Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

James O Lindsay; Daniel Hind; Lizzie Swaby; Hannah Berntsson; Mike Bradburn; Uday Bannur C; Jennifer Byrne; Christopher Clarke; Lauren Desoysa; Ben Dickins; Shahida Din; Richard Emsley; Gemma A Foulds; John Gribben; Christopher Hawkey; Peter M Irving; Majid Kazmi; Ellen Lee; Amanda Loban; Alan Lobo; Yashwant Mahida; Gordon W Moran; Diana Papaioannou; Miles Parkes; Andrew Peniket; A Graham Pockley; Jack Satsangi; Sreedhar Subramanian; Simon Travis; Emily Turton; Ben Uttenthal; Sergio Rutella; John A Snowden

doi:10.1016/S2468-1253(23)00460-0

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

James O Lindsay, Daniel Hind, Lizzie Swaby, Hannah Berntsson, Mike Bradburn, Uday Bannur C, Jennifer Byrne, Christopher Clarke, Lauren Desoysa, Ben Dickins, Shahida Din, Richard Emsley, Gemma A Foulds, John Gribben, Christopher Hawkey, Peter M Irving, Majid Kazmi, Ellen Lee, Amanda Loban, Alan LoboYashwant Mahida, Gordon W Moran, Diana Papaioannou, Miles Parkes, Andrew Peniket, A Graham Pockley, Jack Satsangi, Sreedhar Subramanian, Simon Travis, Emily Turton, Ben Uttenthal, Sergio Rutella, John A Snowden

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population.

METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440.

FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.

INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.

FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Original language	English
Pages (from-to)	333-345
Number of pages	13
Journal	The Lancet Gastroenterology & Hepatology
Volume	9
Issue number	4
DOIs	https://doi.org/10.1016/S2468-1253(23)00460-0
Publication status	Published - Apr 2024

Keywords

Adult
Humans
Crohn Disease/drug therapy
Standard of Care
State Medicine
Ulcer/etiology
Treatment Outcome
Hematopoietic Stem Cell Transplantation/adverse effects
Cyclophosphamide/adverse effects
Granulocyte Colony-Stimulating Factor/therapeutic use
Renal Insufficiency

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lindsay, J. O., Hind, D., Swaby, L., Berntsson, H., Bradburn, M., Bannur C, U., Byrne, J., Clarke, C., Desoysa, L., Dickins, B., Din, S., Emsley, R., Foulds, G. A., Gribben, J., Hawkey, C., Irving, P. M., Kazmi, M., Lee, E., Loban, A., ... Snowden, J. A. (2024). Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. The Lancet Gastroenterology & Hepatology, 9(4), 333-345. https://doi.org/10.1016/S2468-1253(23)00460-0

Lindsay, James O ; Hind, Daniel ; Swaby, Lizzie et al. / Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite) : an open-label, multicentre, randomised controlled trial. In: The Lancet Gastroenterology & Hepatology. 2024 ; Vol. 9, No. 4. pp. 333-345.

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title = "Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial",

abstract = "BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population.METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.",

keywords = "Adult, Humans, Crohn Disease/drug therapy, Standard of Care, State Medicine, Ulcer/etiology, Treatment Outcome, Hematopoietic Stem Cell Transplantation/adverse effects, Cyclophosphamide/adverse effects, Granulocyte Colony-Stimulating Factor/therapeutic use, Renal Insufficiency",

author = "Lindsay, {James O} and Daniel Hind and Lizzie Swaby and Hannah Berntsson and Mike Bradburn and {Bannur C}, Uday and Jennifer Byrne and Christopher Clarke and Lauren Desoysa and Ben Dickins and Shahida Din and Richard Emsley and Foulds, {Gemma A} and John Gribben and Christopher Hawkey and Irving, {Peter M} and Majid Kazmi and Ellen Lee and Amanda Loban and Alan Lobo and Yashwant Mahida and Moran, {Gordon W} and Diana Papaioannou and Miles Parkes and Andrew Peniket and Pockley, {A Graham} and Jack Satsangi and Sreedhar Subramanian and Simon Travis and Emily Turton and Ben Uttenthal and Sergio Rutella and Snowden, {John A}",

year = "2024",

month = apr,

doi = "10.1016/S2468-1253(23)00460-0",

language = "English",

volume = "9",

pages = "333--345",

journal = "The Lancet Gastroenterology & Hepatology",

issn = "2468-1253",

publisher = "Elsevier",

number = "4",

}

Lindsay, JO, Hind, D, Swaby, L, Berntsson, H, Bradburn, M, Bannur C, U, Byrne, J, Clarke, C, Desoysa, L, Dickins, B, Din, S, Emsley, R, Foulds, GA, Gribben, J, Hawkey, C, Irving, PM, Kazmi, M, Lee, E, Loban, A, Lobo, A, Mahida, Y, Moran, GW, Papaioannou, D, Parkes, M, Peniket, A, Pockley, AG, Satsangi, J, Subramanian, S, Travis, S, Turton, E, Uttenthal, B, Rutella, S & Snowden, JA 2024, 'Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial', The Lancet Gastroenterology & Hepatology, vol. 9, no. 4, pp. 333-345. https://doi.org/10.1016/S2468-1253(23)00460-0

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. / Lindsay, James O; Hind, Daniel; Swaby, Lizzie et al.
In: The Lancet Gastroenterology & Hepatology, Vol. 9, No. 4, 04.2024, p. 333-345.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite)

T2 - an open-label, multicentre, randomised controlled trial

AU - Lindsay, James O

AU - Hind, Daniel

AU - Swaby, Lizzie

AU - Berntsson, Hannah

AU - Bradburn, Mike

AU - Bannur C, Uday

AU - Byrne, Jennifer

AU - Clarke, Christopher

AU - Desoysa, Lauren

AU - Dickins, Ben

AU - Din, Shahida

AU - Emsley, Richard

AU - Foulds, Gemma A

AU - Gribben, John

AU - Hawkey, Christopher

AU - Irving, Peter M

AU - Kazmi, Majid

AU - Lee, Ellen

AU - Loban, Amanda

AU - Lobo, Alan

AU - Mahida, Yashwant

AU - Moran, Gordon W

AU - Papaioannou, Diana

AU - Parkes, Miles

AU - Peniket, Andrew

AU - Pockley, A Graham

AU - Satsangi, Jack

AU - Subramanian, Sreedhar

AU - Travis, Simon

AU - Turton, Emily

AU - Uttenthal, Ben

AU - Rutella, Sergio

AU - Snowden, John A

PY - 2024/4

Y1 - 2024/4

N2 - BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population.METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

AB - BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population.METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure.INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease.FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

KW - Adult

KW - Humans

KW - Crohn Disease/drug therapy

KW - Standard of Care

KW - State Medicine

KW - Ulcer/etiology

KW - Treatment Outcome

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Cyclophosphamide/adverse effects

KW - Granulocyte Colony-Stimulating Factor/therapeutic use

KW - Renal Insufficiency

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U2 - 10.1016/S2468-1253(23)00460-0

DO - 10.1016/S2468-1253(23)00460-0

M3 - Article

C2 - 38340759

SN - 2468-1253

VL - 9

SP - 333

EP - 345

JO - The Lancet Gastroenterology & Hepatology

JF - The Lancet Gastroenterology & Hepatology

IS - 4

ER -

Lindsay JO, Hind D, Swaby L, Berntsson H, Bradburn M, Bannur C U et al. Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. The Lancet Gastroenterology & Hepatology. 2024 Apr;9(4):333-345. doi: 10.1016/S2468-1253(23)00460-0

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

Abstract

Keywords

UN SDGs

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