Autologous stem cell transplantation with low-dose cyclophosphamide to improve mucosal healing in adults with refractory Crohn’s disease: the ASTIClite RCT
Lindsay JO., Hind D., Swaby L., Berntsson H., Bradburn M., Bannur C U., Byrne J., Clarke C., Desoysa L., Din S., Emsley R., Foulds GA., Gribben J., Hawkey C., Irving PM., Johnson P., Kazmi M., Lee E., Loban A., Lobo A., Mahida Y., Moran G., Papaioannou D., Parkes M., Peniket A., Pockley AG., Satsangi J., Subramanian S., Travis S., Turton E., Uttenthal B., Rutella S., Snowden JA.
UnlabelledSome 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.BackgroundTreatment-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.ObjectivesThe 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.DesignTwo-arm, parallel-group randomised controlled trial with a 2 : 1 (intervention : control) allocation ratio.SettingNine NHS trusts (eight trusts were recruitment sites; one trust was a treatment-only site).ParticipantsAdults with treatment-refractory Crohn’s disease, for whom surgery was inappropriate or who had declined surgery.InterventionsThe intervention treatment was HSCTlite using cyclophosphamide, and the control was any current available treatment for Crohn’s disease, apart from stem cell transplantation.Main outcomesThe 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.ResultsThe 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 ConclusionsWithin 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.LimitationsThe 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 workOwing 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 registrationThis trial is registered as ISRCTN17160440 and EudraCT 2017-002545-30.FundingThis 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.