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Azacitidine for the treatment of steroid-refractory chronic graft-versus-host disease: the results of the phase II AZTEC clinical trial

Bone Marrow Transplantation volume 56, pages 2948–2955 (2021)Cite this article

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Abstract

Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m2 days 1–5 per 28-day cycle. Azacitidine was tolerated by 13/14 patients, and 7/14 showed an objective response. Clinical responses were mirrored by improvements in patient-reported cGvHD symptoms and quality of life. AZTEC demonstrates that azacitidine is a safe and promising option for the treatment of cGvHD, and continued evaluation in the second stage of this phase II efficacy study is supported.

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Fig. 1: Sequential, individual treatment responses to skin and mouth cGvHD.
Fig. 2: Patient-reported ratings of cGvHD severity and change over time.
Fig. 3: Patient-reported quality of life rating over time.

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Acknowledgements

The AZTEC trial was funded by Bloodwise (now Blood Cancer UK). Azacitidine was provided free of charge by Celgene. The trial was supported by the facilities funded through Birmingham Science City Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project that forms part of the Science City University of Warwick and University of Birmingham Research Alliance.

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Authors and Affiliations

  1. Centre for Clinical Haematology, Queen Elizabeth Hospital Birmingham, Birmingham, UK

    Ram Malladi, Jane Nunnick & Charles Craddock

  2. Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

    Ram Malladi

  3. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK

    Ikhlaaq Ahmed, Graham McIlroy, Aimee Jackson, Jane Nunnick, Shamyla Siddique, Rebecca Bishop, Mohamed Elhaneid, Andrea Hodgkinson & Charles Craddock

  4. Department of Clinical Haematology, Manchester University NHS Foundation Trust, Manchester, UK

    Fiona L. Dignan

  5. Department of Haematology, University Hospitals Bristol, Bristol, UK

    Rachel Protheroe

  6. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    Paul Moss

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  1. Ram Malladi
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Contributions

RM conceived the work; RM, IA, AJ, PM, SS and CC designed the trial; RM, FLD, RP, CC and JN acquired the patient data; RM, IA, GM, AJ, RB, ME and AH analysed and interpreted the results; RM and GM drafted the manuscript; all authors revised the manuscript, approved the final version of the manuscript and are accountable for all aspects of the work, and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Ram Malladi.

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Competing interests

RM has received travel assistance from Celgene. FLD has received travel assistance from Gilead and Jazz; speaker’s fees from Mallinckrodt, Jazz, Pfizer and Janssen; advisory board for Kiadis, Jazz. CC has received research funding from Celgene. All other authors report no competing interests.

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Malladi, R., Ahmed, I., McIlroy, G. et al. Azacitidine for the treatment of steroid-refractory chronic graft-versus-host disease: the results of the phase II AZTEC clinical trial. Bone Marrow Transplant 56, 2948–2955 (2021). https://doi.org/10.1038/s41409-021-01439-y

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