The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.
Blood. 2023 Feb 2;141(5):481-489. doi: 10.1182/blood.2022017442.
The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.
标准的急性移植物抗宿主病（GVHD）的主要治疗方法需要长期、大剂量的全身性皮质类固醇（SCS）治疗，这会延迟免疫系统的重建。我们使用经过验证的临床和生物标志物分期标准，确定了一组低危（LR）GVHD 患者，他们非常有可能对 SCS 有反应。我们假设，选择性 JAK1 抑制剂伊替卡替尼将有效地治疗 LR GVHD，而无需 SCS。我们在一项多中心、2 期临床试验（NCT03846479）中用伊替卡替尼 200mg/d 治疗 70 例 LR GVHD 患者（应答者可接受第二个 28 天周期），并将他们的结果与 140 例同时期、匹配的接受 SCS 治疗的对照患者进行比较。在 7 天内，更多的患者对伊替卡替尼有反应（81% vs 66%，P =.02），两组在第 28 天的反应率都非常高（89% vs 86%，P =.67），且症状性爆发较少（11% vs 12%，P =.88）。由于病毒和真菌感染较少，在 90 天内，伊替卡替尼治疗的患者发生严重感染的比例较低（27% vs 42%，P =.04）。除了白细胞减少症较轻外，两组的血液学毒性≥3 级无显著差异（伊替卡替尼 16% vs 31%，P =.02）。在接受伊替卡替尼治疗的患者中，没有任何其他不良事件发生率超过 10%。在 1 年时，两组非复发死亡率（4% vs 11%，P =.21）、复发（18% vs 21%，P =.64）、慢性 GVHD（28% vs 33%，P =.33）或生存（88% vs 80%，P =.11）均无显著差异。伊替卡替尼单药治疗似乎是 LR GVHD 替代 SCS 治疗的一种安全有效的方法，值得进一步研究。
