Introduction

To assess the therapeutic potential of non-TBI conditioning and T-cell depleted (TCD) allo HCT for high risk malignancies, we conducted a prospective trial comparing: A. our standard 1375 cGy HFTBI + Thiotepa, 5mg/kg/dx2 + cyclophosphamide, 60mg/kg/dx2 vs B. Busulfex, 0.8mg/kg/6hx12(PK adjusted) + Melphalan 70mg/kg/dx2 + Fludarabine 25mg/m²/dx5 vs C. Clofarabine 20mg/m²/dx5 + Melphalan 70mg/m²/dx2 + Thiotepa 5mg/kg/dx2 as preparation for T-cell depleted CD34⁺ PBSC allografts isolated by the CliniMACS system. All pts received Thymoglobulin pre-transplant to prevent infection. No GVHD prophylaxis was given post transplant. Pts were stratified to arms A, B or C based on disease stage and clinical factors enhancing TBI risks (e.g. age >60m prior therapy or comorbidities), with Arm B the non-TBI arm used for myeloid malignancies and Arm C for lymphoid malignancies.

Results

From 5/13/10 to 12/31/16, 283 consenting patients were transplanted (106 in Arm A, 144 in B, 33 in C). All pts engrafted by day 10-11; 3 pts in Arm B and 1 in C had late graft failure with sustained T-cell chimerism. The 3 in Arm B reconstituted after TCD PBSC boost alone (N=2) or after CTX/ATG (N=1) conditioning. Cumulative Incidence (C.I.) of Acute Grade 3-4 GVHD was higher in Arm A (12%) than in B (4.2%) or C (3.0%) (p = 0.03), as was C. GVHD (Arm A 8.5%; B (1.5% p = 0.02); C (3%)). CI of relapse at 3 yrs was similar in all arms (A=28%; B=21%; C15%) (p = 0.22). Although pts in Arm B were older (med. 58.5 yrs) than in A (32 yrs) or C(32 yrs), NRM at 3 yrs for Arm B (16%) and A (14.8) were similar. However, NRM in Arm C (32.7%) was higher (p = 0.09).

Because the median age of patients in Arm B (58.5 yrs) differed significantly from Arms A (31.9 yrs) and C (32.3 yrs); we evaluated DFS for each arm in 20 year cohorts of increasing age (Fig 1 A,B,C). Because of low cohort size, pts in Arm C aged <40 were compared to those ≥ 40. In Arm A, 5 year DFS rates were 54.2% (Age ≤20), 62.9% (Age>20-40) and 54% (Age 40-60). In Arm B, 5 year DFS for pts ≤ 20 was 69.3% and 85.7% for those >20-40, 48.6% for those >40-60 and 46.8% for those 60+ respectively (p = 0.02). In Arm C, 5 year DFS for pts ≤40 was 65% and for those >40, 30.7% (p = 0.01).

Conclusion

These results demonstrate that these chemotherapy-based regimens secure engraftment and hematopoietic reconstitution and similarly low rates of GVHD and relapse. They also suggest an advantage for patients ≤40 treated on Arm B. In >40-60yo patients, DFS for Arm B is equivalent to Arm A and also yields favorable results in older pts (>60-73 yrs). However, while patients ≤40 yrs of age fared well on Arm C, older patients were less likely to achieve extended OS and DFS than those on Arms A or B, likely as a consequence of increased TRM.

中文翻译：

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与基于TBI的条件相比，两种基于化学疗法的预备方案与CD34 ⁺选定的T细胞耗竭型替代品联合用于高危血液系统恶性肿瘤的结果：前瞻性临床试验NCT 01119066

介绍

为了评估非TBI调节和T细胞耗竭（TCD）同种HCT对高危恶性肿瘤的治疗潜力，我们进行了一项前瞻性试验，比较：A.我们的标准1375 cGy HFTBI + Thiotepa，5mg / kg / dx2 +环磷酰胺， 60mg / kg / dx2相对于B. Busulfex，0.8mg / kg / 6hx12（PK调整）+ Melphalan 70mg / kg / dx2 +氟达拉滨25mg / m ² / dx5 vs C.氯法拉滨20mg / m ² / dx5 + Melphalan 70mg / m ² / dx2 + Thiotepa 5mg / kg / dx2作为制备T细胞耗竭的CD34 ⁺通过CliniMACS系统分离的PBSC同种异体移植物。所有患者均接受胸腺球蛋白移植前预防感染。移植后未预防GVHD。根据疾病阶段和增加TBI风险的临床因素（例如，年龄> 60m的既往治疗或合并症），将点分为A，B或C组，其中B组为非TBI组用于髓样恶性肿瘤，C组为淋巴系统恶性肿瘤。

结果

从5/13/10到12/31/16，移植了283名同意患者（A组为106，B组为144，C组为33）。第10-11天移植的所有pt；B组3分和C组1分具有晚期T细胞嵌合现象，但移植失败。仅在TCD PBSC增强后（N = 2）或在CTX / ATG（N = 1）调节后，臂B中的3重构。A组急性3-4 GVHD的累积发生率（CI）高于B组（4.2％）或C（3.0％）（p = 0.03），C组也是如此。GVHD（手臂A 8.5％ ； B（1.5％p = 0.02）； C（3％））。所有组在3年时复发的CI均相似（A = 28％； B = 21％； C15％）（p = 0.22）。尽管手臂B的点数（58.5岁）比A点（32岁）或C点（32岁）大，但是手臂3点（16％）和A（34.8岁）的NRM相似。但是，手臂C的NRM（32.7％）更高（p = 0.09）。

因为B组（58.5岁）患者的中位年龄与A组（31.9岁）和C组（32.3岁）有显着差异。我们在年龄增加的20年队列中评估了每个手臂的DFS（图1 A，B，C）。由于队列规模较小，将年龄小于40岁的C组患者的pts与≥40岁的Cpt进行了比较。在年龄A组中，5年DFS率分别为54.2％（年龄≤20），62.9％（年龄> 20-40）和54％（ 40-60岁）。在B组中，pt≤20的5年DFS分别是> 20-40的那些的69.3％和85.7％，> 40-60的那些的48.6％和60+的46.8％（p = 0.02）。在C组中，pt≤40的5年DFS为65％，大于40的DFS为30.7％（p = 0.01）。

结论

这些结果表明，这些基于化学疗法的方案可确保植入和造血重建，并降低GVHD和复发率。他们还建议使用Arm B≤40的患者有一个优势。在40-40岁以上的患者中，Arm B的DFS等同于Arm A，并且在老年患者（> 60-73岁）中也会产生良好的效果。但是，尽管年龄≤40岁的患者在C组中表现良好，但较之A组或B组，老年患者获得OS和DFS延长的可能性较小，这可能是TRM升高的结果。