Mutations resulting in increased PI3K signaling confer increased risk of B cell lymphoma, recurrent infections, poor viral control, and autoimmunity. Allogeneic HCT is curative, but the optimal approach to HCT for these patients is still evolving as experience grows. Herein, we present the clinical outcomes of 27 patients transplanted for activating PI3K mutations. Required approvals were obtained by contributing centers.

Nineteen PIK3CD patients and 8 PIK3R1 patients received 22 and 10 HCTs respectively, at median age 12 years (range 2-66) at time of first HCT. Significant pre-HCT comorbidities were common, Fig 1. Conditioning platforms varied in intensity; most included serotherapy (84%). With median survivor follow up of 26.3 months from first HCT (range 2.4-71.8), overall survival was 85% (3 infectious deaths and 1 due to organ toxicity); graft failure (GF)-free survival (GFFS) was estimated at 80% at 1 year but declined to 68% by 2 years, Fig 2.

Neutrophil engraftment occurred at median 15.5 days (range 11-33) with autologous recovery in 1 patient at day +14 and another deceased prior to engraftment. Four engrafted patients are alive and well despite mixed donor chimerism (<95%). Nine (33%) patients required 24 total subsequent unplanned donor cell infusions (DCI) for mixed chimerism (n=15), poor graft function (n=2), infection (n=1), GF (n=3), malignancy relapse (n=1), or to improve immune reconstitution (n=2).

Grade 2-4 acute graft versus host disease (GVHD) occurred in 27% patients, with Grade 3-4 acute GVHD and limited self-resolved chronic GVHD in 1 (4%). Organ toxicities and infectious complications are summarized in Fig 3; CMV infection requiring treatment occurred in 11 (41%) patients with disease in 3 (11%).

Serotherapy use, conditioning intensity, and degree of donor human leukocyte antigen (HLA) match were not significantly associated with cumulative incidence of GF or subsequent unplanned DCI (with death as a competing risk), while mTOR inhibitor use post-HCT was associated with subsequent unplanned DCI for graft augmentation or GF (p=0.006). An mTOR inhibitor was used within the year following 12 HCTs, for primary GVHD prophylaxis (n=7) or to treat disease manifestations or GVHD; loss of chimerism and/or need for subsequent DCI occurred in 9 of these.

Patients with activating PI3K mutations are at overall significant risk of GF or need for subsequent DCI. While we found no association with GF or DCI for discrete elements such as serotherapy use, donor source, or conditioning intensity, small numbers preclude conclusions regarding the optimal HCT approach, and more HCTs with longer follow up are needed to refine these preliminary findings. Post-HCT mTOR inhibitor exposure was associated with need for subsequent unplanned DCI, perhaps by providing a survival advantage to host lymphocytes, and may thus be detrimental in these patients during the early post-HCT timeframe.

导致PI3K信号转导增加的突变会增加B细胞淋巴瘤，反复感染，病毒控制不良和自身免疫的风险。同种异体HCT可以治愈，但是随着经验的增长，针对这些患者的最佳HCT方法仍在发展中。本文中，我们介绍了27例因激活P​​I3K突变而移植的患者的临床结局。所需的批准是由捐助中心获得的。

首次HCT时，中位年龄12岁（范围2-66）的19例PIK3CD患者和8例PIK3R1患者分别接受了22次和10次HCT。HCT前合并症很常见，图1。调节平台的强度各不相同。大多数包括血清疗法（84％）。自首次HCT起中位生存期随访26.3个月（范围2.4-71.8），总生存率为85％（3例感染死亡和1例因器官毒性死亡）；无移植物存活（GF）的生存期（GFFS）在1年时估计为80％，但到2年时下降到68％，图2。

中性粒细胞植入发生在中位数15.5天（范围11-33），其中1名患者在+14天自体恢复，另一名患者在植入前死亡。尽管有混合的供体嵌合体（<95％），但有四名移入患者仍活着并且健康。9名（33％）患者需要进行24次随后的计划外供体细胞输注（DCI），以进行混合嵌合（n = 15），移植物功能不良（n = 2），感染（n = 1），GF（n = 3），恶性肿瘤复发（n = 1），或改善免疫重建（n = 2）。

在27％的患者中发生2-4级急性移植物抗宿主病（GVHD），其中3-4级的急性GVHD和有限的自我解决的慢性GVHD发生在1名患者中（4％）。器官毒性和感染并发症总结在图3中。需要治疗的CMV感染发生在11例（41％）疾病患者中，其中3例（11％）。

血清疗法的使用，调节强度和供体人类白细胞抗原（HLA）的匹配程度与GF的累积发生率或随后的计划外DCI（以死亡为竞争风险）无关，而在HCT之后使用mTOR抑制剂与随后的治疗相关用于移植物或GF的计划外DCI（p = 0.006）。在12个HCT之后的一年内，mTOR抑制剂被用于预防GVHD（n = 7）或治疗疾病表现或GVHD。其中9个发生了嵌合现象的丧失和/或需要后续的DCI。

具有活化PI3K突变的患者总体上有明显的GF风险或需要随后的DCI。尽管我们发现与GF或DCI无关，例如血清疗法的使用，供体来源或调节强度等离散因素，但少量的研究无法得出关于最佳HCT方法的结论，需要更多的HCT进行长期随访以完善这些初步发现。HCT后mTOR抑制剂的暴露与后续计划外DCI的需要有关，可能是通过为宿主淋巴细胞提供生存优势，因此可能对这些患者在HCT后的早期阶段有害。