Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Abstract

Summary Background Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC). Results Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05). Conclusions Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.

A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients

“…The total rate of adverse events was relatively low for both tioguanine‐ (35 per 100 patient years) and LDTA‐ (37 per 100 patient years) treated patients. Simsek et al showed in a retrospective cohort of 274 tioguanine‐treated patient with 1567 patient‐years of follow‐up an adverse events rate of 12 per 100 patient years 19 . However, in this cohort, the median treatment duration was 51 months (IQR 36‐89).…”

“…For LDTA, a prospective (n = 74) and retrospective (n = 89) cohort of LDTA patients with prior failure to conventional thiopurines showed a discontinuation rate of 15% and 18% due to adverse events, respectively 17,18 . A retrospective cohort study of tioguanine‐patients conducted in the Netherlands showed a lower rate of adverse events requiring discontinuation (11%) 19 . However, in a systematic review of 353 tioguanine‐treated patients with median follow‐up between 3 and 22 months, approximately 20% discontinued treatment, mostly due to adverse events 20 .…”

“…The effectiveness of tioguanine and LDTA was comparable after 2 years of treatment in our cohort (tioguanine: 33% vs LDTA: 23% P = 0.172 in surgery‐, biological‐ and corticosteroid‐free clinical remission). In literature, a number of cohorts have reported a sustained effect of tioguanine ranging between 22% and 60% after 12 months of treatment 19 . For LDTA, a randomised controlled trial (n = 73) has shown that LDTA achieved a corticosteroid‐free clinical remission rate of 53% after 24 weeks 24 .…”

“…For tioguanine more research is needed on this subject. Simsek et al described that a 6‐TGN concentration of >682 pmol/8 × 10 8 red blood cell count was associated with clinical effectiveness in tioguanine‐treated patients, however, other studies are needed to confirm these findings 19 . Furthermore, no information is available on 6‐TGN levels which correlate with tioguanine‐associated toxicity.…”

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients

“…Up to 50% of the azathioprine or mercaptopurine using patients discontinue treatment with these drugs, mainly due to adverse events [4]. Thioguanine (TG), an equally effective but better-tolerated thiopurine-derivative, has been proposed as an alternative treatment option for patients who failed previous traditional therapies [5][6][7].…”