Introduction

DPP-IV is a homodimeric type II transmembrane receptor identical to the leucocyte surface antigen CD26. The interaction of CD26/DPP-IV on T cells with its ligand caveolin-1 on antigen-presenting cells (APC) enhances T cell activation, proliferation, and cytokine production. It also upregulates CD86 on APC resulting in co-stimulation. In a xenograft mouse model, reducing CD26 expression by a monoclonal antibody prevented aGVHD and preserved graft-versus-tumor effects (Hatano et al. BJH 2013). In a pilot trial testing sitagliptin for enhancement of cord blood engraftment, we observed a lower than expected rate of aGVHD (Farag et al. Stem Cell Dev 2013) and hypothesized that CD26/DPP-IV inhibition with sitagliptin may prevent aGVHD following allogeneic PBSC transplants.

Objective

Conduct a prospective phase II trial to test if sitagliptin can reduce the rate of grade II-IV aGVHD by day +100 following myeloablative allogeneic PBSC transplants (ClinicalTrials.gov, NCT02683525). The primary endpoint was grade II-IV aGVHD by day +100.

Methods

Patients received thiotepa (15 mg/kg) and cyclophosphamide (120 mg/kg), followed by G-CSF mobilized PBSC from matched related (6/6 HLA match) or unrelated (10/10 HLA match) donors. Sitagliptin (600 mg q12 hours) was given on days -1 to day +14, together with tacrolimus and sirolimus through day +100, then tapering until day +180. In a Simon two-stage design, <8 of a total of 36 patients developing grade II-IV aGVHD by day +100 would demonstrate a reduction of aGVHD from a historical rate of 30% to <15% with 80% power and type 1 error = 0.1.

Results

Thirty-six (17 M; 19 F) patients of median age 46 (20-59) years were enrolled. Patients had AML (n=19), ALL (n=9), MDS (n=4), and CML (n=4). Transplants were from matched related (13 patients) or unrelated (23 patients) donors. Acute GVHD occurred in 2 of 36 patients by day +100 (1 grade II; 1 grade IV), for cumulative incidences of 5.6% (95% confidence interval [CI], 0% - 13.2%) and 2.8% (95% CI, 0% - 8.2%) for grade II-IV aGVHD and grade III-IV aGVHD at day +100, respectively (Fig 1). An additional patient developed late-onset grade II aGVHD at day +140 following abrupt stopping of immunosuppression on day +100 for low donor chimerism in absence of relapse. Significant toxicities though day +30 included grades III-IV mucositis (n=15), acute kidney injury (4 with high tacrolimus levels, 1 sepsis), viral reactivation/infection (4 CMV, 2 BK, 1 EBV, 1 HHV6), and passenger lymphocyte syndrome (n=2). Non-relapse mortality was 0% at 12 months. With median follow-up of 699 (118-1312) days, the relapse-free survival was 77.2% (95% CI, 63.2% - 91.1%) and overall survival was 94.3% (95% CI, 86.7% - 100%) at 12 months (Fig 2a-b).

Conclusion

CD26/DPP-IV inhibition with sitagliptin is well-tolerated and significantly reduced the rate of aGVHD by day +100 in patients undergoing myeloablative allogeneic PBSCT transplantation.

中文翻译：

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CD26 /二肽基肽酶（DPP）-IV抑制作用的前瞻性II期临床试验可预防异种异体异体外周血干细胞（PBSC）移植后的急性移植物抗宿主病（aGVHD）。

介绍

DPP-IV是与白细胞表面抗原CD26相同的同型二聚体II型跨膜受体。T细胞上CD26 / DPP-IV与抗原呈递细胞（APC）上的配体小窝蛋白1的相互作用增强了T细胞的活化，增殖和细胞因子的产生。它还会上调APC上的CD86，从而引起共刺激。在异种移植小鼠模型中，通过单克隆抗体降低CD26表达可防止aGVHD并保留移植物抗肿瘤效应（Hatano等人，BJH， 2013年）。在一项西他列汀用于增强脐带血植入的试验研究中，我们观察到aGVHD的发生率低于预期（Farag等人，Stem Cell Dev 2013），并假设西他列汀对CD26 / DPP-IV的抑制作用可能阻止了同种异体PBSC移植后的aGVHD 。

目的

进行一项前瞻性II期试验，以测试西他列汀在清髓同种异体PBSC移植后+100天之前是否能降低II-IV aGVHD的发生率（ClinicalTrials.gov，NCT02683525）。主要终点是在第100天之前达到II-IV级aGVHD。

方法

患者接受了thiotepa（15 mg / kg）和环磷酰胺（120 mg / kg），然后从匹配的相关供体（6/6 HLA匹配）或不相关的（10/10 HLA匹配）供体中接受G-CSF动员的PBSC。在第-1天至第+14天给予西他列汀（600 mg q12小时），以及他克莫司和西罗莫司直至+100天，然后逐渐减量至+180天。在Simon的两阶段设计中，在+100天之前发展为II-IV级aGVHD的36名患者中，只有<8名将表现出aGVHD的降低，从历史水平的30％降至<15％，功率为80％且类型为1误差= 0.1。

结果

入选了中位年龄为46（20-59）岁的三十六（17 M; 19 F）患者。患者患有AML（n = 19），ALL（n = 9），MDS（n = 4）和CML（n = 4）。移植来自相配的相关（13例患者）或不相关的（23例）供体。截至+100天（36级患者）中，有36例患者中有2例发生了急性GVHD，累积发生率分别为5.6％（95％置信区间[CI]，0％-13.2％）和2.8％（95％CI） II-IV级aGVHD和III-IV级aGVHD在+100天时分别为0％-8.2％（图1）。另一位患者在+140天突然停止免疫抑制，因为在没有复发的情况下出现低供体嵌合，在+140天突然出现了II型aGVHD晚期发作。尽管在第30天以上具有明显的毒性，包括III-IV级粘膜炎（n = 15），急性肾损伤（他克莫司水平高的4种，败血症1种），病毒的激活/感染（4 CMV，2 BK，1 EBV，1 HHV6）和乘客淋巴细胞综合征（n = 2）。12个月时非复发死亡率为0％。中位随访699（118-1312）天，无复发生存率为77.2％（95％CI，63.2％-91.1％），总生存率为94.3％（95％CI，86.7％-100％）在12个月时（图2a-b）。

结论

西他列汀对CD26 / DPP-IV的抑制作用耐受良好，并且在进行清髓同种异体PBSCT移植的患者中+100天，aGVHD的发生率显着降低。