Introduction

Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with MDS. Prior studies have shown no overall-survival (OS) advantage of any conditioning regimen over the others. Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM) compared to myeloablative conditioning (MAC), however, relapse rates are higher, resulting in similar OS. Fludarabine and treosulfan (FT) is a reduced-toxicity regimen with intense anti leukemia activity in patients with myeloid malignancies. We explored outcomes following FT conditioning in comparison with other regimens.

Methods

We retrospectively analyzed SCT outcomes of MDS patients reported to the chronic malignancies working party of EBMT (n=1722). The conditioning regimens were defined according to standard EBMT criteria and included FT (n=367), RIC (n=687) or MAC (n=668).

Results

FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0.001). More FT recipients had untreated MDS at SCT, 45%, 26% and 36%, respectively (P < 0.001). Disease status at diagnosis, cytogenetics, secondary origin and prior transformation to AML, were not different between the regimens. With a median follow-up of 20 months (1-171), 807 patients are alive, 328 died of relapse and 587 had NRM. The 5-year rates of relapse, NRM and OS for the entire group were 21% (95%CI, 19-23), 35% (95%CI, 33-38) and 44% (95%CI, 42-437), respectively. Relapse rates were similar after FT and MAC, 16% (13-21) and 19% (16-22), respectively, significantly lower than after RIC, 25% (21-28) (P = 0.003). Multivariate analysis (MVA) identified age >55 years (HR 1.42), advanced histology (RAEB 1/2, HR 2.01/ 1.73), prior transformation to AML (HR 1.87), refractory disease to prior therapies (HR 1.75) secondary origin (HR 1.33) and poor cytogenetics (HR 2.83) as associated with higher relapse risk. FT conditioning was associated with a lower risk (HR 0.63, P = 0.006). NRM was lower after FT and RIC than after MAC, 34% (29-39), 33% (30-37) and 38% (35-40), respectively (P = 0.05). MVA identified age >55 years (HR 1.39) and MAC (HR 1.34) as associated with higher NRM, while SCT from sibling donor (HR 0.81) and in CR (HR 0.80) were associated with a lower risk. In all, 5-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), after FT, RIC and MAC, respectively (Figure 1, P = 0.03). MVA identified age >55 years (HR 1.39), advanced histology (RAEB 1/2, HR 1.35/ 1.10), prior transformation to AML (HR 1.37), and poor cytogenetics (HR 1.58) as associated with lower OS. FT conditioning was associated with better OS (HR 0.79, P = 0.01).

Conclusions

FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials.

中文翻译：

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与标准降低强度或清髓条件治疗方案相比，使用基于硫丹的骨髓增生异常综合征（MDS）患者的异基因干细胞移植。EBMT慢性恶性肿瘤工作组的报告

介绍

同种异体干细胞移植（SCT）是MDS患者的潜在治疗方法。先前的研究表明，任何一种调理方案都没有比其他方案具有总体生存（OS）优势。强度降低调理（RIC）与非清髓调理（MAC）相比通常具有较低的非复发死亡率（NRM），但是，复发率较高，导致相似的OS。氟达拉滨和treosulfan（FT）是一种降低毒性的方案，对患有髓样恶性肿瘤的患者具有强烈的抗白血病活性。与其他方案相比，我们探讨了FT调节后的结局。

方法

我们回顾性分析了报告给EBMT慢性恶性肿瘤工作组（n = 1722）的MDS患者的SCT结果。调理方案是根据标准EBMT标准定义的，包括FT（n = 367），RIC（n = 687）或MAC（n = 668）。

结果

FT和RIC接受者比MAC接受者年龄大，中位年龄分别为59、59和51岁（P <0.001）。接受FT治疗的FT接受者中，未经治疗的MDS分别为45％，26％和36％（P <0.001）。各方案在诊断时的疾病状态，细胞遗传学，继发起源和先前向AML的转化无差异。中位随访20个月（1-171），有807例患者存活，328例死于复发，587例患有NRM。整个组的5年复发率，NRM和OS分别为21％（95％CI，19-23），35％（95％CI，33-38）和44％（95％CI，42-437） ）， 分别。FT和MAC后的复发率相似，分别为16％（13-21）和19％（16-22），显着低于RIC后的25％（21-28）（P = 0.003）。多变量分析（MVA）确定年龄> 55岁（HR 1.42），高级组织学（RAEB 1/2，HR 2.01 / 1.73），先前已转换为AML（HR 1.87），难治性疾病至先前疗法（HR 1.75）次要来源（HR 1.33）和不良的细胞遗传学（HR 2.83），与复发风险较高相关。FT调理的风险较低（HR 0.63，P = 0.006）。FT和RIC后的NRM分别低于MAC后的34％（29-39），33％（30-37）和38％（35-40）（P = 0.05）。MVA确认年龄> 55岁（HR 1.39）和MAC（HR 1.34）与较高的NRM相关，而同胞供者的SCT（HR 0.81）和CR（HR 0.80）与较低的风险相关。总的来说，在FT，RIC和MAC之后，五年期OS分别为50％（44-55），43％（38-47）和43％（39-47）（图1，P = 0.03）。MVA确定年龄> 55岁（HR 1.39），高级组织学（RAEB 1/2，HR 1.35 / 1.10），先前向AML的转化（HR 1.37）和细胞遗传学不良（HR 1。58）与较低的OS相关联。FT调节与更好的OS相关（HR 0.79，P = 0.01）。

结论

FT与MAC具有相似的低复发率，而与RIC具有相似的低NRM，从而使结果优于RIC和MAC。FT可能是MDS中SCT的首选治疗方案。这些观察结果值得在随机前瞻性试验中进一步研究。