skip to main content
Idioma:
Tipo de recurso Mostra resultados com: Mostra resultados com: Índice

A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease

Lin, Chenyu ; DiCioccio, Rachel A. ; Haykal, Tarek ; McManigle, William C. ; Li, Zhiguo ; Anand, Sarah M. ; Poe, Jonathan C. ; Bracken, Sonali J. ; Jia, Wei ; Alyea, Edwin P. ; Cardones, Adela R. ; Choi, Taewoong ; Gasparetto, Cristina ; Grunwald, Michael R. ; Hennig, Therese ; Kang, Yubin ; Long, Gwynn D. ; Lopez, Richard ; Martin, Melissa ; Minor, Kerry K. ; Quinones, Victor L. Perez ; Sung, Anthony D. ; Wiggins, Kristi ; Chao, Nelson J. ; Horwitz, Mitchell E. ; Rizzieri, David A. ; Sarantopoulos, Stefanie

Transplantation and cellular therapy, 2023-03, Vol.29 (3), p.179.e1-179.e10 [Periódico revisado por pares]

United States: Elsevier Inc

Texto completo disponível

Citações Citado por
  • Título:
    A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease
  • Autor: Lin, Chenyu ; DiCioccio, Rachel A. ; Haykal, Tarek ; McManigle, William C. ; Li, Zhiguo ; Anand, Sarah M. ; Poe, Jonathan C. ; Bracken, Sonali J. ; Jia, Wei ; Alyea, Edwin P. ; Cardones, Adela R. ; Choi, Taewoong ; Gasparetto, Cristina ; Grunwald, Michael R. ; Hennig, Therese ; Kang, Yubin ; Long, Gwynn D. ; Lopez, Richard ; Martin, Melissa ; Minor, Kerry K. ; Quinones, Victor L. Perez ; Sung, Anthony D. ; Wiggins, Kristi ; Chao, Nelson J. ; Horwitz, Mitchell E. ; Rizzieri, David A. ; Sarantopoulos, Stefanie
  • Assuntos: Aminopyridines - therapeutic use ; Animals ; B cells ; Bronchiolitis Obliterans Syndrome ; clinical trial ; fostamatinib ; Graft versus host disease ; Graft vs Host Disease - prevention & control ; Humans ; Mice ; Neoplasm Recurrence, Local - complications ; Oxazines - pharmacology ; Oxazines - therapeutic use ; Pyridines - pharmacology ; Pyridines - therapeutic use ; spleen tyrosine kinase ; stem cell transplantation ; Steroids - therapeutic use ; Syk Kinase - therapeutic use
  • É parte de: Transplantation and cellular therapy, 2023-03, Vol.29 (3), p.179.e1-179.e10
  • Notas: Equal contribution.
  • Descrição: •Fostamatinib had a manageable safety profile in the post-transplant setting.•One of five patients developed cGVHD while on fostamatinib prophylaxis.•Among SR-cGVHD patients, the ORR was 77% with 70% of responses lasting > 1 year.•Fostamatinib allowed for a strong and durable steroid-sparing effect.•Plasmablast-like B cells decreased with therapy in responders. Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD−CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation. [Display omitted]
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
Links
Voltar para lista de resultados

  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

Buscando em bases de dados remotas. Favor aguardar.