TY - JOUR
T1 - Pacritinib combined with sirolimus and low-dose tacrolimus for GVHD prevention after allogeneic hematopoietic cell transplantation
T2 - Preclinical and phase I trial results
AU - Pidala, Joseph
AU - Walton, Kelly
AU - Elmariah, Hany
AU - Kim, Jongphil
AU - Mishra, Asmita
AU - Bejanyan, Nelli
AU - Nishihori, Taiga
AU - Khimani, Farhad
AU - Perez, Lia
AU - Faramand, Rawan G.
AU - Davila, Marco L.
AU - Nieder, Michael L.
AU - Sagatys, Elizabeth M.
AU - Holtan, Shernan G.
AU - Lawrence, Nicholas J.
AU - Lawrence, Harshani R.
AU - Blazar, Bruce R.
AU - Anasetti, Claudio
AU - Sebti, Said M.
AU - Betts, Brian C.
N1 - Publisher Copyright:
© American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/ TAC) after allogeneic hematopoietic cell transplantation. Patients and Methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3þ3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n ¼ 12). Acute GVHD was scored through day þ100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. Results: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4þ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. Conclusions: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.
AB - Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/ TAC) after allogeneic hematopoietic cell transplantation. Patients and Methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3þ3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n ¼ 12). Acute GVHD was scored through day þ100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. Results: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4þ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. Conclusions: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.
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U2 - 10.1158/1078-0432.CCR-20-4725
DO - 10.1158/1078-0432.CCR-20-4725
M3 - Article
C2 - 33753457
AN - SCOPUS:85106189568
SN - 1078-0432
VL - 27
SP - 2712
EP - 2722
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -