克拉屈滨联合阿糖胞苷治疗高危/难治性儿童急性髓细胞白血病及侵袭性NK/T细胞淋巴瘤

Cladribine combined with cytarabine in treatment of high-risk/refractory acute myelocytic leukemia and invasive NK/T cell lymphoma

目的探讨应用克拉屈滨联合阿糖胞苷治疗高危/难治性儿童急性髓细胞白血病(AML)及侵袭性NK/T细胞淋巴瘤(NKTCL)的有效性及安全性。方法选择2015年12月至2017年7月,于首都儿科研究所附属儿童医院血液科治疗的2例高危/难治性AML患儿及1例侵袭性NKTCL患儿为研究对象。对于高危/难治性AML患儿,采用克拉屈滨+阿糖胞苷+米托蒽醌+重组人粒细胞集落刺激因子(CLAG-M)方案治疗,即d 2~6静脉滴注克拉屈滨5mg/(m2·d),d 2~6静脉滴注阿糖胞苷2g/(m^2·d),d 2~4静脉滴注米托蒽醌10mg/(m^2·d),d 1~6皮下注射重组人粒细胞集落刺激因子3~5μg/(kg·d)。对于侵袭性NKTCL患儿,采用克拉屈滨+阿糖胞苷方案治疗,即d 1~5静脉滴注克拉屈滨5mg/(m^2·d),d 1~5静脉滴注阿糖胞苷500mg/(m^2·d)。回顾性分析3例患儿的临床病例资料,对其临床表现、诊断、治疗及预后进行总结。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》的要求,征得受试儿监护人知情同意,并于治疗前与其签署临床治疗知情同意书。结果 (1)患儿1为女性,16岁,临床诊断为高危/难治性AML M5。患儿1接受CLAG-M方案诱导治疗1个疗程后,达到完全缓解,骨髓细胞形态学检查未见白血病细胞,流式细胞术检测结果显示,骨髓微小残留病变(MRD)为1.37%,MLL-AF9融合基因定量检测结果为0。但是,该例患儿在后续巩固治疗中,因骨髓抑制(血小板减少)导致的颅内出血而死亡。(2)患儿2为女性,6岁,临床诊断为高危/难治性AML M2。患儿2接受CLAG-M方案诱导治疗1个疗程后,达到完全缓解,骨髓细胞形态学检查未见白血病细胞,流式细胞术检测结果显示,骨髓MRD为0.81%;接受CLAG-M方案治疗第2个疗程后,骨髓MRD<0.001%。随后,患儿2接受单倍体异基因造血干细胞移植,迄今移植后无事件生存时间已达2年。(3)患儿3为男性,4岁,因"皮肤破损5月余"在本院接受住院治疗,临床诊断为侵袭性NKTCL。患儿3接受克拉屈滨+阿糖胞苷治疗1个疗程7d后,未再出现新皮疹;20d后,皮肤出血、溃烂明显减轻,鼻翼、躯干及四肢破损皮肤约80%结痂,鼻翼处皮肤破损范围约缩小50%;40d后,50%~60%躯干、四肢破损皮肤愈合,达到部分缓解。患儿3最终带瘤进行同胞全相合造血干细胞移植后1个月,骨髓细胞形态学复查结果为完全缓解,骨髓MRD<0.001%。移植后2个月,患儿3侵袭性NKTCL复发,对其进行供者淋巴细胞输注治疗1次,肿瘤负荷未再增多。迄今,患儿3移植后带瘤生存时间已达1年。(4)3例患儿在治疗过程中,均出现Ⅳ度骨髓抑制及不同程度感染,经对症及抗感染治疗后,上述症状均被控制。结论 CLAG-M方案、克拉屈滨+阿糖胞苷方案治疗部分高危/难治性儿童AML及侵袭性NKTCL有效,是此类患儿进行造血干细胞移植前的有效桥接手段。防治感染是这2种方案治疗高危/难治性AML及侵袭性NKTCL患儿成败的关键。由于本研究仅为回顾性病例研究,应用克拉屈滨联合阿糖胞苷治疗高危/难治性儿童AML及侵袭性NKTCL的疗效,仍有待大样本量的多中心、随机对照研究进一步证实。

Objective To explore the efficacy and safety of cladribine combined with cytarabine in treatment of children with high-risk/refractory acute myelocytic leukemia（AML）and invasive natural killer/T cell lymphoma（NKTCL）.Methods From December 2015 to July 2017,2 cases of children with high risk/refractory AML and 1 case of child with invasive NKTCL in Children′s Hospital,Capital Institute of Pediatrics were selected as the research subjects.For 2 cases of children with high-risk/refractory AML,they were treated by cladribine ＋ cytarabine ＋ mitoxantrone ＋recombinant human granulocyte colony-stimulating factor（CLAG-M）scheme：intravenous infusion of cladribine 5 mg/（m2·d）,d 2-6;intravenous infusion of cytarabine 2 g/（m2·d）,d 2-6;intravenous infusion of mitoxantrone 10 mg/（m2·d）,d 2-4;subcutaneous injection of recombinant human granulocyte colony-stimulating factor 3-5μg/（kg·d）,d 1-6.For the child with invasive NKTCL,he was treated by cladribine ＋ cytarabine scheme：intravenous infusion of cladribine 5 mg/（m2·d）,d 1-5 and intravenous infusion of cytarabine 500 mg/（m2·d）,d 1-5.Clinical case data of those3 children were retrospectively analyzed and their clinical manifestations,diagnoses,treatments and prognoses were summarized.This study met the requirements of the World Medical Association Declaration of Helsinki revised in 2013.The guardians of those 3 children signed informed consent form for clinical treatment before treatment.Results（1）The patient 1 was a female,16 years old,and was clinically diagnosed as high-risk/refractory AML M5.She received CLAG-M scheme as the induction therapy.And after the first course of treatment,she achieved complete remission,there was no leukemia cell in the bone marrow cells morphological examination,and the minimal residual disease（MRD）of bone marrow was 1.37% detected by flow cytometry,the quantitative detection of MLL-AF9 fusion gene was 0.However,patient 1 died of intracranial bleeding due to bone marrow suppression（thrombocytopenia）during subsequent consolidation therapy.（2） The patient 2 was a female,6 years old,and was clinically diagnosed as high-risk/refractory AML M2.After 1 course of CLAG-M scheme induced treatment,she achieved complete remission.And none leukemia cell was found in bone marrow cells morphological examination.The result of flow cytometry showed that bone marrow MRD was 0.81%.Bone marrow MRD was less than 0.001% after receiving the second course of CLAG-M treatment.Since then,haploid allogeneic hematopoietic stem cell transplantation has been carried out in patient 2.Up to now,the event free survival time of patient 2 has reached2 years after transplantation.（3）The patient 3 was a male,4 years old,hospitalized in our hospital due to ＂skin damage for more than 5 months＂ and was clinically diagnosed as invasive NKTCL.After 1 course of treatment with cladribine＋cytarabine,no new rash appeared within 7 days.After 20 days,the bleeding and ulceration of the skin were significantly reduced,about 80% of the damaged skin of the nose,trunk and limbs scabbed,and the damaged skin of the nose wing was about 50%less.After40 days,50%to 60% of the damaged skin of the trunk and limbs healed,reaching partial remission.In the end,the patient 3 received sibling hematopoietic stem cell transplantation with tumor.One month after transplantation,the bone marrow cells morphological examination showed that he had achieved complete remission,and the bone marrow MRD was less than 0.001%.Two months after transplantation,the invasive NKTCL of the patient 3 recurred,and the donor lymphocyte infusion was performed once,and the tumor burden did not increase again.So far,the tumor-bearing survival time of patient 3 has reached 1 year after transplantation.（3） Ⅳ degree of bone marrow suppression and different levels of infection were observed in all those 3 children during treatment,but the symptoms were controlled after symptomatic and anti-infection treatments.Conclusions The CLAG-M scheme,cladribine＋ cytarabine scheme are effective in treating some children with high-risk/refractory AML and invasive NKTCL,and they are effective bridges for such patients before hematopoietic stem cell transplantation.Prevention and treatment of infection is the key to the success of these two schemes in treatment of children with high-risk/refractory AML and invasive NKTCL.Because this study is only a retrospective case study,the efficacy of cladribine combined with cytarabine in treatment of children with high-risk/refractory AML and invasive NKTCL remains to be confirmed by large-sample,multicenter and randomized controlled trials.