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JAK2/mTOR Inhibition Fails to Prevent Acute GVHD Despite Reduced Th1/Th17 cells: Final Phase II Trial Results.
Pidala, Joseph A; Holtan, Shernan G; Walton, Kelly; Kim, Jongphil; Cao, Biwei; Elmariah, Hany; Mishra, Asmita; Bejanyan, Nelli; Nishihori, Taiga; Khimani, Farhad; Perez, Lia E; Faramand, Rawan G; Davila, Marco L; McSain, Shannon; Pleskow, Jordan; Baron, Jeffrey; Anasetti, Claudio; Moran Segura, Carlos M; Weisdorf, Daniel J; Blazar, Bruce R; Miller, Jeffrey S; Bachanova, Veronika; El Jurdi, Najla; Betts, Brian C.
Afiliación
  • Pidala JA; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.
  • Holtan SG; University of Minnesota, United States.
  • Walton K; Roswell Park Cancer Center, Buffalo, New York, United States.
  • Kim J; H.Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States.
  • Cao B; Moffitt Cancer Center, Tampa, Florida, United States.
  • Elmariah H; Moffitt Cancer Center, Tampa, Florida, United States.
  • Mishra A; H. Lee Moffitt Cancer Center and Research Institute, TAMPA, Florida, United States.
  • Bejanyan N; Moffitt Cancer Center, Tampa, Florida, United States.
  • Nishihori T; Moffitt Cancer Center, Tampa, Florida, United States.
  • Khimani F; H. Lee Moffitt Cancer Center, Tampa, Florida, United States.
  • Perez LE; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.
  • Faramand RG; Moffitt Cancer Center, Tampa, Florida, United States.
  • Davila ML; Moffitt Cancer Center, United States.
  • McSain S; Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States.
  • Pleskow J; Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States.
  • Baron J; Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States.
  • Anasetti C; Moffitt Cancer Center, Tampa, Florida, United States.
  • Moran Segura CM; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.
  • Weisdorf DJ; University of Minnesota, Minneapolis, Minnesota, United States.
  • Blazar BR; University of Minnesota, Minneapolis / MN / 55455, Minnesota, United States.
  • Miller JS; U of MN, Minneapolis, Minnesota, United States.
  • Bachanova V; University of Minnesota, Minneapolis, Minnesota, United States.
  • El Jurdi N; University of Minnesota, Minneapolis, Minnesota, United States.
  • Betts BC; University of Minnesota, United States.
Blood ; 2024 Jul 24.
Article en En | MEDLINE | ID: mdl-39046783
ABSTRACT
Our phase I graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib, (recommended phase II dose 100mg po BID day 0 to +70) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits IL-6 receptor activity and pathogenic Th1/Th17 differentiation in preclinical models and the phase I trial. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT. This single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3+ CD4+ T cells at day +21 (primary endpoint %pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II-IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n=28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary endpoint, reducing %pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of Tregs to Th1 and Th17 cells with PAC/SIR/TAC at RP2D PAC compared to dose level 1 PAC. The cumulative incidence of grade II-IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46 v 43%). While PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos