Müller-Scholden Lara, Deinlein Frank, Eyrich Matthias, Schlegel Paul Gerhardt, Wiegering Verena, Wölfl Matthias
Pediatric Oncology, Hematology and Stem Cell Transplantation Program, University Children's Hospital Würzburg, Würzburg, Germany.
Front Pediatr. 2022 May 6;10:881612. doi: 10.3389/fped.2022.881612. eCollection 2022.
EBV associated lymphoproliferative disorders (EBV LPD) are a known complication following solid organ or hematopoietic stem cell transplantation. The disturbance of the immune system leads to a lack of control of latent EBV-infected B-cells, as control by T-cells is mandatory to prevent uninhibited cell proliferation. EBV LPD in other settings is less frequent and etiology and pathogenesis are not completely understood.
We present the case of an 18-year old adolescent suffering from lymphoblastic T-cell lymphoma who developed a life-threatening EBV associated B-cell lymphoma while he was under therapy with 6-MP (6- mercaptopurine). An underlying homozygous TPMT (thiopurine S-methyltransferase) deficiency with subsequent insufficient degradation of 6-MP was identified as contributory for the development of a distinct lymphopenia leading to EBV LPD. The patient was successfully treated by discontinuation of 6-MP and initiating rituximab monotherapy.
Rare cases of EBV LPD during therapy with 6-MP are reported in patients with leukemia, but no data about TPMT pharmacogenomics are available. In contrast the disease development in the presented case may be explained by the iatrogenic immunosuppression in the context of TPMT deficiency. While using 6-MP testing of genetic variations is not required for every protocol, although the use of thiopurines in patients with TPMT deficiency can cause severe immunosuppression. Our case suggests that insufficient degradation of 6-MP can have significant consequences despite dose reduction.
When using thiopurines, TPMT genetics should be initiated and strict drug monitoring and dose adjusting must be performed by a specialized center.
EBV相关淋巴增殖性疾病（EBV LPD）是实体器官或造血干细胞移植后已知的并发症。免疫系统紊乱导致对潜伏性EBV感染的B细胞缺乏控制，因为T细胞的控制对于防止细胞不受抑制地增殖至关重要。EBV LPD在其他情况下较少见，其病因和发病机制尚未完全明确。
我们报告了一例18岁患有淋巴母细胞性T细胞淋巴瘤的青少年病例，该患者在接受6-巯基嘌呤（6-MP）治疗时发生了危及生命的EBV相关B细胞淋巴瘤。发现潜在的纯合子硫嘌呤甲基转移酶（TPMT）缺乏以及随后6-MP降解不足是导致明显淋巴细胞减少并进而引发EBV LPD的原因。通过停用6-MP并开始利妥昔单抗单药治疗，患者得到成功治疗。
白血病患者在接受6-MP治疗期间发生EBV LPD的罕见病例已有报道，但尚无关于TPMT药物基因组学的数据。相比之下，本病例中的疾病发展可能是由TPMT缺乏情况下的医源性免疫抑制所解释。虽然并非每个治疗方案都需要对使用6-MP进行基因变异检测，但TPMT缺乏的患者使用硫嘌呤类药物可导致严重免疫抑制。我们的病例表明，尽管剂量降低，6-MP降解不足仍可能产生重大后果。
使用硫嘌呤类药物时，应启动TPMT基因检测，且必须由专业中心进行严格的药物监测和剂量调整。
