN >235 * >4 months Gupta (2001) 54 Pediatric IBD NS Belaiche (2001) 24 Adult IBD NS Lowry (2001) 170 Adult IBD No correlation Cuffari (2000) 82 Adult IBD 6-TG >250 * colitis/fistula Cuffari (2001) 22 Refractory CD Dose optimization Dubinsky (2002) 51 Adult IBD 6-TGN correlate with clinical response Wright (2004) 159 Adult IBD TGN 44 (p<0.04)

29 6-TGN only helps to check compliance! 20 patients with drug compliance problems, arrow indicates relapse Wright 2004

30 mediated lymphocyte activation 6-Thio GTP Tiede et al. 2003

31 Thiopurine Metabolism AZA 6-MMP TPMT 6-MP XO 6-TU catabolism 6-MMPR TPMT HPRT 6-TIMP Apoptosis IMPDH 6-TXMP Rac GMPS 6-TGN anabolism 6-Thio-GTP 6-Thio-GDP

32 MCV the poor man s 6-TG? MCV is a simple and inexpensive alternative to 6-TGN Thomas 2003

33 Dose Escalation

34 6-TGN level (pmols/8 x 10 8 RBC) Dose Escalation and 6-TGN Levels (Dubinsky et al. 2003) 1.6 mg/kg 1.8 mg/kg?? Time 0 Time 1 Non-Responders P = 0.03 n: 37 n: 14 Time 0 Time 1 Responders

35 6-MMPR and 6-TGN Inverse Correlation 6-TGN 6-MMPR

36 Azathioprine metabolism and efficacy 6-MMPR Resistance AZA 6-MP 6-TIMP TPMT 6-TGN Remission

37 6-TGN Production Correlates with Response Median change in 6-TGN * p= Median change in 6-MMPR p= Non-Responders Responders 0 Non-Responders Responders

38 Effect of dose increases following a standard dose of azathioprine Toxicity and Efficacy mg/kg 6/11 Remission 40 on 2 mg/kg AZA 1 11 Toxicitiy (8 Myelosuppression) >2.5 mg/kg Rayner /29 Remission

39 Human TPMT Polymorphisms TPMT*1 (wild type) I II III IV V VI VII VIII IX X TPMT*2 G238C TPMT*3A G460A A719G TPMT*3B G460A TPMT*3C A719G

40 TPMT and 6-TGN Inverse Correlation 6-TGN TPMT

41 Correlation between RBC thioguanine nucleotides (TGNs) and minimum RBC TPMT activity p < 0.01 Relling et al., J Natl Cancer Inst 1999

42 TPMT and 6-TGN: inverse correlation Median 6-TGN (pmol/8x10 8 RBC) p < n=85 n=8 TPMT H /TPMT H TPMT H /TPMT L TPMT GENOTYPE Dubinsky MC et al. Gastroenterol. 2000

43 TPMT and therapeutic response TPMT < 12 TPMT > 12 TPMT Activity. Cuffari 2004

44 Slight association between leukopenia and levels of 6-MP - metabolites P = 0.03 Gupta et al., 2001

45 TPMT Pharmacogenetics Toxicity and Efficacy Hepatotoxicity 6-MMPR AZA 6-MP 6-TIMP TPMT 6-TGN

46 6-MMPR and Hepatotoxicity 6000 p < 0.05 Median 6-MMPR (pmol/8x10 8 RBC) n=157 Absent HEPATOTOXICITY n=16 Present Dubinsky MC et al. Gastroenterol;118:2000

47 No correlation between hepatotoxicity and levels of 6-MP metabolites Gupta et al., 2001

48 Importance of TPMT Polymorphisms A Safety Perspective TPMT activity 6-TGN 6-MMPR Toxicity Risk absent very high absent Severe myelosuppression intermediate high low mild to moderate myelosuppression normal to high normal to low normal to high possible hepatotoxicity super high low high hepatotoxicity

49 Analysis of TPMT activity prior to treatment initiation to improve the safety of AZA/6-MP TPMT H /TPMT H : Initiate at mg/kg/d (6-MP) or mg/kg/d (AZA) TPMT H /TPMT L : 50% normal starting dose TPMT L /TPMT L : Alternate therapies should be considered vs 10% standard dose

50 N N N NH S O 2 N N N CH 3 Azathioprine Non-enzymatic Activation Why not use 6-Thioguanine? Methylmercaptopurine TPMT RNA TPMT 6-MP TPMT TPMT TPMT TPMT DNA

51 6-Thioguanine in Crohn s Disease Study design 6-TG 40 mg/die 6-TG 80 mg/die (optional) Steroid tapering BL

52 6-Thioguanine: Clinical Efficacy % 60 CDAI Remission Response Intent-to-treat: Remission: 35%, Response: 57% 12/13 Patients achieved remission after 4 weeks Dose escalation in 12 Patients, success in only weeks Herrlinger 2003

53 6-Thioguanine in Crohn s Disease Subgroup Analysis Azathioprine Intolerance: 12/16 Patients tolerated 6-TG Azathioprin Resistance: 0/6 6-TG no effect

54 6-TG and Severe Toxicity Thrombozyten Dosisreduktion Absetzen von 6-TG AP 0 GOT GPT BL GGT weeks Patient R.W.

55

56 6-Thioguanine Nodular regenerative Hyperplasia Toxic endothelial damage of sinusoids Embolisation of these cells Ischemia and Fibrosis Hyperplastic Nodules Portal Hypertension Splenomegaly with Thrombocytopenia

57 6-Thioguanine Longterm Toxicity 123 Patients (108 investigated) 81 normal lab 27 abnormal lab Mean Treatment with 6-TG: 12.2 Months cumulative dose: mg (~40mg/Tag)) 9 biopsied 3/9 NRH 2/9 Fibrosis 14 biopsied 11/14 NRH 5/11 Fibrosis Dubinsky 2002

58 6-Thioguanine is dead

59 Conclusions If you wish to push antimetabolites to the limit: choose the 2.5 mg/kg dose the measurement of 6-TGN levels helps only to identify lack of compliance the prestart TPMT avoids only 27% of leukopenias none of the measurements is of any use to avoid other side effects like nausea or pancreatitis