Background

Our centre performed the first ex-vivo T-lymphocyte depleted (TCD) haploidentical allograft in 1987 in a child with PID. Different TCD methods have been used including CAMPATH-1M TCD marrow (n=34), CD34+ selected marrow (CD34-S, n=34), CD3/CD19 TCD PBSC (n=7), and CD3-TCRαβ/CD19 TCD PBSC (αβ-TCD, n=30)). This study aimed to examine transplant outcomes according to different methods in children with PID.

Methods

Between Jan 1987 and Mar 2019, 105 PID patients underwent first TCD allograft and were included in the study. Thirteen patients who received gene-modified add-back T cells were excluded. The main outcomes of interest were OS, EFS and graft failure. An event was defined as death, graft failure or second procedures for slipping chimerism. Other endpoints were neutrophil engraftment, GvHD, immune reconstitution and donor chimerism. Log-rank test was used to compare OS and EFS according to TCD methods. Cumulative incidences (CI) graft failure was calculated using a competing risk analysis, considering death as a competing event. Multilevel mixed effects modelling was performed for the longitudinal analysis of immune reconstitution and CAMPATH-1M was used as a reference group.

Results

Donors were haploidentical donor (n=84, 83%), MUD/MFD (n=9, 9%) and MMFD/MMUD (n=8, 8%). 94% received conditioning. Thirteen (12%) patients had aGvHD, of whom 3 had grade III-IV. None had cGvHD. The cause of death changed from predominantly infection (18/25, 72%) in CAMPATH-IM and CD34-S to non-infectious causes in all 6 deaths in CD3/CD19 and αβ-TCD. Analysis by TCD methods revealed a 5-year OS of 58% (95% CI, 40-73%) for CAMPATH-1M, 68% (49-81%) for CD34-S, 69% (22-91%) for CD3/CD19 TCD and 83% (61-93%) for (αβ-TCD (p=0.24). Age was a significant predictor of OS for non-SCID PID (p=0.02). The corresponding EFS was 46% (29-62%) for CAMPATH-1M, 47% (30-62%) for CD34-S, 69% (95% CI, 22-91%) for CD3/CD19 TCD and 83% (61-93%) for αβ-TCD (p=0.04) (Fig 1B) The CI of graft failure reduced significantly, from 29% (14-61%) for CAMPATH-1M, to 19% (95%CI, 8-45%) for CD34-S, 17% (2-18%) for CD3/CD19 TCD and none had graft failure in αβ-TCD (p=0.002) (Figure 1C). CD4+ lymphocytes were significantly higher in CD34-S at months 4 (p=0.02), 5 (p=0.01), and 6 (p=0.006) post-HCT and at month 4 (p=0.04) post-HCT in αβ-TCD when compared to CAMPATH-1M (Fig 1D). The median donor myeloid chimerism at last follow-up was higher in newer TCD; 100% (range, 0-100%) for αβ-TCD, 93% (0-100%) for CD3/CD 19 depletion, 6% (0 -49%) for CD34-S, 20% (0-100%) for CAMPATH-1M (p<0.001). There was no significant difference in donor T-lymphocyte chimerism between TCD.

Conclusions

Outcomes after CD3+TCR αβ/CD19+ depletion are superior to previously used TCD methods. In an experienced centre it is a safe alternative procedure and enables a wide spectrum of PID to be transplanted. The result has led to evolution of donor hierarchy in our centre.

中文翻译：

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原发性免疫功能低下儿童造血细胞移植后不同的体内T细胞耗竭策略对结果的影响

背景

Our centre performed the first ex-vivo T-lymphocyte depleted (TCD) haploidentical allograft in 1987 in a child with PID. Different TCD methods have been used including CAMPATH-1M TCD marrow (n=34), CD34+ selected marrow (CD34-S, n=34), CD3/CD19 TCD PBSC (n=7), and CD3-TCRαβ/CD19 TCD PBSC (αβ-TCD, n=30)). This study aimed to examine transplant outcomes according to different methods in children with PID.

Methods

Between Jan 1987 and Mar 2019, 105 PID patients underwent first TCD allograft and were included in the study. Thirteen patients who received gene-modified add-back T cells were excluded. The main outcomes of interest were OS, EFS and graft failure. An event was defined as death, graft failure or second procedures for slipping chimerism. Other endpoints were neutrophil engraftment, GvHD, immune reconstitution and donor chimerism. Log-rank test was used to compare OS and EFS according to TCD methods. Cumulative incidences (CI) graft failure was calculated using a competing risk analysis, considering death as a competing event. Multilevel mixed effects modelling was performed for the longitudinal analysis of immune reconstitution and CAMPATH-1M was used as a reference group.

Results

捐赠者是单倍体捐赠者（n = 84，83％），MUD / MFD（n = 9，9％）和MMFD / MMUD（n = 8，8％）。94％的人接受了调理。13名（12％）患者患有aGvHD，其中3名具有III-IV级。没有人拥有cGvHD。死亡原因从CAMPATH-IM和CD34-S的主要感染（18 / 25，72％）改变为CD3 / CD19和αβ-TCD的全部6例死亡中的非感染性原因。通过TCD方法进行的分析显示，CAMPATH-1M的5年OS为58％（95％CI，40-73％），CD34-S为68％（49-81％），69％（22-91％） CD3 / CD19 TCD和（αβ-TCD为83％（61-93％）（p = 0.24）。年龄是非SCID PID的OS的重要预测指标（p = 0.02）。相应的EFS为46％（29） CAMPATH-1M -62％），CD34-S 47％（30-62％），CD3 / CD19 TCD 69％（95％CI，22-91％）和αβ83％（61-93％） TCD（p= 0.04）（图1B）移植失败的CI显着降低，从CAMPATH-1M的29％（14-61％）降至CD34-S的19％（95％CI，8-45％），17％（ CD3 / CD19 TCD占2-18％），αβ-TCD中没有一个移植失败（p = 0.002）（图1C）。HCT后第4个月（p = 0.02），5（p = 0.01）和6（p = 0.006）和HCT后第4个月（p = 0.04）的CD34-S中的CD4 +淋巴细胞明显高于αβ-与CAMPATH-1M相比，TCD（图1D）。在最新的TCD中，最后一次随访的供体骨髓中位嵌合率较高。αβ-TCD为100％（范围0-100％），CD3 / CD 19耗尽为93％（0-100％），CD34-S为6％（0 -49％），20％（0-100％） ）对于CAMPATH-1M（p<0.001）。在TCD之间，供体T淋巴细胞嵌合没有显着差异。

结论

CD3 + TCRαβ/ CD19 +耗竭后的结果优于以前使用的TCD方法。在经验丰富的中心，这是一种安全的替代程序，可以移植各种PID。结果导致了我们中心捐助者等级制度的演变。