Y-ECCO Literature Review: Tommaso Innocenti

However, subsequent observations demonstrated potential advantages of HSCT in patients with refractory CD when using “more traditional” endpoints [4] and suggested that the higher intensity of cyclophosphamide for stem-cell mobilisation and conditioning may have facilitated many of the infectious adverse events (AEs) in the ASTIC population [5]. On this basis, Lindsay and colleagues sought to conduct the ASTIClite trial, to investigate the safety and efficacy of HSCT with a reduced intensity (potentially safer) conditioning regimen and a more traditional (and potentially more achievable) primary endpoint.

Methods

ASTIClite was an open-label, multicentre, two-arm, parallel, randomised controlled trial designed to investigate the safety and efficacy of autologous HSCT compared with standard of care in patients with refractory CD. Presence of significantly active CD on endoscopy [Simple Endoscopic Score for Crohn’s Disease (SES-CD) ulcer subscore of ≥2 in at least one segment] was mandatory for inclusion; other inclusion criteria were CD refractory to at least two classes of biological therapy, impaired quality of life and surgery being considered inappropriate or declined by patients. Perianal/intrabdominal sepsis, current infection and clinically significant comorbidities were exclusion criteria. Medications for CD had to be stopped according to their half-lives. Notably, eligibility had to be confirmed twice by a multidisciplinary team. After inclusion, patients were randomly assigned (2:1) to either HSCT or standard of care.

Peripheral blood stem-cell mobilisation was obtained through administration of cyclophosphamide 1 g/m2 (vs 4 g/m2 in the ASTIC trial). After stem-cell collection, the conditioning regimen included a total cyclophosphamide dose of 120 mg/kg (vs 200 mg/kg), plus rabbit anti-thymocyte globulin and fludarabine.

The primary endpoint was defined as the absence of endoscopic ulceration (assessed by central reading) without surgery or death at one year. Secondary endpoints included clinical remission and patient-reported outcomes among others. Safety endpoints were chemotherapy toxicity, including mortality. Quality of life was also assessed.

Key findings

After randomisation of 23 patients (13 in the intervention group and 10 in the control group), the trial was prematurely halted due to unexpected, serious AEs (SAEs), including the death of two patients in the intervention group.

Only 13 patients (seven in the intervention group and six in the control group) had complete data for the primary outcome, including patients with early treatment failure or death. The primary endpoint of ulcer-free endoscopic remission was met by three of the seven patients in the intervention group (five when including two patients for whom local endoscopic score was provided instead of central reading), compared with none in the control group.

Although statistical comparisons between the groups were precluded by the small number of patients for whom valid data were available, participants in the intervention group showed numerically higher quality of life scores and lower clinical and endoscopic disease activity scores. Regarding the AEs, 38 SAEs were reported by all (100%) participants in the intervention group, and 16 SAEs by four (44%) participants in the control group. Two patients in the HSCT group died: one during follow-up of pulmonary veno-occlusive disease and one after the end of follow-up of respiratory and renal failure that had arisen immediately after HSCT. No clear cause was found in either case, including any direct links to the mobilisation and conditioning regimen, although thrombotic microangiopathy was proven in three participants in the intervention group and a common mechanism was suspected in the two fatal cases, as discussed below.

Discussion

ASTIClite was the second randomised controlled trial designed to investigate the safety and efficacy of autologous HSCT for patients with CD. The cyclophosphamide dose for both stem cell mobilisation and conditioning was reduced compared with the original dose in the ASTIC trial, and fludarabine was added, as would be consistent with other reduced-intensity conditioning regimens [6]. The primary endpoint was in line with current standards for clinical trial design and current clinical practice goals [7]. Despite the reduced-intensity regimen, ASTIClite had to be stopped early due to unexpected SAEs. All patients experiencing ulcer healing were in the HSCT arm, and median endoscopic, clinical and patient-reported scores were lower in the intervention group; however, there was a clear imbalance in the distribution of the AEs, with at least one AE reported in all participants who underwent HSCT, of whom two eventually died. Since microangiopathic endothelial damage was demonstrated in many patients with SAEs, a common mechanism was suspected. However, no reasonable cause was found by the authors. A key difference in the ASTIClite regimen compared with the ASTIC one was the addition of fludarabine; however, it is important to note that fludarabine has not been associated with thrombotic microangiopathy after autologous HSCT (while it is a common complication of allogenic HSCT) [8]. Certainly, the burden of side effects outweighed the benefits in this trial, as two of the 13 patients in the intervention arm (of whom only ten eventually underwent conditioning and transplantation) died, an even higher percentage than the 6.4% reported in literature [9].

Conclusion

ASTIClite demonstrates the importance of evaluating potentially high-risk interventions within the confines of randomised controlled trials before seeking to introduce these interventions into routine clinical practice. In the face of no alternative medical or surgical therapies, HSCT can be a treatment option that some patients enquire about and wish to explore. However, the ASTIClite trial provides important data about the potential risks of pursuing such an approach even with supposedly safer lower-intensity regimens. On the other hand it is also important to note that, while the short-term high risk of severe side effects precludes use of HSCT as a routine treatment for CD [2], one could argue that the alternative of no treatment can hugely impact on the lives of those with refractory CD [10]. Indeed, this is well highlighted by the life-threatening disease activity-related SAEs observed in the control group of this trial, who received no HSCT. Therefore, it may be that there could still be a potential future role for HSCT in some patients – however, this would need to be considered only in the context of alternative safer regimens and very close monitoring [10]. Ultimately, a deeper knowledge of the pathophysiology of side effects (including microangiopathy) is strongly warranted to better understand whether there is or is not a role for HSCT, since even a reduction of conditioning intensity failed to reduce the burden of side effects for patients with refractory CD in ASTIClite. 

References

1. Hossain A, Lördal M, Olsson AE, et al. Sustained clinical benefit, improved quality of life, and reduced intestinal surgery from maintenance infliximab treatment in inflammatory bowel disease. Scand J Gastroenterol 2020;55:178–83. doi:10.1080/00365521.2020.1722738.
2. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7. doi:10.1016/S0140-6736(08)60304-9.
3. Safroneeva E, Vavricka SR, Fournier N, et al. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn’s disease. Aliment Pharmacol Ther 2015;42:977–89. doi:10.1111/apt.13363.
4. Ben-Horin S, Novack L, Mao R, et al. Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: a systematic review and an individual-patient data meta-analysis of randomized controlled trials. Gastroenterology 2022;162:482–94. doi:10.1053/j.gastro.2021.10.037.
5. Biasci D, Lee JC, Noor NM, et al. A blood-based prognostic biomarker in IBD. Gut. 2019;68:1386–95. doi:10.1136/gutjnl-2019-318343.
6. Hossain A, Lördal M, Olsson AE, et al. Sustained clinical benefit, improved quality of life, and reduced intestinal surgery from maintenance infliximab treatment in inflammatory bowel disease. Scand J Gastroenterol 2020;55:178–83. doi:10.1080/00365521.2020.1722738.
7. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7. doi:10.1016/S0140-6736(08)60304-9.
8. Safroneeva E, Vavricka SR, Fournier N, et al. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn’s disease. Aliment Pharmacol Ther 2015;42:977–89. doi:10.1111/apt.13363.
9. Ben-Horin S, Novack L, Mao R, et al. Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: a systematic review and an individual-patient data meta-analysis of randomized controlled trials. Gastroenterology 2022;162:482–94. doi:10.1053/j.gastro.2021.10.037.
10. Biasci D, Lee JC, Noor NM, et al. A blood-based prognostic biomarker in IBD. Gut. 2019;68:1386–95. doi:10.1136/gutjnl-2019-318343.

Tommaso Innocenti  - Short Biography

Tommaso Innocenti is a gastroenterologist at the IBD Referral Centre of Careggi University Hospital (Florence, Italy) and a PhD student at the University of Florence. He is currently involved in multiple national and international IBD-related research projects. Tommaso’s main interests in basic and translational science include research into new biomarkers of disease activity and severity, while in clinical research he is mainly focusing on intestinal ultrasound as a tool for tight disease monitoring.