Some text in this abstract has been reproduced from Lindsay J, Din S, Hawkey C, Hind D, Irving P, Lobo A, et al. OFR-9 An RCT of autologous stem-cell transplantation in treatment refractory Crohn’s disease (low-intensity therapy evaluation): ASTIClite. Gut 2021;70(Suppl. 4):A4.
Background: Treatment-refractory Crohn’s disease is characterised by chronic symptoms, poor quality of life and high costs to the NHS, and through days of work lost by patients. A previous trial of autologous haematopoietic stem cell transplant (HSCT) failed its end point of medication-free clinical remission for 3 months with no evidence of disease activity, and reported high toxicity. Subsequent studies suggest that HSCT achieves complete mucosal healing in 50% of patients, and that toxicity likely relates to the cyclophosphamide dose.
Objectives: The primary objective was to assess the efficacy of HSCTlite (HSCT with low-dose cyclophosphamide) compared with standard care for inducing regression of intestinal ulceration in patients with refractory Crohn’s disease at week 48. Secondary objectives included the assessment of disease activity, quality of life and regimen safety. Mechanistic objectives included immune reconstitution after HSCTlite.
Design: Two-arm, parallel-group randomised controlled trial with a 2 : 1 (intervention : control) allocation ratio.
Setting: Nine NHS trusts (eight trusts were recruitment sites; one trust was a treatment-only site).
Participants: Adults with treatment-refractory Crohn’s disease, for whom surgery was inappropriate or who had declined surgery.
Interventions: The intervention treatment was HSCTlite using cyclophosphamide, and the control was any current available treatment for Crohn’s disease, apart from stem cell transplantation.
Main outcomes: The primary outcome was treatment success at week 48 [mucosal healing (Simple Endoscopic Score for Crohn’s Disease ulcer subscore of 0) without surgery or death], assessed by central readers blinded to allocation and timing of assessment. Key secondary outcomes were clinical remission, Simple Endoscopic Score for Crohn’s Disease scores at week 48, change in Crohn’s Disease Activity Index scores and safety.
Results: The trial was halted owing to Suspected unexpected serious adverse events that took place after randomising 23 patients (HSCTlite arm, n = 13; usual-care arm, n = 10). Ten out of the 13 patients randomised to the HSCTlite arm received the intervention and nine (one death) reached the 48-week follow-up. In the usual-care arm 9 out of the 10 patients randomised reached the 48-week follow-up (one ineligible). The primary outcome was available for 7 out of 10 HSCTlite patients (including the patient who died) and six out of nine usual-care patients. Absence of endoscopic ulceration without surgery or death was reported in three out of seven (43%) HSCTlite patients, compared with zero out of six (0%) usual-care patients. Centrally read Simple Endoscopic Score for Crohn’s Disease scores [mean (standard deviation)] were 10.8 (6.3) and 10.0 (6.1) at baseline, compared with 2.8 (2.9) and 18.7 (9.1) at week 48, in the HSCT and usual-care arms, respectively. Clinical remission (Crohn’s Disease Activity Index scores of < 150) occurred in 57% and 17% of patients in the HSCTlite and usual-care arms, respectively, at week 48. Serious adverse events were more frequent in the HSCTlite arm [38 in 13 (100%) patients] than in the usual-care arm [16 in 4 (40%) patients]. Nine suspected unexpected serious adverse reactions were reported in six HSCTlite patients, including three cases of delayed renal failure due to proven thrombotic microangiopathy. Two HSCTlite patients died.
Conclusions: Within the limitations of reduced patient recruitment and numbers of patients assessed, HSCTlite meaningfully reduced endoscopic disease activity, with three patients experiencing resolution of ulceration. Suspected unexpected serious adverse reactions, particularly relating to thrombotic microangiopathy, make this regimen unsuitable for future clinical use.
Limitations: The early trial closure prevented complete recruitment, and the impact of the coronavirus pandemic prevented completion of some study investigations. Small participant numbers meant analysis could only be descriptive.
Future work: Owing to undetermined aetiology of thrombotic microangiopathy, further trials of HSCTlite in this population are not considered appropriate. Priorities should be to determine optimal treatment strategies for patients with refractory Crohn’s disease, including those with a stoma or multiple previous resections.
Trial registration: This trial is registered as ISRCTN17160440 and EudraCT 2017-002545-30.
Funding: This award was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership. This is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 3. See the NIHR Funding and Awards website for further award information.
Background: Crohn’s disease occurs when the gut immune system reacts to its bacterial content, causing bowel inflammation. For some patients, standard treatments for Crohn’s disease are ineffective, leading to debilitating symptoms, poor quality of life and the possibility of operations that can result in a stoma. Initial reports suggested that treatment-resistant Crohn’s disease could be improved with stem cell transplantation (haematopoietic stem cell transplant), whereby a patient’s own immune stem cells are returned to them after their current immune system is wiped out by chemotherapy.
Objectives: The ASTIClite trial aimed to test HSCT with low-dose chemotherapy (HSCTlite) to investigate whether or not this could be a safe and effective treatment for Crohn’s disease. The ASTIClite trial also looked at how HSCT works.
Methods: The ASTIClite trial was a randomised controlled trial that aimed to recruit 99 patients with treatment-resistant Crohn’s disease, across eight UK NHS centres. Patients were followed up every few weeks, and at 48 weeks we assessed whether or not HSCT was more likely to lead to healing of intestinal inflammation than standard care. Some patients experienced severe side effects, and the trial was closed early after 23 patients were recruited in view of the reported issues with the safety of the trial treatment.
Results: Because the trial was stopped early, 23 patients joined ASTIClite (HSCT arm, n = 13; usual-care arm, n = 10), which was a much lower number than originally planned. At 48 weeks, three out of seven HSCT patients had absence of ulceration, with zero out of six in the usual-care arm having absence of ulceration. Three out of six HSCT patients had disease remission, compared with zero out of three usual-care patients. All patients in the HSCT arm experienced at least one side effect (n = 38 serious side effects in total), and two patients died. In the usual-care arm, 4 out of 10 patients experienced adverse events (n = 16 serious adverse events in total).
Conclusions: Although firm conclusions are not possible because of the limited numbers of patients recruited before trial closure, it does appear that HSCT using the ASTIClite regimen reduced Crohn’s disease activity in some patients. However, the numbers of serious and unexpected side effects mean that this treatment plan would be unsuitable for future clinical use.
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