cGvHD

Abatacept in steroid-refractory chronic graft-versus-host disease

On 21 June 2018, a study (NCT01954979) was published in Blood assessing the safety, efficacy, and immune effects of abatacept, a recombinant soluble fusion protein inhibiting T cell activation via blockade of co-stimulation, for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGvHD).1 The paper was published by Myrna R. Nahas from Beth Israel Deaconess Medical Center, Section of Hematological Malignancies and Bone Marrow Transplantation, Harvard Medical School, Boston, MA, USA, and colleagues.

Sixteen heavily pre-treated patients (median age = 54 years; range 24–72) with SR-cGvHD were enrolled between April 2014 and October 2015 in this phase I dose-escalation study, which followed a 3+3 design with two escalating doses of abatacept to determine the maximum tolerated dose: 3 mg/kg (n = 3) and 10 mg/kg (n = 3). An additional expansion cohort was treated at a dose of 10 mg/kg (n = 10). The most commonly affected organ systems were skin (94%), joints (81%), mouth (75%), and eyes (75%).

Key findings:
  • Safety
    • Most common serious grade 3–4 adverse events were pulmonary infections at both dose levels
    • No dose-limiting toxicities were observed
  • Efficacy
    • Clinical partial response: 44%
    • Complete resolution of grade 2 pulmonary cGvHD was observed in one patient
    • Reduction in prednisone usage in clinical responders: 51.3%
  • Immunomodulatory effects in responders
    • Increased PD-1 expression on circulating CD4 T cells, P = 0.009
    • Increased PD-1 expression on circulating CD8 T cells, P = 0.007
    • No significant difference was found in Th1 (IFNγ) or Th2 (IL-10) cytokine secretion

The authors concluded that abatacept was well-tolerated “with pulmonary infections being the only grade 3 or 4 possibly related adverse events observed in this phase I study.” Furthermore, no dose-limiting toxicities were observed. The authors added that abatacept showed a clinical response in 44% of patients as well as it was able to reduce prednisone usage by 51.3%. Based on this data, a phase II study is ongoing.

Reference
  1. Nahas MR. et al. Phase I clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood. 2018 March 16. DOI: 10.1182/blood-2017-05-780239.
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