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Begelomab for steroid-resistant acute GvHD

Hematopoietic stem cell transplantation (HSCT) is an incredibly powerful tool in the treatment of hematological malignancies. Testament to this is the capacity of a single stem cell to repopulate the entire lymphohematopoietic system of a lethally irradiated animal.1 Indeed, for diseases such as myelodysplastic syndromes, transplant represents the only real avenue towards long-term remission or ‘cure’.2

Despite the success of HSCT, graft-versus-host disease (GvHD) remains a lethal adverse event, limiting the use of this crucial therapy.3 GvHD occurs when donor T-cells respond to genetically defined proteins on host cells, the most important being Human Leukocyte Antigens (HLA).3-5

The powerful anti-lymphocytic and anti-inflammatory nature of steroids have proved to reduce the deleterious impact of GvHD drastically. However, despite steroids being the gold standard in this field, complete remission is seen in less than half of patients.6

Resistance and dependence on steroid treatment renders patients at a higher risk of morbidity and mortality as a result of uncontrolled GvHD, prolonged exposure to steroids, or infection.7 Additionally, there is no standard treatment for steroid-resistant acute GvHD (SR-aGvHD).8

The CD26-targeting monoclonal antibody begelomab has potential in the treatment of SR-GvHD, with CD26 playing a key role in T-cell activation and immune regulation.9

A recent study published in Bone Marrow Transplantation investigated the use of begelomab in the treatment of SR-aGvHD. The cohort consisted of 69 patients, 28 of which were from two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19) and 41 on a compassionate use study; the median age was 42 and 44, respectively. Eight patients had grade II GvHD, 33 grade III and 28 grade IV.

Responses for grade III GvHD were recorded in 83% and 73% of patients and responses in grade IV GvHD were recorded in 66% and 56% of patients in the two groups, respectively. Non-relapse mortality at six months was 28% and 38%. Overall, there were 64%, 56%, 68% responses for skin, liver, and gut stage III–IV GvHD, respectively. The one-year overall survival was 50% for the prospective studies and 33% for the compassionate use patients. Additionally, no adverse events directly attributable to begelomab were reported.

The investigators concluded that begelomab induces responses over 60% of SR-aGvHD patients, including those with severe gut and liver GvHD, having failed one or more treatment lines.10

Written By Thomas Southgate

References

  1. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/ negative hematopoietic stem cell. Science. 1996;273:242-5.
  2. Fazal S. (2019). Therapies and Treatment Options 2019’ [PowerPoint presentation]. Available from: https://www.mds-foundation.org/wp-content/uploads/2019/02/MDS-Foundation-2019-Final.pdf (Last Accessed: 11/03/20).
  3. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol. 2007;25:139–170. 
  4. Petersdorf EW, Longton GM, Anasetti C, et al. The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation. Blood. 1995;1995;86:1606–1613.
  5. Krensky AM, Weiss A, Crabtree G, Davis MM, Parham P. T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med. 1990;322:510–517. 
  6. MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8:387–94. 
  7. Flowers ME, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9.
  8. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2012;18:1150–63.
  9. National Cancer Institute. NCI Drug Dictionary; Begelomab. Available from: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/begelomab (Last accessed 02/04/2020).
  10. Bacigalupo A, Angelucci E, Raiola AM et al. Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-Begelomab. Bone Marrow Transplantation. 2020 Mar; doi.org/10.1038/s41409-020-0855-z.