Autologous stem cell transplantation with low-dose cyclophosphamide to improve mucosal healing in adults with refractory Crohn’s disease: the ASTIClite RCT

Abstract

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 18.5 kg/m2). Have received a diagnosis of CD using colonoscopy, histology and/or radiology. Have had a disease duration of at least 6 months. Have a disease distribution accessible to endoscopic assessment (jejuno-ileal, ileo-caecal or colonic). Have had active clinical CD activity with impaired quality of life at any time within 3 months prior to randomisation into the trial, as assessed by a gastroenterology clinician. Be refractory or intolerant to azathioprine, mercaptopurine or methotrexate. Be refractory or intolerant to at least two classes of biologic therapy [currently anti-tumour necrosis factor (TNF) therapy, vedolizumab (Entyvio, Takeda UK Limited, London, UK) or ustekinumab (Stelara, Janssen Pharmaceuticals, New Brunswick, NJ, USA)] despite dose optimisation. Be considered unsuitable for surgery or have had surgery declined. Have endoscopic evidence of active disease in screening [Simple Endoscopic Score for Crohn’s Disease (SES-CD) ulcer size subscore of ≥ 2 in at least one segment]. SES-CD will be used as standard for patients with disease in the ileum and/or colon. Should the disease be only proximal to the ileum, the SES-CD would still be used to score the relevant bowel segment. Have undergone a satisfactory European Society for Blood and Marrow Transplantation. Autoimmune Disease Working Party-recommended screening assessment prior to HSCT. Be willing to discontinue all immunosuppressant medication after randomisation if allocated to the HSCT arm. Be, in the opinion of the Trial Management Group (TMG), fit enough to undergo treatment. Participants were ineligible if any of the following conditions were met: Have received a diagnosis of ulcerative colitis or indeterminate colitis. Have no evidence of active CD on screening endoscopic assessment. Have strictures that prevent assessment for endoscopic active disease. Have undrained perianal fistulae (patients with previous perianal disease or perianal disease adequately drained with a seton in situ were eligible). Presence of undrained perianal sepsis on screening pelvic [magnetic resonance imaging (MRI) scan, or computerised tomography (CT) scan if MRI was contraindicated]. Have evidence of intra-abdominal sepsis on abdominal MRI (or CT scan if MRI scan was contraindicated). Have an active or latent mycobacterial infection. Have had prior exposure to hepatitis B virus, hepatitis C virus or human immunodeficiency virus (HIV). Have evidence of an enteric or systemic infection. Be pregnant or breastfeeding, or planning pregnancy within the study duration. The possibility of current pregnancy was to be ruled out with a pregnancy test at the screening assessment. Be unwilling to use adequate contraception (if appropriate) until at least 12 months after the last dose of study drug. Have a contraindication to the use of cyclophosphamide, fludarabine, filgrastim or rabbit anti-thymocyte globulin (Thymoglobulin, Sanofi UK, Reading, UK). Have a significant medical comorbidity that precludes HSCT, as adjudicated by the TMG. Have significant psychiatric comorbidity. Have significant language barriers likely to affect their understanding of the study or their ability to complete outcome questionnaires. Be participating in another interventional clinical trial. Be considered medically unfit for HSCT as defined by any of the following criteria – Renal: creatinine clearance of 6.7 kPa. Forced expiratory volume or forced vital capacity of 1.0 × 109/l for two consecutive days. Participants randomised to the usual-care arm continued with conventional, biologic or nutritional therapy for the management of CD, until the primary end point was assessed. Follow-up Participants were followed up at 8, 14, 24, 32, 40 and 48 weeks. Day 0 of the follow up was the date of stem cell reinfusion for HSCT arm participants and day 49, post randomisation, for usual-care arm participants to align the timelines in both groups. Main outcome measures The primary outcome was treatment success at week 48, defined as mucosal healing [no endoscopic ulceration (SES-CD ulcer subscore of zero, assessed by central readers blind to allocation and time of assessment)] without surgery or death. Key secondary outcomes included clinical remission using the Crohn’s Disease Activity Index (CDAI), the Harvey–Bradshaw Index and patient-reported outcomes; SES-CD at week 48; change in CDAI SES-CD between baseline and week 48; assessment of safety through reports of AEs and SAEs; patient-reported quality of life; and healthcare resource use. Mechanistic outcomes included analysis of re-engraftment. Results The trial was halted because of unexpected SAEs after 23 patients (HSCT arm, n = 13; usual-care arm, n = 10) had been randomised. Patients had advanced disease [mean (standard deviation) CD duration 13.8 (7) years, mean CDAI at baseline 337.5 (182.4)], with 20 (91%) having undergone at least one resection and nine (41%) having a stoma (these figures are calculated based on the 22 participants in the intention-to-treat population, as opposed to the 23 participants randomised). Of the 13 participants randomised to receive HSCTlite, three withdrew before transplantation, 12 reached mobilisation, and 10 went on to receive stem cell reinfusion. Of the 10 usual-care arm participants, eight received medications specifically to treat CD (including biologic therapies and corticosteroids), one underwent surgery for CD (small bowel resection) and one withdrew. All patients contributed to the safety analysis, and 10 patients who completed HSCT and nine patients receiving usual care contributed to the efficacy analyses. The primary outcome using central reading was available for 7 out of 10 HSCT and six out of nine usual-care patients at week 48. Absence of endoscopic ulceration without surgery or death (at 48 weeks) was reported in three out of seven (43%) HSCT patients, compared with zero out of six (0%) usual-care patients. Centrally read SES-CD scores [mean (SD)] 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. Centrally read change in SES-CD fell by 6.4 (4.3) in HSCT patients, whereas it increased by 7.5 (3.5) in usual-care patients. Clinical remission (CDAI < 150) occurred in 57% and 17% of patients in the HSCT and usual-care arms, respectively, at week 48. Serious adverse events were more frequent in patients undergoing HSCT [38 in 13 (100%) patients] than in those who received usual care [16 in 4 (40%) patients]. Importantly, nine suspected unexpected serious adverse reactions (SUSARs) were reported in six HSCT patients, including three cases of delayed renal failure due to proven thrombotic microangiopathy (TMA). Two patients in the HSCT arm died (one from pulmonary venous occlusive disease at week 24 and one from infection and renal failure (not proven to be TMA) at week 60 after trial completion. There was a marked difference in the profile of all the immune cell subsets studied between the HSCTlite and usual-care arms after HSCT. Of all the subsets studied, only the numbers of CD3+CD8+CD31+ recent thymic emigrant cytotoxic T helper cells, CD3+CD8+CD49d+α4integrin+CCR9+ gut-homing cytotoxic T cells, CD3+CD4+CD45RA-CCR7–effector memory T helper cells and CD8+ cytotoxic T cells had returned to equivalence with the usual-care arm at week 48, with levels of CD3+, CD4+, CD4+ recent thymic emigrants, CD3+CD4+CD45RA–CCR7+ central memory T helper cells, CD4+ effector T helper cells and CD3+CD4+CD45RA+CCR7+ naive T helper cells remained lower in the HSCTlite arm than in the usual-care arm. After in vitro stimulation, CD4+ and CD8+ lymphocytes from HSCT patients expressed higher levels of Th1 and Th17 cytokines [i.e. IFN gamma, TNF, interleukin (IL) 17] as well as Th2 cytokines (i.e. IL-4) than did lymphocytes from usual-care participants at most time points. Conclusion The ASTIClite trial was designed to assess the efficacy and safety of autologous stem cell transplantation in patients with treatment-refractory CD using a mobilisation and conditioning regimen with lower doses of cyclophosphamide than previously assessed.17 Central reading of the endoscopic primary end point was used, as it was not possible to blind patients or investigators to treatment allocation. The trial was halted early because of several SUSARs and one patient death. Several patients undergoing HSCT experienced marked improvement in endoscopic disease activity with associated improvement in general and disease-specific quality of life. However, the large number of adverse events, including three cases of biopsy-proven TMA and one case of pulmonary venous occlusive disease, preclude the use of this regimen in future clinical practice. Further research is required to identify the optimal treatment for this population with refractory CD, which is associated with poor quality of life and significant morbidity. Trial registration This trial is registered as Current Controlled Trials ISRCTN17160440 and EudraCT 2017-002545-30. Funding This award was funded by the Efficacy and Mechanism Evaluation 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.

Keywords

• crohn’s disease
• autologous haematopoietic stem cell transplant
• randomised controlled trial