Heelan Francine, Mallick Ranjeeta, Bryant Adam, Radhwi Osman, Atkins Harold, Huebsch Lothar, Bredeson Chris, Allan David, Kekre Natasha
University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada.
The Ottawa Hospital Department of Biostatistics, University of Ottawa, Ottawa, Ontario, Canada.
Biol Blood Marrow Transplant. 2020 Jul;26(7):1298-1302. doi: 10.1016/j.bbmt.2020.02.026. Epub 2020 Mar 9.
Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of graft-versus-host disease (GVHD) with hematopoietic cell transplantation, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that ATG dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. We sought to determine if ALC at the time of transplant could impact clinical outcomes. We conducted a retrospective single-center study analyzing all consecutive patients at The Ottawa Hospital who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (thymoglobulin) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analyses were used to determine if any patient- or transplant-related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. In total, 111 patients met inclusion, with a median age of 50 years (range, 19 to 70). The most common diagnoses were acute myelogenous leukemia (43%), Myelodysplasia/myeloproliferative neoplasms (13%), and lymphoma (12%). The median weight at time of conditioning was 80.3 kg (range, 45 to 216). The median ALC on the first day of ATG administration was 0.1 × 10/L (range, 0 to 190). The median total dose of ATG received was 201 mg (range, 112 to 540 mg). The incidence of acute and chronic GVHD was 35.1% and 21.6%, respectively. In the multivariate model, the actual dose of ATG given to patients was not associated with GVHD (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.99 to 1.25; P = .07), relapse (HR, 1.13; 95% CI, 0.98 to 1.30; P = .1), or mortality (HR, 1.09; 95% CI, 0.92 to 1.28; P = .32). Similarly, the pretransplant ALC was not associated with GVHD (HR, 1; P = .82), relapse (HR, 1; P = .90), or mortality (HR, 1; P = .39). If patients had received ALC-based dosing according to previously published work (Admiraal et al., Lancet Haematol 2017), the mean total dose of ATG received would have been 1205 mg, more than 5 times the mean dose that was actually given based on weight. With GVHD outcomes being similar to that published by Admiraal et al. and ALC not independently associated with outcomes in our study, further studies are still needed to compare standard weight-based dosing to ALC-based dosing of ATG in matched unrelated donor stem cell transplant.
抗胸腺细胞球蛋白（ATG）用于降低造血细胞移植中移植物抗宿主病（GVHD）的发生率和严重程度，但最佳剂量尚未确定。我们之前已经证明，预处理中2.5mg/kg的ATG可降低无关供体移植中GVHD的发生率。最近的文献表明，基于绝对淋巴细胞计数（ALC）的ATG给药可能会使药物暴露更优化。我们试图确定移植时的ALC是否会影响临床结果。我们进行了一项回顾性单中心研究，分析了渥太华医院2009年至2014年间所有接受匹配无关供体干细胞移植并使用ATG的连续患者。患者在第-2天接受0.5mg/kg的兔ATG（胸腺球蛋白），在第-1天接受2.0mg/kg。采用单因素和多因素分析来确定是否有任何患者或移植相关因素，包括体重、ALC和给予的ATG总剂量，会影响GVHD、复发或死亡率。共有111名患者符合纳入标准，中位年龄为50岁（范围19至70岁）。最常见的诊断是急性髓系白血病（43%）、骨髓增生异常/骨髓增殖性肿瘤（13%）和淋巴瘤（12%）。预处理时的中位体重为80.3kg（范围45至216kg）。ATG给药第一天的中位ALC为0.1×10/L（范围0至190）。接受的ATG中位总剂量为201mg（范围112至540mg）。急性和慢性GVHD的发生率分别为35.1%和21.6%。在多因素模型中，给予患者的ATG实际剂量与GVHD（风险比[HR]，1.11；95%置信区间[CI]，0.99至1.25；P=0.07）、复发（HR，1.13；95%CI，0.98至1.30；P=0.1）或死亡率（HR，1.09；95%CI，0.92至1.28；P=0.32）均无关。同样，移植前的ALC与GVHD（HR，1；P=0.82）、复发（HR，1；P=0.90）或死亡率（HR，1；P=0.39）也无关。如果根据之前发表的研究（Admiraal等人，《柳叶刀·血液学》2017年），患者接受基于ALC的给药，那么接受的ATG平均总剂量将为1205mg，是基于体重实际给予的平均剂量的5倍多。由于GVHD结果与Admiraal等人发表的结果相似，且在我们的研究中ALC与结果无独立相关性，因此仍需要进一步研究来比较匹配无关供体干细胞移植中ATG基于标准体重给药与基于ALC给药的情况。
