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目的总结应用包括大剂量阿糖胞苷(Ara-C)的短疗程化疗方案治疗儿童急性淋巴细胞白血病(ALL)的临床疗效。方法总结1992-01—2001-07在北京大学人民医院儿科初治并长期随访的ALL患儿84例,其中男52例,女32例,长期无病生存(EFS)5年以上,随访时间至2006-07。结果标危型患儿EFS率79.59%,高危型患儿的EFS率为25.81%;长期存活患儿中最长EFS为14年6个月,最短EFS为5年,中位EFS为9年11个月。有6例发生中枢神经系统白血病。未出现与大剂量Ara-C化疗相关的患儿死亡。结论(1)采用包括大剂量Ara-C的短疗程化疗方案能够获得较高的完全缓解率及EFS率,且副反应小。(2)采用该短疗程方案不加用颅脑放疗,中枢神经系统白血病的发生率无提高。(3)ALL患儿对Ara-C的敏感性存在明显的个体差异。     

Flow cytometric determination with bromodeoxyuridine/DNA assay of sensitivity of S-phase cells to cytosine arabinoside in childhood acute lymphoblastic leukemia

The percentages of S-phase cells in leukemic and normal bone marrow cells and their sensitivity to cytosine arabinoside (Ara-C) were determined by in-vitro bromodeoxyuridine (BrdUrd)/DNA analysis in children with acute lymphoblastic leukemia. The lymphoblasts during relapse showed a higher proliferating activity than at the time of the diagnosis. The sensitivity of S-phase cells to Ara-C was measured by the percentages of the residual S-phase cells capable of incorporating BrdUrd after incubation with various concentration of Ara-C (1 ng-10 micrograms/ml). A constant dose response was found in the normal bone marrow cells of disease-free children who were in complete remission with a marked reduction of the S-phase population at a concentration of 100 ng/ml. In the leukemic bone marrow cells, in contrast, there was a wide variation in sensitivity to Ara-C. The sensitivity did not correlate with the proliferating activity of leukemic cells. In two patients, there was a good correlation between in-vitro sensitivity and clinical response to Ara-C.     

Treatment of acute nonlymphocytic leukemia in the elderly with intermediate high-dose cytosine arabinoside

Effective treatment of the elderly patients (greater than or equal to 65 years) with acute nonlymphocytic leukemia (ANLL) remains elusive and controversial. In the present study, single-agent Cytosine Arabinoside (ARA-C) was administered at an intermediate dose level (500 mg/m2 intravenously [I.V.] 1-hour infusion q12 hours for 12 doses) to 30 newly diagnosed and previously untreated patients. Complete remission was achieved in seven patients after the initial cycle of treatment, in two patients after retreatment, and in one patient after delayed recovery of his peripheral count over a 6-month period. The toxicity of this schedule was primarily hematologic, and the response rate was in keeping with that reported by other groups using aggressive multiagent regimens.     

Chemotherapy with cyclophosphamide,vincristine, cytosine arabinoside,and prednisone (COAP) in childhood acute lymphoblastic leukemia (ALL)

Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness in markedly diminished in patients with prior bone marrow relapse.     

Intracellular retention of cytosine arabinoside triphosphate in blast cells from children with acute myelogenous and lymphoblastic leukemia

The importance of the cellular pharmacokinetics of cytarabine triphosphate (ara-CTP) with regard to therapeutic efficacy is well established. In vitro and in vivo monitoring of pharmacokinetic parameters of leukemic blast cells were initiated in order to contribute to the pharmacological basis of optimal ara-C treatment strategies. Peripheral or bone marrow blast cells from 66 leukemic patients [51 acute myelogenous leukemia (ALL), 15 acute lymphoblastic leukemia (AML) were separated and incubated with ara-C for 1 hour and in ara-C-free medium for another 3 hours, and the intracellular formation and retention of ara-CTP was measured. In eight children who received continuous ara-C infusion for induction treatment, the ara-CTP concentration in circulating blast cells was monitored in vivo. The in vitro values observed in this assay corresponded to the cellular levels monitored in vivo. The ara-CTP retention differed clearly among the individual groups, as classified by immunophenotype at the time of the initial diagnosis: non-T-ALL 67 ± 25% (× ± SD, n = 33), T-ALL 37 ± 15% (n = 8), and AML 34 ± 18% (n = 14). The difference in ara-CTP retention between non-T-ALL and AML (P < 0.05) as well as T-ALL (P < 0.05) was significant. There was a tendency toward lower ara-CTP retention in relapsed as compared with newly diagnosed ALL, but the difference was not significant. The maximal accumulation of ara-CTP (after 1 hour incubation) was comparable in AML, T-ALL, non-T-ALL, and blast cells from children in relapse. The observed similarity of cellular accumulation in all groups and the significantly more rapid decrease in T-ALL and AML provide the pharmacokinetic rationale supporting the prolonged infusion duration for ara-C in these subgroups as an alternative to the intensification by high-dose ara-C schedules with short-term infusion. © 1996 Wiley-Liss, Inc.     

Chemotherapy with cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP) in childhood acute lymphoblastic leukemia (ALL).

Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness is markedly diminished in patients with prior bone marrow relapse.     

Treatment of adult acute lymphoblastic leukemia with adriamycin, vincristine, and prednisone

At the present time, it is possible to achieve up to a 95% complete remission in childhood acute lymphoblastic leukemia, using the combination of vincristine and prednisone. Nevertheless, it has not been possible to reproduce these results in the adult. For this reason, a third drug, in this case adriamycin in a low dose, was added to the vincristine-prednisone combination in the treatment of adult acute lymphoblastic leukemia (ALL). Complete remission was achieved in 45 of the 50 patients (90%). The median duration of remission was 23 months and the median survival time in this group was 31 months. The complications were minimal and the tolerance was good. From the point of view of our results and others reported in the literature, we consider that the combination of vincristine, prednisone, and adriamycin is a useful method for induction of remission of adult ALL.     

L-asparaginase used with cytosine arabinoside in treatment of childhood acute lymphocytic leukemia refractory to vincristine and prednisone

Eleven patients with acute lymphocytic leukemia in relapse were treated with L-asparaginase and cytosine arabinoside (1-β-D-arabinofuranosylcytosine) in induction therapy and the same drugs plus cyclophosphamide in maintenance therapy. Three patients had complete remissions lasting 6, 16, and 78+ weeks. One patient experienced partial remission and four had decreased bone marrow or peripheral blasts but were not clinically improved. The responses, which were brief, lasted 1-16 weeks with one exception of 78+ weeks. Four patients had allergic reactions to L-asparaginase that were unpredictable with assays of antibodies against L-asparaginase.     

L-asparaginase used with cytosine arabinoside in treatment of childhood acute lymphocytic leukemia refractory to vincristine and prednisone.

Eleven patients with acute lymphocytic leukemia in relapse were treated with L-asparaginase and cytosine arabinoside (1-beta-D-arabinofuranosylcytosine) in induction therapy and the same drugs plus cyclophosphamide in maintenance therapy. Three patients had complete remissions lasting 6, 16, and 78+ weeks. One patient experienced partial remission and four had decreased bone marrow or peripheral blasts but were not clinically improved. The responses, which were brief, lasted 1-16 weeks with one exception of 78+ weeks. Four patients had allergic reactions to L-asparaginase that were unpredictable with assays of antibodies against L-asparaginase.     

Usefulness of cytosine arabinoside (NSC-63878) and prednisone (NSC-10023) in refractory childhood lymphoblastic leukemia

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.     

Remission induction in acute nonlymphocytic leukemia: comparison of a seven-day and ten-day infusion of cytosine arabinoside in combination with adriamycin

Forty-six previously untreated patients with acute nonlymphocytic leukemia were treated with a remission induction regimen consisting of three daily doses of Adriamycin (30 mg/m2/day) and a ten-day continuous infusion of cytosine arabinoside (ara C) (100 mg/m2/day). The overall remission rate was 72%, with 88% of the patients less than 50 and 62% of patients greater than 50 years old achieving complete remission status. Thirty-one of the 33 complete remissions occurred after a single course of chemotherapy. Retrospective comparison of this regimen with its predecessor (identical, except that a seven-day infusion of ara C was administered) demonstrated that the increase in duration of ara C administration resulted in greater antileukemic effectiveness without an increase in hematologic toxicity to the patient.     

Ikaros基因与儿童急性淋巴细胞白血病预后的关系

Ikaros是淋巴细胞发育和增殖所必需的转录因子,在部分儿童急性淋巴细胞白血病(ALL)中表现为不同的缺失状态,其中以Ik6显性负相亚型过表达多见.Ikaros缺失是B祖细胞型ALL患者预后不良的一个独立危险因素.国外学者最近还确立了ALL的一种新亚型"BCR/ABL1-like ALL",同样以Ikaros缺失、预后不良为主要特征.由此推测,Ikaros对儿童ALL的诊断和治疗可能起着关键的作用.     

Ikaros基因与儿童急性淋巴细胞白血病预后的关系

Ikaros是淋巴细胞发育和增殖所必需的转录因子,在部分儿童急性淋巴细胞白血病(ALL)中表现为不同的缺失状态,其中以Ik6显性负相亚型过表达多见.Ikaros缺失是B祖细胞型ALL患者预后不良的一个独立危险因素.国外学者最近还确立了ALL的一种新亚型BCR/ABL1-like ALL,同样以Ikaros缺失、预后不良为主要特征.由此推测,Ikaros对儿童ALL的诊断和治疗可能起着关键的作用.     

Usefulness of cytosine arabinoside (NSC-63878) and prednisone (NSC-10023) in refractory childhood lymphoblastic leukemia.

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.     

左旋门冬酰胺酶在儿童急性淋巴细胞白血病中的应用

小儿急性淋巴细胞白血病 (ＡＬＬ)的疗效近 10多年来有了很大的提高 ,其 5年无病生存 (ＥＦＳ)率已达 80 %甚至更高。这主要是因为应用了以左旋门冬酰胺酶 (Ｌ ａｓｐａｒａｇｉ ｎａｓｅ ,Ｌ ａｓｐ)和蒽环类的抗癌药如柔红霉素 (ＤＮＲ)及去甲氧柔红霉素 (ＩＤ)为主的联合诱导方案 ,以及加强了髓外白血病的预防措施的结果。尽管小儿ＡＬＬ有如此好的疗效 ,但仍有约 2 0 %的病例治疗失败 ,分析其原因 ,一是因为早期药物的毒副作用发生并发症死亡 ;另一是后期的复发。在这两者中 ,Ｌ ａｓｐ都占有非常重要的位置 ,故详尽地了解其在小儿ＡＬ…     

格列卫联合CCLG-2008方案治疗11例儿童费城染色体阳性急性淋巴细胞白血病临床观察

目的探讨应用格列卫(甲磺酸伊马替尼)联合CCLG-2008方案治疗儿童费城染色体阳性(Ph+)急性淋巴细胞白血病(ALL)的疗效及对预后的影响。方法 11例儿童ALL经骨髓细胞形态学、细胞化学、免疫学分型、融合基因检测确诊为费城染色体阳性B细胞ALL。采用CCLG-2008方案化疗,期间加用格列卫口服治疗。结果疗程第33 d骨髓检查9例得到缓解(缓解率81.9%),1例于第二疗程加用格列卫治疗后缓解,1例持续不缓解,放弃治疗后死亡。监测BCR/ABL融合基因,9例转阴(中位转阴时间118.5 d),最短转阴时间是43 d,最长194 d;1例治疗4个月,基因未转阴,放弃治疗,1例治疗24个月,基因持续阳性,骨髓处于缓解状态,中位随访时间为29个月。结论格列卫联合CCLG-2008方案治疗Ph+儿童ALL,对提高患儿血液学缓解率,提高BCR/ABL基因的转阴率有意义。能否提高经化学治疗的长期生存率,有待继续观察。     

Use of L-asparaginase and cytosine arabinoside for refractory acute lymphocytic leukemia with particular reference to T-cell leukemia

Ten patients with late-stage acute lymphocytic leukemia were treated with L-asparaginase and cytosine arabinoside. Complete remission was achieved in 8 patients including 5 of 5 patients with T-cell leukemia. Major toxicity included anaphylactic reactions in 3 of the 10 patients.