Cai Yijun, Ali Amir, Filler Elan, Bayati Rua, Toma Tanjia, Zaki Omar, Yaghmour George, Ladha Abdullah, Woan Karrune, Tam Eric, Chaudhary Preet M
Titus Family Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States.
Jane Anne Nohl Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Front Oncol. 2024 Feb 12;14:1329893. doi: 10.3389/fonc.2024.1329893. eCollection 2024.
Graft-versus-host disease (GVHD) is a common complication in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized as either acute or chronic based on symptomatology and histopathological findings. Despite advancements in disease-targeting therapeutics, steroid-refractory GVHD remains a significant contributor to mortality in HSCT recipients, highlighting the gaps in our understanding of its pathophysiology and treatment strategies. We present the case of a 46-year-old woman diagnosed with acute undifferentiated leukemia, who exhibited persistently elevated levels of serum total bilirubin (T.Bili), alkaline phosphatase (ALP), and liver function tests (LFTs) beginning on [day +201] post-haploidentical peripheral blood stem cell (PBSC) transplantation. The patient received fludarabine/total body irradiation (Flu/TBI) as a myeloablative conditioning regimen and post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) as GVHD prophylaxis. A liver biopsy confirmed the diagnosis of GVHD, while other possible etiologies were excluded by corresponding tests. Initial treatment with prednisone and tacrolimus, and the later addition of ruxolitinib, all showed poor response indicated by worsening T.Bili, ALP, and LFTs at the same time. Based on a multidisciplinary comprehensive assessment, we decided to administer 1,000 mg/m (1,600 mg) of cyclophosphamide ("pulse Cy"), which resulted in a dramatic improvement in T.Bili and transaminases starting from the very next day. A durable response to pulse cyclophosphamide was observed, as all indicators normalized ("complete response") within 55 days without relapses. The patient remains in good health with no recurrence of hepatic GVHD. To our knowledge, this is the first case in which Grade IV hepatic GVHD, refractory to multiple agents including steroids, tacrolimus, and ruxolitinib, demonstrated a complete response to pulse cyclophosphamide. The success highlights the potential therapeutic role of cyclophosphamide, a potent and cost-effective chemotherapy agent, in treating multi-agent-refractory GVHD. Large-scale clinical trials are warranted to validate its efficacy in this setting.
移植物抗宿主病（GVHD）是接受异基因造血干细胞移植（HSCT）患者的常见并发症。根据症状和组织病理学发现，GVHD分为急性或慢性。尽管针对疾病的治疗方法有所进展，但类固醇难治性GVHD仍然是HSCT受者死亡的重要原因，这突出了我们对其病理生理学和治疗策略理解上的差距。我们报告了一例46岁诊断为急性未分化白血病的女性病例，该患者在单倍体相合外周血干细胞（PBSC）移植后第201天开始血清总胆红素（T.Bili）、碱性磷酸酶（ALP）和肝功能检查（LFTs）持续升高。患者接受氟达拉滨/全身照射（Flu/TBI）作为清髓预处理方案，并接受移植后环磷酰胺/他克莫司/霉酚酸酯（PTCy/Tac/MMF）作为GVHD预防措施。肝脏活检确诊为GVHD，同时通过相应检查排除了其他可能的病因。最初使用泼尼松和他克莫司治疗，后来加用鲁索替尼，所有治疗均显示效果不佳，T.Bili、ALP和LFTs同时恶化。基于多学科综合评估，我们决定给予1000mg/m²（即1600mg）环磷酰胺（“脉冲式环磷酰胺”），结果从第二天起T.Bili和转氨酶就有显著改善。观察到对脉冲式环磷酰胺有持久反应，所有指标在55天内恢复正常（“完全缓解”）且无复发。患者目前健康状况良好，肝脏GVHD未复发。据我们所知，这是首例对包括类固醇、他克莫司和鲁索替尼在内的多种药物难治的IV级肝脏GVHD对脉冲式环磷酰胺表现出完全缓解的病例。这一成功突出了环磷酰胺这种强效且经济有效的化疗药物在治疗多药难治性GVHD中的潜在治疗作用。有必要进行大规模临床试验以验证其在这种情况下的疗效。
