Mahmoudjafari Zahra, Kintsch Emily, Xue Zhenyi, Bhatt Valkal, Galvin John, Locatelli Franco, Zeiser Robert
University of Kansas, Westwood, Kansas, United States.
Incyte Corporation, Wilmington, Delaware, United States.
Blood Adv. 2025 Jun 5. doi: 10.1182/bloodadvances.2025016212.
Azole antifungal agents, commonly used for preventing invasive fungal infections in graft-versus-host disease (GVHD), are known to affect ruxolitinib metabolism. Post hoc analyses of the REACH2/REACH3 phase 3 trials (ClinicalTrials.gov: NCT02913261/NCT03112603) examined the impact of these clinically relevant drug interactions on ruxolitinib treatment outcomes in patients with steroid-refractory acute GVHD (aGVHD; REACH2) and steroid-refractory/steroid-dependent chronic GVHD (cGVHD; REACH3). In REACH2, the overall response rate (ORR) at Day 28 was significantly higher with ruxolitinib versus best available therapy (BAT; 67.5% vs 44.3%; P=0.0003) among patients who received concomitant azoles; among those who did not, Day 28 ORR was 45.9% vs 28.6%, respectively. In REACH3, ORR at Week 24 was significantly higher with ruxolitinib versus BAT in patients who did (46.6% vs 29.4%; P=0.006) or did not receive (57.1% vs 19.4%; P<0.0001) concomitant azoles. Concomitant azoles neither increased the rate of cytopenias in patients treated with ruxolitinib in REACH2/REACH3, nor impacted the median (range) dose of ruxolitinib up to Day 28 in REACH2 (azoles/no azoles, 20.0 [9.0-21.0]/20.0 [8.4-20.0] mg/day) or Week 24 in REACH3 (azoles/no azoles, 19.4 [4.8-20.5]/19.9 [5.5-20.0] mg/day). However, patients receiving concomitant azoles were more likely to have ruxolitinib dose modifications in REACH2/REACH3, highlighting the importance of dose optimization in these patients. Overall, concomitant azole treatment was generally well tolerated and did not affect treatment outcomes with appropriate ruxolitinib dose optimization. Consistent with primary REACH2/REACH3 results, ruxolitinib provided greater clinical benefit than BAT in patients with steroid-refractory aGVHD and steroid-refractory/steroid-dependent cGVHD, irrespective of concomitant azole treatment.
唑类抗真菌药物常用于预防移植物抗宿主病（GVHD）中的侵袭性真菌感染，已知其会影响鲁索替尼的代谢。REACH2/REACH3 3期试验（ClinicalTrials.gov：NCT02913261/NCT03112603）的事后分析研究了这些具有临床相关性的药物相互作用对类固醇难治性急性GVHD（aGVHD；REACH2）和类固醇难治性/类固醇依赖性慢性GVHD（cGVHD；REACH3）患者鲁索替尼治疗结局的影响。在REACH2中，接受联合唑类药物治疗的患者中，鲁索替尼在第28天的总体缓解率（ORR）显著高于最佳可用疗法（BAT；67.5%对44.3%；P=0.0003）；未接受联合唑类药物治疗的患者中，第28天的ORR分别为45.9%和28.6%。在REACH3中，接受联合唑类药物治疗（46.6%对29.4%；P=0.006）或未接受联合唑类药物治疗（57.1%对19.4%；P<0.0001）的患者中，鲁索替尼在第24周的ORR显著高于BAT。在REACH2/REACH3中，联合使用唑类药物既未增加接受鲁索替尼治疗患者的血细胞减少发生率，也未影响REACH2中至第28天（联合唑类药物/未联合唑类药物，20.0[9.0 - 21.0]/20.0[8.4 - 20.0]mg/天）或REACH3中至第24周（联合唑类药物/未联合唑类药物，19.4[4.8 - 20.5]/19.9[5.5 - 20.0]mg/天）鲁索替尼的中位（范围）剂量。然而，在REACH2/REACH3中，接受联合唑类药物治疗的患者更有可能调整鲁索替尼剂量，这突出了这些患者剂量优化的重要性。总体而言，联合使用唑类药物治疗一般耐受性良好，在进行适当的鲁索替尼剂量优化后不影响治疗结局。与REACH2/REACH3的主要结果一致，无论是否联合使用唑类药物，鲁索替尼在类固醇难治性aGVHD和类固醇难治性/类固醇依赖性cGVHD患者中都比BAT提供了更大的临床益处。
