Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial.
Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial.
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DOI：
10.1016/j.bbmt.2015.09.004
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Dennis M
中科院分区：
文献类型：
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作者：
Craddock C;Jilani N;Siddique S;Yap C;Khan J;Nagra S;Ward J;Ferguson P;Hazlewood P;Buka R;Vyas P;Goodyear O;Tholouli E;Crawley C;Russell N;Byrne J;Malladi R;Snowden J;Dennis M
疾病复发是急性髓系白血病(AML)异基因干细胞移植(SCT)后治疗失败的主要原因。除了在急性髓细胞白血病中表现出显著的临床活性外，氮胞替丁(AZA)还上调假定的肿瘤抗原，诱导CD8+T细胞反应，具有增强移植物抗白血病效应的潜力。因此，我们研究了51例接受同种异体SCT的AML患者在移植后第一年使用AZA的可行性和临床后遗症。14名患者没有开始AZA，原因是移植并发症或撤回同意。37例患者在移植后中位时间54天(40~194天)开始AZA，大多数患者耐受性良好。31例患者完成了3个或3个以上的AZA周期。16例患者在移植后中位时间8个月内复发。没有患者发展为广泛的慢性移植物抗宿主病。在28名患者中研究了移植后CD8+T细胞对一种或多种肿瘤特异性多肽的诱导反应。诱导CD8+T细胞反应与降低疾病复发风险(风险比[HR]，0.30；95%可信区间[CI]，0.10至.85；P=0.02)和提高无复发生存率(HR，0.29；95%CI，0.10至0.83；P=0.02)相关，并将死亡作为竞争风险考虑在内。总而言之，AZA在移植后耐受性良好，似乎有能力降低CD8+T细胞对肿瘤抗原有反应的患者的复发风险。这些观察结果需要在一项前瞻性临床试验中得到证实。在异基因干细胞移植后，大多数急性髓系白血病患者对阿扎替丁耐受性良好。移植后应用氮杂西汀与慢性移植物抗宿主病的风险较低有关。显示CD8+T细胞对肿瘤抗原有反应的患者复发风险较低。
Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8+ T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8+ T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8+ T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8+ T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial. Azacitidine is well tolerated in the majority of patients with acute myeloid leukemia after allogeneic stem cell transplantation. Administration of post-transplantation azacitidine is associated with a low risk of chronic graft-versus-host disease. Patients who demonstrate a CD8+ T cell response to tumor antigens demonstrate a lower risk of relapse.