Daunomycin,cytosine arabinoside and 6-thioguanine (DAT) vs vincristine,cytosine arabinoside and 6-thioguanine (VAT) in the induction treatment of acute nonlymphocytic leukemia: A randomized collaborative study

One hundred patients were entered in a cooperative study comparing the efficacy of two different regimens in the induction treatment of acute nonlymphocytic leukemia (ANLL). Patients were randomly allocated to receive either the DAT or VAT combination; half of the patients were also randomized to receive CNS prophylaxis including intrathecal methotrexate + prednisone and cranial irradiation. Consolidation and maintenance therapy were uniform in responding patients. Out of 82 evaluable patients 41 (50%) attained complete remission (CR) with no significant difference between the two regimens. Median remission duration was slightly longer in the DAT group (32.5 vs 22 weeks); median survival was 34 weeks for all evaluable patients with no difference between the two schedules. Meningeal relapse occurred only in two patients after 19 and 99 weeks of continuous remission. Fourteen patients are still alive after 61 to ≥ 155 weeks, of whom seven are in their initial remission (six in the DAT and one in the VAT group). We conclude that 1) DAT and VAT are equally effective in inducing CR in a high proportion of ANLL patients; 2) until marrow remission can be prolonged significantly, preventing CNS leukemia will not have any significant impact on the course of ANLL.     

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.     

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.     

Daunomycin, cytosine arabinoside and 6-thioguanine (DAT) vs vincristine, cytosine arabinoside and 6-thioguanine (VAT) in the induction treatment of acute nonlymphocyte leukemia: a randomized collaborative study.

One hundred patients were entered in a cooperative study comparing the efficacy of two different regimens in the induction treatment of acute nonlymphocytic leukemia (ANLL). Patients were randomly allocated to receive either the DAT or VAT combination; half of the patients were also randomized to receive CNS prophylaxis including intrathecal methotrexate + prednisone and cranial irradiation. Consolidation and maintenance therapy were uniform in responding patients. Out of 82 evaluable patients 41 (50%) attained complete remission (CR) with no significant difference between the two regimens. Median remission duration was slightly longer in the DAT group (32.5 vs 22 weeks); median survival was 34 weeks for all evaluable patients with no difference between the two schedules. Meningeal relapse occurred only in two patients after 19 and 99 weeks of continuous remission. Fourteen patients are still alive after 61 to greater than or equal to 155 weeks, of whom seven are in their initial remission (six in the DAT and one in the VAT group). We conclude that 1) DAT and VAT are equally effective in inducing CR in a high proportion of ANLL patients; 2) until marrow remission can be prolonged significantly, preventing CNS leukemia will not have any significant impact of the course of ANLL.     

Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: Failure of subsequent treatment with cyclophosphamide,cytosine arabinoside,vincristine and prednisone (COAP)

Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 21/2–5 years of continuous disease-free remission, 20–25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequte for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.     

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.     

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.     

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.     

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.     

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.     

Combinations of arabinosyl cytosine and 6-thioguanine for treatment of adults with acute leukemia

The combination of arabinosyl cytosine and 6-thioguanine has been effective for the treatment of acute leukemia. Three schedules of this combination were studied to determine which was most effective, especially in patients who had prior exposure to either or both of these drugs. Sequential and simultaneous 5-day courses of the combination were ineffective. A regimen consisting of a 5-day course of arabinosyl cytosine followed by a 5-day course of 6-thioguanine and another 5-day course of arabinosyl cytosine produced responses in 36% of 25 patients. Seven of the nine patients who responded were refractory to prior therapy with arabinosyl cytosine and 5 were refractory to prior therapy with 6-mercaptopurine. However, the median duration of response was only six weeks. Four patients developed central nervous system complications and three of these patients died while in complete remission. Major toxicity from all three regimens was myelosuppression. This regimen was about as effective as most other regimens used as secondary therapy in patients with acute myelogenous leukemia, but its toxicity was too great for routine usage.     

Treatment of childhood acute lymphoblastic leukemia with intermediate-dose cytosine arabinoside and adriamycin

Eight pediatric patients with acute lymphoblastic leukemia (ALL) were treated with intermediate-dose cytosine arabinoside (ID-AraC, 1 g/m2) in combination with adriamycin except one patient. Of the eight patients, four refractory to the initial induction therapy and one in bone marrow relapse gained complete remission with two to three cycles of this therapy. Four of the five patients have been in continuous remission for 4 to 24 months with the maintenance therapy of monthly administration of ID-AraC. One patient in central nervous system (CNS) relapse has continued in remission from CNS leukemia after two cycles of the therapy. Side effects of ID-AraC and adriamycin were generally mild to moderate and tolerable in all children. These results suggest that the use of ID-AraC and adriamycin might prove effective in the treatment of ALL refractory to other regimens.     

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.     

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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。     

Therapy in childhood acute nonlymphocytic leukemia (ANLL). Evolution of current concepts of chemotherapy

Chemotherapy remains the major treatment modality in childhood acute nonlymphocytic leukemia (ANLL). Current remission induction rates range from 60% to 80%; but even with the improved rate of response to therapy, the median duration of remission has seldom exceeded 1 year. On the other hand, an increasing number of children with ANLL who were treated with intensive induction and maintenance chemotherapy regimens for a prescribed period followed by discontinuation of therapy are remaining in remission. The evolution of present-day chemotherapy approaches to childhood ANLL are reviewed in this article.     

Vincristine (NSC-67574), cytosine arabinoside (NSC-63878), 6 thioguanine (NSC-752) and daunorubicin (NSC-82151) (VAT-D): a pilot study of combination chemotherapy for remission induction in acute myeloid leukemia in adults.

Fifteen newly diagnosed unselected adult patients with acute nonlymphocytic leukemia were treated in a pilot study of the combination of vincristine, cytosine arabinoside, 6-thioguanine, and daunorubicin (VAT-D) for remission induction therapy. Eleven of fifteen (75%) achieved a remission bone marrow. Median duration of remission was seven months in all responders (11 patients). The 11 patients achieving initial remission reached a median survival of 14 months. Twelve of seventeen attempts at reinduction of remission with VAT-D were successful. The total amount of daunorubicin required for induction was less than that required in the majority of reported acute leukemia treatment regimens utilizing daunorubicin.     

A comparative trial of daunorubicin, cytosine arabinoside, and thioguanine, and a combination of the three agents for the treatment of acute myelocytic leukemia.

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M2 daily X 3, cytosine arabinoside and thioguanine 100 mg/M2 each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M2 given on dav 1 and cytosine arabinoside plus thioguanine each given at a dose of 100 mg/M2 every 12 hours for five days. All patients received cyclophosphamide 600 mg/M2 followed in 24 hours by hydroxyurea 500 mg/M2 every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M2 daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M2 of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.