Prognostic Relevance of “Early-Onset” Graft-Versus-Host Disease Following Nonmyeloablative Hematopoietic Cell Transplantation.
Prognostic Relevance of “Early-Onset” Graft-Versus-Host Disease Following Nonmyeloablative Hematopoietic Cell Transplantation.
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非清髓性造血细胞移植后“早发”移植物抗宿主病的预后相关性。
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发表时间：
2004
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通讯作者：
R. Storb
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作者：
M. Mielcarek;L. Burroughs;W. Leisenring;P. Martin;Razvan Diaconezcu;B. Sandmaier;D. Maloney;T. Chauncey;M. Maris;J. Shizuru;K. Blume;U. Hegenbart;D. Niederwieser;S. Forman;B. Bruno;A. Woolfrey;R. Storb
我们已经表明，非清髓性造血细胞移植（HCT）后发生移植物抗宿主病（GVHD）的中位时间比清髓性造血细胞移植（HCT）后晚2个月（Blood 102:756, 2003）。在这里，我们询问GVHD的发病时间与非消融性HCT后的生存之间是否存在关联。我们回顾性分析了395例血液病患者的结果，这些患者来自hla匹配相关（n=297）或非相关供者（n=98）的非清髓性HCT。非消融方案包括有或无氟达拉滨的2 Gy全身照射，接枝后用霉酚酸酯和环孢素进行免疫抑制。II-IV级急性GVHD和广泛慢性GVHD的累积发病率，亲属供者分别为45%和47%，非亲属供者分别为68%和68%。泼尼松启动的中位时间是急性和慢性GVHD发病的标志，兄弟姐妹供体患者的中位时间为79天（范围8-799），非亲属供体患者的中位时间为28天（范围5-104）。在相关移植物后发生GVHD的患者中（n=187），在第50天前开始使用强的松的患者中，4年非复发死亡率（NRM）的累积发生率为55%（“早期开始”），而在第50天或之后开始使用强的松的患者中（“晚开始”；p =1）， 4年非复发死亡率（NRM）的累积发生率为29%，既不能预测发病时间，也不能预测GVHD的总发病率。在开始使用泼尼松治疗GVHD的患者中，有移植前合并症的患者发生NRM的风险显著高于无合并症的患者（风险比为2.6；95%可信区间为1.2-5.4;p=0.01）。非亲属供体非清髓性HCT后，泼尼松起始时间与患者存活无关联。总之，早发性GVHD（在第50天之前开始使用强的松）与来自hla相同的相关供者的非清髓性HCT后NRM增加和生存率差相关，并确定了可能从更积极的GVHD初始治疗中获益的患者亚组。
We have shown that graft-versus-host disease (GVHD) after nonmyeloablative hematopoietic cell transplantation (HCT) occurs a median of 2 months later than after myeloablative HCT ( Blood 102:756, 2003). Here, we asked whether there was an association between the time of onset of GVHD and survival after nonablative HCT. We retrospectively analyzed outcomes among 395 patients with hematologic diseases who had nonmyeloablative HCT from HLA-matched related (n=297) or unrelated donors (n=98). The nonablative regimen consisted of 2 Gy total body irradiation with or without fludarabine followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II-IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with grafts from related donors, and 68% and 68%, respectively, with those from unrelated donors. The median time to prednisone initiation, a marker for the onset of both acute and chronic GVHD, was 79 (range, 8–799) days among patients with sibling donors and 28 (range, 5–104) days among patients with unrelated donors. Among patients with GVHD following related grafts (n=187), the cumulative incidence of non-relapse mortality (NRM) at 4 years was 55% among the tertile of patients who initiated prednisone before day 50 (“early initiation”), and 29% when prednisone was initiated on or after day 50 (“late initiation”; p =1) was neither predictive for the time of onset nor the overall incidence of GVHD. Among patients who initiated prednisone for the treatment of GVHD, those with pretransplant comorbidities had a significantly greater hazard of NRM than those without comorbidities (hazard ratio, 2.6; 95% confidence interval, 1.2–5.4; p=0.01). There was no association between time to prednisone initiation and survival after nonmyeloablative HCT from unrelated donors. In conclusion, early-onset GVHD (prednisone initiation before day 50) was associated with increased NRM and poor survival after nonmyeloablative HCT from HLA-identical related donors and identified a subgroup of patients who might benefit from more aggressive primary therapy of GVHD.
Hazard of Non-Relapse Mortality According to Time to Prednisone Initiation (HLA-Matched Related Transplants)
| Prednisone Initiation for Treatment of GVHD [Day] | Hazard Ratio† | 95% Confidence Interval | P* | P** |
|:-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| ------------- | ----------------------- | ------ | ----- |
| †Cox proportional hazards model treating “early vs. late prednisone initiation” as a time-dependent covariate; *compared to “not initiated”; **comparison of prednisone initiation <day 50 vs.≥day 50 |
| Not initiated | 1.0 | \---| | \---| | \---| |
| <50 | 11.4 | 5.3–24.4 | <0.001 | \---| |
| ≥50 | 6.3 | 2.8–14.5 | <0.001 | 0.04 |