急性淋巴细胞白血病应用门冬酰胺酶致静脉栓塞3例

例1，男，3岁，B系急性淋巴细胞性白血病（ALL），标危。DOLP早期强化[门冬酰胺酶（L-Asp）6000U／次]。1个月前曾予左侧股静脉置管，早期强化开始将导管拔出。应用L-Asp5次后出现左下肢无疼痛肿胀，累及腹股沟区。数字减影血管造影（DSA）示左髂静脉未显影，诊断左髂静脉血栓形成见图1。凝血检查示抗凝血酶Ⅲ（AT-Ⅲ）活性56．2％。经患肢足背浅静脉予肝素2000U1次／d、尿激酶5000U2次／d静脉滴注，新鲜冰冻血浆支持治疗。     

儿童急性淋巴细胞白血病应用门冬酰胺酶治疗的临床研究

目的回顾性总结和分析应用左旋门冬酰胺酶(L-Asp)治疗儿童急性淋巴细胞白血病(ALL)的经验、不良反应及其应对措施,以期对未来用药提供借鉴。方法 102例ALL患儿入组。分析超敏反应对疗效的影响,总结凝血功能异常及暂时性高血糖(TH)的应对措施,对L-Asp相关胰腺炎(AAP)病例作简要总结。结果(1)34例(33.3%)出现超敏反应,多数程度较轻且发生于诱导期以后的治疗过程中。(2)PT延长16例(20.3%),APTT延长17例(21.5%),FIB不同程度降低,50例(63.3%)低于1g/L,4例(5.I%)低于0.5g/L。(3)70例(68.6%)出现不同程度的血糖升高,11例(10.8%)诊断TH,其中4例(36.4%)有高血糖家族史。(4)4例(3.9%)发生AAP,1例再次应用L-Asp后未出现AAP。结论(1)超敏反应组和无超敏反应组的预计5年OS和EFS差异无显著性。(2)L-Asp治疗过程中出现的凝血功能改变原则上在无严重合并症时可不行预防性凝血因子的替代治疗。(3)高年龄组(≥6岁)及有糖尿病家族史者发生TH的可能性更大。(4)AAP发生后48 h内症状缓解、淀粉酶和脂肪酶低于正常值上限3倍以及影像学未提示假性囊肿或坏死者可尝试再次应用L-Asp化疗。     

不同来源门冬酰胺酶在儿童急性淋巴细胞白血病应用的对照研究

目的观察菊欧文菌源性门冬酰胺酶(asp)及大肠杆菌源性asp在儿童急性淋巴细胞白血病(ALL)治疗中的药物疗效及不良反应。方法随机选取新诊断的ALL患儿15例,其中9例患儿接受国产菊欧文菌源性asp治疗,6例患儿接受大肠杆菌源性asp治疗,化疗前后对两组患儿血浆内L-asp活性及门冬酰胺(ASN)水平进行检测,同时对两组患儿不良反应进行比较。结果在用药前,两组患儿血浆内L-asp活性与ASN水平差异无显著性;用药期间两组患儿血浆内的asp活性逐渐升高,ASN水平差异无显著性(P>0.05);停药后,L-asp活性及ASN水平在一周后可缓慢恢复至用药前水平。结论国产菊欧文菌源性asp有望成为ALL患儿化疗方案中有效的备选用药。     

急性淋巴细胞白血病患儿大剂量静脉滴注门冬酰胺酶治疗后脑脊液门冬酰胺浓度

目的　测定急性淋巴细胞白血病 (ALL)患儿大剂量静注门冬酰胺酶 (ASP)治疗前、后脑脊液 (CSF)中门冬酰胺 (ASN)浓度 ,从临床及药代动力学方面 ,探讨ASP在中枢神经系统 (CNS)白血病治疗中的药理作用及最佳给药方式。方法　 10例ALL患儿分别 4次接受德国小儿白血病协作组多中心协作治疗方案 (COALL 97)中的主要药物ASP(每隔 4～ 6周 1次静脉注射 4 0 0 0 0U/m2 )的联合化疗。在静脉注射L ASP前及给药后第1、3、4、5周采集CSF ,用安捷伦高效流相色谱仪检测CSF中ASN浓度 ,并观察临床疗效。结果　CSF中ASN浓度分别为 :给药前 1.894± 0 .5 8μmol/L ;给药后第 1周 0 .0 5 6± 0 .0 13μmol/L ;第 3周 0 .117± 0 .0 0 0 0 8μmol/L ;第 4周 0 .2 12± 0 .0 13μmol/L ;第 5周 0 .897± 0 .0 89μmol/L。ALL患儿应用L ASP后CSF中ASN浓度明显降低 (P <0 .0 5 ) ,同时测定CSF中谷氨酰胺浓度在给药前后均无显著变化。结论　 1次注射 4 0 0 0 0U/m2 ASP后能使CSF中ASN浓度降低并持续至第 5周后回升。这种用药方法有预防或治疗CNS白血病的作用     

左旋门冬酰胺酶对儿童急性淋巴细胞白血病凝血功能的影响

为探讨左旋门冬酰胺酶影响儿童急性淋巴细胞白血病凝血功能的机制,对１８例急性淋巴细胞白血病患儿在用Ｌ－Ａｓｐ治疗前后检测了血浆凝血酶元时间（ＰＴ）,活化的部分凝血活酶时间（ＡＰＴＴ）,凝血酶时间（ＴＴ）,血浆纤维蛋白原（ＦＩＢ）和外周血小板计数（Ｐｌｔ）。结果与用药前比较,用药结束后一天的ＰＴ,ＡＰＴＴ,ＴＴ均显著延长,ＰＴ仍在正常范围：ＦＩＢ显著降低,Ｐｌｔ显著增高,但仍在正常范围。用药结束后一周     

急性淋巴细胞白血病晚期骨髓复发并门冬酰胺酶静默失活1例

对2019年10月中山大学附属第一医院诊治的1例急性淋巴细胞白血病(ALL)患儿采用培门冬酶治疗后静默失活的临床资料进行回顾性分析。患儿,男,9岁3个月,ALL晚期骨髓复发,使用产自大肠杆菌的聚乙二醇修饰的培门冬酶化疗后因未出现预期的不良反应,如高血氨、低纤维蛋白原、低抗凝血酶Ⅲ(ATⅢ)等,进一步检测血浆门冬酰胺(A...     

左旋门冬酰胺酶对儿童急性淋巴细胞白血病凝血功能的影响

为探讨左旋门冬酰胺酶影响儿童急性淋巴细胞白血病凝血功能的机制 ,对1 8例急性淋巴细胞白血病患儿在用L—Asp治疗前后检测了血浆凝血酶元时间(PT) ,活化的部分凝血活酶时间 (APTT) ,凝血酶时间 (TT) ,血浆纤维蛋白原 (FIB)和外周血小板计数 (Plt)。结果与用药前比较 ,用药结束后一天的PT、APTT、TT均显著延长 ,PT仍在正常范围 ;FIB显著降低 ;Plt显著增高 ,但仍在正常范围。用药结束后一周后的PT、APTT、TT已恢复正常 ,但FIB仍低于正常。结果表明 ,L—Asp主要影响蛋白质的合成而引起蛋白质成份的凝血因子减少 ,从而引起凝血功能障碍 ,且对纤维蛋白原的合成影响更为显著     

门冬酰胺酶治疗急性淋巴细胞白血病应用现状

门冬酰胺酶（Asp）是治疗急性淋巴细胞白血病（ALL）的关键药物之一。临床医生应对Asp治疗ALL的基本概况,如药效、毒副反应等;不同类型门冬酰胺酶在国内外的使用情况;以及关于Asp治疗ALL的3点建议有所了解,以便提高临床疗效。     

门冬酰胺酶相关儿童急性胰腺炎诊治研究

目的通过收集国内病例资料,分析和归纳儿童门冬酰胺酶(ASP)相关胰腺炎(AAP)的临床特征和诊治经验,不断提高儿童AAP的早期诊断率和疗效水平。方法归纳我院和近年来国内报道的临床资料完整的66例患儿诊治经过,参照国际AAP诊断标准,分析我国儿童AAP的流行病学、临床表现、辅助检查规律以及治疗方法和疗效。结果归纳66例儿童AAP资料可见:(1)最终疗效:病死率为36%(24/66例),其中24例死亡病例中19例(79%)死于休克。(2)流行病学:无高发年龄段和性别差异,大多数(79%)发生于首次接受ASP的诱导治疗期。(3)临床表现:腹痛、腹胀和呕吐分占91%、72%和69%:(4)血胰腺酶水平:血淀粉酶和血脂肪酶增高分别占89%和100%。(5)影像学检查:早期腹部B超和CT检查的阳性率分别为84%和82%。(6)综合治疗:奥曲肽为主要药物之一,但并未能降低病死率。(7)左旋门冬酰胺酶(L-ASP)和培门冬酶(PEG-ASP)两组中,坏死性胰腺炎分别占25%和50%,P0.05;病死率分别为36%和1I%,P0.05。结论多数AAP发生于诱导治疗期。腹痛并非必然症状,血脂肪酶的敏感度高于血淀粉酶,早期B超和CT影像学检查阳性率也有限,因此需要全面分析判断以助早期诊断。需要在奥曲肽治疗的同时,积极进行综合治疗以提高疗效水平。PEG-ASP在预防AAP及降低其严重程度方面较L-ASP未见明显优越性。     

COALL-97方案治疗急性淋巴细胞白血病临床及实验室研究

目的　引用德国儿童急性淋巴细胞白血病协作组 (cooperativeALLstudygroup ,COALL)的COALL 97方案治疗急性淋巴细胞白血病 (ALL) ,从临床疗效防治及目前国内外选用有效治疗ALL的药物 ,左旋门冬酰胺酶 (L Asp)的药代动力学方面 ,探讨在我国治疗儿童ALL的最佳方案及L Asp的最佳给药方式。方法　ALL患儿 1 2例自愿接受COALL 97方案在我院完成早期强化治疗后 ,回当地继续口服巯基嘌呤 (6 MP) /硫鸟嘌呤 (6 TG)加甲氨蝶呤 (MTX)持续治疗 ,每隔 3个月、半年来院复查 ,总疗程 1 .5～ 2 .0年。结果　诱导治疗后d1 4做骨髓检查 8例呈缓解骨髓像 ,治疗 2 8d后 1 2例均完全缓解 (CR) ,CR率1 0 0 % ,HR ALL患儿 1例CR后 1 0个月时骨髓复发并重症感染死亡。应用高压液相色谱技术 (HR HPLC)检测 1次注射 40 0 0 0U/m2 L Asp后能使血清和脑脊液 (CSF)中门冬酰胺 (ASN)浓度降低 ,并持续至第 5周后回升。 结论　COALL 97方案可被我国ALL患儿所接受 ;在治疗ALL的临床实践中 ,该方案确有可借鉴之处 ;1次 / 2～ 6周静脉注射 40 0 0 0U/m2 L Asp联合化疗的用药方式不仅作用强、持续时间长 ,耐药性小、不良反应少 ,且避免患儿每天或隔天静脉注射痛苦及患儿家长的经济和精神负担。     

Correction of hemostatic imbalances induced by L-asparaginase therapy in children with acute lymphoblastic leukemia

Thirteen children with ALL and L-asp-induced alterations of the coagulation system were treated with fresh-frozen plasma and antithrombin III (AT III) concentrate. Fresh-frozen plasma was given three times daily to maintain fibrinogen levels greater than 100 mg/dl. AT III concentrate was administered in a continuous infusion over 24 h as long as replacement with fresh-frozen plasma was given. When fibrinogen was greater than 100 mg/dl and AT III less than 80% of normal, only AT III concentrate was administered in a continuous infusion. In all patients treated with the replacement regimen described, fibrinogen levels were maintained greater than 100 mg/dl and AT III levels greater than 80%. No bleeding or thrombosis and no signs of disseminated intravascular coagulation were observed. Our study shows that correction of the alterations of the coagulation system induced by asparaginase can be achieved with a replacement regimen substituting both procoagulant material and the most important inhibitor of the coagulation system.     

急性淋巴细胞白血病患儿左旋门冬酰胺酶联合化疗期间血糖监测的临床研究

目的探讨急性淋巴细胞性白血病(ALL)患儿应用左旋门冬酰胺酶(L-ASP)联合化疗期间药物性高血糖发生的概率及高危因素,以及药物性高血糖与药物性胰腺炎的相关性。方法 2002年5月1日至2008年4月30日共收治594例ALL患儿,以2005年5月1日为分界线,之前的197例ALL初治患儿和43例复发再治患儿应用XH-99方案;之后的354例患儿按儿童ALL-05方案进行化疗。在应用L-ASP联合化疗期间检测空腹血糖,对发生药物性高血糖的患儿采取暂缓L-ASP化疗,减少激素剂量,以及糖尿病饮食控制和注射胰岛素的治疗措施。结果共12例患儿发生药物相关性高血糖,发生率为2.02%;发生高血糖患儿与未发生高血糖患儿比较,中位年龄差异有统计学意义(11.5岁对5.0岁,P<0.01)。两种治疗方案患儿药物性高血糖发生率差异无统计学意义(P=0.26)。12例药物性高血糖患儿经治疗后,均得到控制。未发生药物性高血糖的患儿中发生药物相关性胰腺炎2例。结论 ALL患儿采用L-ASP联合化疗期间,药物性高血糖发生率约2%,年龄是发生药物性高血糖的重要因素,药物性高血糖可控制。[临床儿科杂志,2012,30(5):415-417]     

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity

Abstract

Background: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. Methods: In this prospective observational study, patients ≤18?years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500?IU/m² by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. Results: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87?±?22.35?IU/L and 216.03?±?73.40?IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Conclusion: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.     

Hemostatic changes in children with acute lymphoblastic leukemia treated according to two different L-asparaginase schedules

Hemostatic changes in 20 children with acute lymphoblastic leukemia (ALL) who were induced with L-asparaginase (L-asp), vincristine (VCR), and prednisone (PDN) (Group A) were prospectively evaluated. These data were compared with those of a previous group of ALL patients who received L-asp as a single agent during consolidation (Group B). In Group A patients, mean plasma antithrombin activity decreased in the first 2 weeks, though not significantly. Relative to pretreatment values, mean fibrinogen concentration diminished particularly by week 3 (p less than 0.001). Activated partial thromboplastin time (APTT) decreased in the last week as well as after cessation of therapy with L-asp (p less than 0.05). Mean platelet count increased significantly by week 3 (p less than 0.05). Thromboelastograms performed in seven patients confirmed the tendency for thrombosis evidenced by a decreased APTT. Patients in Group B (L-asp alone during consolidation) had decreased concentrations of fibrinogen, AT, and Factors IX and X after L-asp therapy. APTT was prolonged. Our data demonstrate that the tendency for thrombosis is the predominant manifestation of L-asp induced coagulopathy, when the drug is associated with VCR and PDN. Thus the risk/benefit ratio for the use of L-asp early in induction in children with low risk ALL needs to be further evaluated.     

Antithrombin supplementation III in childhood acute lymphoblastic leukemia treated with L-asparaginase

The change of plasma antithrombin III (AT) levels after supplementation of AT concentrates was examined in ALL children with acquired AT deficiency following L-asparaginase (ASP) administration. The patients received AT concentrates of 34.5 ±7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 ±0.62% and 0.70 ±0.16 mg/dL per unit AT infused per kilogram of body weight, respectively. The activity decreased to 62.0 ±7.7% of the peak values by 48 hours after supplementation. The administration of AT concentrates constantly increased the plasma AT activity in ALL children treated with ASP, which may minimize the acquired prothrombotic state.     

Cerebrovascular complications of L-asparaginase in the therapy of acute lymphoblastic leukemia

L-asparaginase is frequently used in combination therapy for the treatment of lymphoid malignancies. We report 5 children aged between 8 and 14 years with neurologic complications presenting with headache and seizures during the first three weeks of L-asparaginase treatment. Three patients had venous thrombosis, one presented a parenchymal hemorrhage, and one showed a peculiar encephalopathy with extended cortical and subcortical lesions suggesting a neurotoxic reaction. Decreased fibrinogen and antithrombin III levels were found. Early MRI is critical even in cases with mild neurologic symptoms. Diagnosis should be followed by early cessation of l-asparaginase application.     

Effect of glucocorticoids, E. coli- and Erwinia L-asparaginase on hemostatic proteins in children with acute lymphoblastic leukemia.

BACKGROUND: The concentrations of plasma hemostatic proteins were analyzed prospectively in 42 children with acute lymphoblastic leukemia (ALL), treated according to the protocol ALL-BFM-90. PROCEDURE: Treatment included glucocorticosteroids (GC), E. coli L-asparaginase (Asparaginase, Medac) or Erwinia L-asparaginase (Erwinase, Speywood), vincristine, anthracyclines and intrathecal methotrexate. The analysis of hemostatic proteins was performed during induction and re-induction therapy. RESULTS: At diagnosis, the plasma concentrations of fibrinogen, antithrombin III (AT), plasminogen and protein C were within normal limits, whereas the von Willebrand factor antigen (vWF:Ag) was elevated. After eight days of mono-therapy with GC the concentration of fibrinogen decreased to 59%, vWF:Ag decreased to 67%, AT increased to 124%, protein C increased to 201% of the initial value (mean all p < or = 0.01), while the concentration of plasminogen remained unchanged. During the re-induction phase, the concentrations of the hemostatic proteins, with exception of vWF:Ag, altered in a similar way in response to GC as observed during the induction phase. Administration of two doses of E. coli L-asparaginase (10,000 U/m2) during the induction therapy led to a significant decrease of AT (123 +/- 24 to 63 +/- 15%/mL), protein C (168 +/- 34 to 87 +/- 19%/mL), plasminogen (94 +/- 21 to 41 +/- 12%/mL) and fibrinogen (148 +/- 59 to 79 +/- 30 mg/dL, p < or = 0.01 for all parameters). In contrast, administration of two doses of Erwinia L-asparaginase (10,000 U/m2) during re-induction therapy did not lead to change in the concentration of AT, protein C or plasminogen, and the decrease in fibrinogen (162 +/- 17 to 121 +/- 24 mg/dL) was less pronounced. CONCLUSIONS: Our results indicate that GC and E. coli L-asparaginase, in particular, induce hemostatic alterations which have implications on our understanding of thrombotic and hemorrhagic events during the treatment of ALL in children.