Ipe Abraham, Angiolillo Anne, Jacobsohn David, Cheng Jinjun, Bornhorst Miriam, Turner Joyce, Vatsayan Anant
School of Medicine and Health Sciences, George Washington University, Washington, DC, United States.
Department of Leukemia/Lymphoma, Children's National Hospital, Washington, DC, United States.
Front Pediatr. 2023 Mar 1;11:1067131. doi: 10.3389/fped.2023.1067131. eCollection 2023.
Germline Checkpoint Kinase 2 gene ( mutations can increase the risk of solid tumors. Recently, they have been identified as risk factors for hematologic malignancies. However, to the best of our knowledge, B-acute lymphoblastic leukemia (B-ALL) has never been described as a presenting manifestation of germline mutation. Chimeric antigen receptor-T (CAR-T) cell therapy directed against CD19 antigen (tisagenlecleucel) is a novel cellular therapy for treatment of relapsed/refractory (R/R) B-ALL. The use of tisagenlecleucel has not been described in patients with mutation.
We describe a case of a pediatric patient with a heterozygous pathogenic germline mutation (c.1100delC; p.Thr367Metfs*15) successfully treated with tisagenlecleucel for relapsed B-ALL to avoid hematopoietic cell transplant (HCT). The twelve-year-old boy was diagnosed with National Cancer Institute (NCI) high-risk B-ALL (white blood cell count >50,000/mcL), with no extramedullary disease. Cytogenetic analysis revealed normal karyotype but fluorescent hybridization (FISH) showed 93% positivity for rearrangement. He was treated as per Children's Oncology Group (COG) AALL1131 therapy and achieved a complete remission. Seven months after diagnosis, he was found to have papillary thyroid carcinoma with no evidence of metastatic disease. The patient underwent a total thyroidectomy with central lymph node biopsy and radioactive iodine therapy. The patient's biological mother and fraternal twin brother carry the same germline mutation with no history of malignancy. The biological father tested negative for the familial mutation. The patient's genetic panel also identified three variants of unclear significance: (c.37 °C > T; p.Arg124Cys), (c.62G > A; p.Cys21Tyr) and (c.139A > G; p.Met47Val). Extended family history also revealed a diagnosis of anaplastic thyroid cancer in maternal uncle at the age of 44 years. Fifteen months after diagnosis the patient had a relapse of B-ALL (both medullary and extramedullary with blasts in CSF), which was successfully treated with tisagenlecleucel. The patient remains in remission 3 years after receiving tisagenlecleucel.
As conventional chemotherapy and radiation can potentially increase the risk of DNA damage and development of secondary malignancies, CD19 CAR-T therapy (tisagenlecleucel) can be used as a substitute for intensive re-induction chemotherapy and HCT in patients with a germline mutation.
种系检查点激酶2基因（）突变会增加实体瘤风险。最近，它们被确定为血液系统恶性肿瘤的危险因素。然而，据我们所知，B淋巴细胞白血病（B-ALL）从未被描述为种系突变的首发表现。针对CD19抗原的嵌合抗原受体T（CAR-T）细胞疗法（tisagenlecleucel）是一种治疗复发/难治性（R/R）B-ALL的新型细胞疗法。tisagenlecleucel在携带突变的患者中的应用尚未见报道。
我们描述了一例患有杂合致病性种系突变（c.1100delC；p.Thr367Metfs*15）的儿科患者，该患者因复发的B-ALL成功接受tisagenlecleucel治疗，从而避免了造血细胞移植（HCT）。这名12岁男孩被诊断为美国国立癌症研究所（NCI）高危B-ALL（白细胞计数>50,000/微升），无髓外疾病。细胞遗传学分析显示核型正常，但荧光原位杂交（FISH）显示重排阳性率为93%。他按照儿童肿瘤学组（COG）AALL1131方案进行治疗并实现完全缓解。诊断7个月后，他被发现患有甲状腺乳头状癌，无转移疾病证据。患者接受了全甲状腺切除术及中央淋巴结活检和放射性碘治疗。患者的生母和异卵双胞胎兄弟携带相同的种系突变，无恶性肿瘤病史。生父的家族突变检测为阴性。患者的基因检测还发现了三个意义不明确的变异：（c.37°C>T；p.Arg124Cys）、（c.62G>A；p.Cys21Tyr）和（c.139A>G；p.Met47Val）。家族病史还显示患者的舅舅在44岁时被诊断为间变性甲状腺癌。诊断15个月后，患者的B-ALL复发（髓内和髓外均有，脑脊液中有原始细胞），经tisagenlecleucel成功治疗。接受tisagenlecleucel治疗3年后，患者仍处于缓解状态。
由于传统化疗和放疗可能会增加DNA损伤和继发恶性肿瘤的发生风险，对于携带种系突变的患者，CD19 CAR-T疗法（tisagenlecleucel）可作为强化再诱导化疗和HCT的替代方案。
