Pidala Joseph, Holtan Shernan G, Walton Kelly, Kim Jongphil, Cao Biwei, Elmariah Hany, Mishra Asmita, Bejanyan Nelli, Nishihori Taiga, Khimani Farhad, Perez Lia, Faramand Rawan G, Davila Marco L, McSain Shannon, Pleskow Jordan, Baron Jeffrey, Anasetti Claudio, Moran Segura Carlos, Weisdorf Daniel J, Blazar Bruce R, Miller Jeffrey S, Bachanova Veronika, El Jurdi Najla, Betts Brian C
Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
Blood. 2024 Nov 28;144(22):2295-2307. doi: 10.1182/blood.2024024789.
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.
我们开展了一项1期移植物抗宿主病（GVHD）预防试验，使用JAK2抑制剂帕西替尼（PAC；推荐的2期剂量：第0天至 +70天，每日口服100毫克，分两次服用）联合西罗莫司和他克莫司（SIR/TAC），结果表明该方案在异基因造血细胞移植（alloHCT）后是安全的，且未出现全JAK骨髓抑制现象。在临床前模型和1期试验中，PAC可抑制白细胞介素6（IL-6）受体活性以及致病性辅助性T细胞1（Th1）/辅助性T细胞17（Th17）的分化。在此，我们报告8/8人类白细胞抗原匹配的alloHCT后完成的PAC/SIR/TAC 2期试验情况。这项单臂2期试验（NCT02891603）旨在确定PAC/SIR/TAC在第 +21天是否能抑制磷酸化信号转导和转录激活因子3（pSTAT3）+ CD4+ T细胞的百分比（主要终点：pSTAT3+ CD4+ T细胞百分比≤35%），并在第 +100天评估II至IV级急性GVHD的发生率。还评估了PAC/SIR/TAC对T细胞亚群、CD28（pS6和pH3ser10）以及白细胞介素2受体（pSTAT5）信号转导的影响。符合条件的患者（n = 28）因血液系统恶性肿瘤或骨髓增殖性肿瘤接受alloHCT。允许采用降低强度或清髓性预处理。PAC/SIR/TAC达到了主要终点，在第 +21天将pSTAT3+ CD4+ T细胞百分比降至9.62%。在第 +21天，Th1/Th17细胞减少，与1期剂量的PAC相比，使用2期推荐剂量PAC的PAC/SIR/TAC增加了调节性T细胞与Th1和Th17细胞的比例。PAC/SIR/TAC在第 +100天的II至IV级急性GVHD累积发生率与SIR/TAC的历史值相似（46%对43%）。尽管PAC/SIR/TAC抑制了pSTAT3和Th1/Th17细胞，但该方案并未改善急性GVHD的预防效果。
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