Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Nov 28;144(22):2295-2307.
doi: 10.1182/blood.2024024789.

JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results

Joseph Pidala  1 , Shernan G Holtan  2 , Kelly Walton  2 , Jongphil Kim  3 , Biwei Cao  3 , Hany Elmariah  1 , Asmita Mishra  1 , Nelli Bejanyan  1 , Taiga Nishihori  1 , Farhad Khimani  1 , Lia Perez  1 , Rawan G Faramand  1 , Marco L Davila  4 , Shannon McSain  4 , Jordan Pleskow  5 , Jeffrey Baron  5 , Claudio Anasetti  1 , Carlos Moran Segura  6 , Daniel J Weisdorf  2 , Bruce R Blazar  7 , Jeffrey S Miller  2 , Veronika Bachanova  2 , Najla El Jurdi  2 , Brian C Betts  2
Affiliations
Clinical Trial

JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results

Joseph Pidala et al. Blood. .

Abstract

Our phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to 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 end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of regulatory T cells to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: J.P. reports research support from Novartis, Amgen, Takeda, Janssen, Johnson and Johnson, Pharmacyclics, AbbVie, CTI BioPharma Corp, a Sobi company, and Bristol Myers Squibb; and reports consulting and advisory board membership with Syndax, CTI BioPharma Corp, a Sobi company, Amgen, and Regeneron. S.G.H. reports other support from Incyte and VITRAC Therapeutics. S.G.H. is a clinical trial adjudicator for CSL Behr. B.C.B. reports research support from CTI BioPharma Corp, a Sobi company, VITRAC Therapeutics, and Incyte. B.C.B. holds a patent (WO2015120436A2) related to CD4+ T-cell phosphorylated STAT3 as a marker and therapeutic target of acute graft-versus-host disease (GVHD) and a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. B.C.B. has a patent for WO2019165156 on CD83 chimeric antigen receptor (CAR) T, previously licensed to CRISPR Therapeutics. D.J.W. reports grants from Fate Therapeutics and Incyte outside the submitted work. J.S.M. consults for and holds stock in Fate Therapeutics, GT BioPharma, and Vycellix; and reports research support from Fate Therapeutics and GT Biopharma. J.S.M. serves on the Scientific Advisory Board of ONK Therapeutics, Wugan, and Sanofi. M.L.D. reports grants from CRISPR, Kite/Gilead, and Novartis; other support from Bellicum, Adicet, Adaptive Biotechnologies; and personal fees from Capstan and CARGO. M.L.D. has a patent for CD83 CAR previously licensed to CRISPR. B.R.B. reports research funding from BlueRock Therapeutics and Carisma Therapeutics and consulting fees from BlueRock Therapeutics, Editas Medicine, Janssen Oncology, Sandoz, Legend Biotech, GentiBio Inc, and Magenta Therapeutics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
PAC/SIR/TAC suppresses STAT3 and enhances STAT5 phosphorylation in CD4+ T cells. (A) Percentage (%) of pSTAT3+ CD4+ T cells pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (B) %pSTAT3+ CD4+ T cells at day +21 among patients treated with PAC/SIR/TAC at dose level 1 with ineffective JAK2 inhibition vs PAC/SIR/TAC at the recommended phase 2 dose (RP2D) of PAC (primary end point: %pSTAT3+ CD4+ T cells ≤ 35%). (C) %pSTAT3+ CD4+ T at days +21 and +100 based on pacritinib dosing. (D) %pSTAT5+ CD4+ T (IL-2 receptor signaling element) cells pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (E) %pSTAT5+ CD4+ T cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. (F) Graph demonstrating the ratio of pSTAT5+ to pSTAT3+ CD4+ T cells at day +21 based on dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. (G) %pS6+ CD4+ T cells (CD28 signaling element) pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (H) %pS6+ CD4+ T cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. (I) %pH3 Ser10+ CD4+ T cells (CD28 signaling element) pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (J) %pH3 Ser10+ CD4+ T cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. ∗P < .05, ∗∗P = .01-.001, ∗∗∗P = .001-.0001, ∗∗∗∗P < .0001. NS, not significant.
Figure 2.
Figure 2.
PAC/SIR/TAC inhibits inflammatory Th1 and Th17 cells, while increasing Th2 cells. (A) %CD4+ Th1 cells pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (B-C) Percentage (B) and absolute number (C) of CD4+ Th1 cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs recommended phase 2 dose (RP2D) PAC/SIR/TAC. (D) %CD4+ Th17 cells pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (E-F) Percentage (E) and absolute number (F) of CD4+ Th17 cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. (G) %CD4+ Th2 cells pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (H-I) Percentage (H) and absolute number (I) of CD4+ Th2 cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. ∗P < .05, ∗∗P = .01-.001, ∗∗∗∗P < .0001.
Figure 3.
Figure 3.
PAC/SIR/TAC increases the ratio of Treg to Th1 and Th17 cells. (A) %CD4+ Tregs pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (B-C) Percentage (B) and absolute number (C) of CD4+ Tregs at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs recommended phase 2 dose (RP2D) PAC/SIR/TAC. (D) Graph showing the ratio of Tregs to Th1 and Th17 cells pretransplant and at days +21 and +100 on phase 2 PAC/SIR/TAC. (E) Graph demonstrating the ratio of Tregs to Th1 and Th17 cells at day +21 based on dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. ∗P < .05. NS, not significant.
Figure 4.
Figure 4.
PAC/SIR/TAC maintains T, B, and NK cell engraftment. (A) Number of CD3+ T cells pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (B-D) Number of CD3+ (B), CD4+ (C), and CD8+ (D) T cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs recommended phase 2 dose (RP2D) PAC/SIR/TAC. (E) Number of CD19+ B cells pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (F) Number of CD19+ B cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. (G) Number of CD16+, CD56+ NK cells pretransplant and at days +21 and +100 among patients treated on phase 2 PAC/SIR/TAC. (H) Number of CD16+, CD56+ NK cells at day +21 among patients treated with dose level 1 PAC/SIR/TAC vs RP2D PAC/SIR/TAC. ∗P < .05 and ∗∗∗P = .001-.0001. NS, not significant.
Figure 5.
Figure 5.
Clinical outcomes following PAC/SIR/TAC therapy. (A) Cumulative incidence of grade II to IV acute GVHD. (B) Cumulative incidence of National Institutes of Health (NIH) moderate/severe chronic GVHD. (C) Overall survival. (D) Cumulative incidence of malignancy relapse post-HCT.
Figure 6.
Figure 6.
Acute GVHD did not correlate with duration of PAC therapy, depth of pSTAT3 inhibition, or T-cell subsets. (A-C) Percentage (%) of pSTAT3+ CD4+ T cells at day +21 among patients treated on phase 2 PAC/SIR/TAC based on presence or absence of grade II to IV acute GVHD by day +100 (A), grade II to IV acute GVHD by day +30 (B), or use of systemic immune suppression (IS) beyond PAC/SIR/TAC to treat grade II to IV acute GVHD (C). (D-G) %CD4+ Th1 (D), Th2 (E), Th17 (F), or Treg (G) cells at day +21 among patients treated on phase 2 PAC/SIR/TAC based on presence of absence of grade II to IV acute GVHD by day +100. (H) Treg:Th1 + Th17 ratio at day +21 among patients without or with grade II to IV acute GVHD. NS, not significant.
See this image and copyright information in PMC

References

    1. Hill GR, Betts BC, Tkachev V, Kean LS, Blazar BR. Current concepts and advances in graft-versus-host disease immunology. Annu Rev Immunol. 2021;39(1):19–49. - PMC - PubMed
    1. Chen X, Das R, Komorowski R, et al. Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood. 2009;114(4):891–900. - PMC - PubMed
    1. Tawara I, Koyama M, Liu C, et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res. 2011;17(1):77–88. - PMC - PubMed
    1. Kennedy GA, Varelias A, Vuckovic S, et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014;15(13):1451–1459. - PubMed
    1. Kennedy GA, Tey SK, Buizen L, et al. A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis. Blood. 2021;137(14):1970–1979. - PubMed

Publication types

MeSH terms