Low-dose cytosine arabinoside in acute non-lymphoblastic leukemia

Eighteen previously untreated patients with acute non-lymphoblastic leukemia (ANLL) were treated with cytosine arabinoside (Ara-C) in low doses (10 mg/m2 every 12 hours) subcutaneously for 3 weeks. Complete remission (CR) was achieved in four patients (22.2%), and myelosuppression was observed in nearly all of them. Thrombocytopenia (20 X 10(3)/microliters) was pronounced in the third week of treatment and six patients (33.3%) needed platelet support. Contrary to earlier claims, our experience suggests that treatment with low-dose Ara-C is associated with significant cytopenias. Ara-C does not obviate the need for intensive supportive care and CR rates are no longer better. Low-dose Ara-C does not seem to be a choice in previously untreated ANLL patients who otherwise have a high probability of achieving a CR with standard multidrug chemotherapy protocols.     

High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia

Seventy-eight patients with acute nonlymphoblastic leukemia in relapse were treated with high-dose cytosine arabinoside (3 g/m2 intravenously (IV) every 12 hours for 12 doses) alone, or with three days of anthracycline antibiotics (doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 IV daily) after completing the course of cytosine arabinoside. Consolidation and maintenance therapy was not given. When anthracyclines were added there was no increase in frequency or severity of nonhematologic toxicity including conjunctivitis, photophobia, dermatitis, cerebellar dysfunction, and gastrointestinal disturbance. All 78 patients achieved aplasia of the bone marrow. Five patients in each group died before bone marrow recovery. The use of anthracyclines did not prolong bone marrow recovery, with both groups demonstrating adequate granulocyte and platelet counts about four weeks after beginning treatment. Forty-one (53%) of the total 78 patients achieved a complete remission. In patients not clinically resistant to conventional-dose cytosine arabinoside, both regimens were equally effective inducing a complete remission (high-dose cytosine arabinoside alone, 12/19 [63%]; with anthracycline, 11/17 [65%], P = .270); in patients clinically resistant, the regimen including anthracycline was superior (15/27 [56%] v 3/15 [20%], P = .022). The duration of unmaintained response was similar (median, five months), but the longest remissions occurred when anthracyclines were used. Thus, high-dose cytosine arabinoside is effective in producing remissions in relapsed patients with acute nonlymphoblastic leukemia, and the addition of an anthracycline enhances this effect.     

Complete remission obtained in refractory acute lymphocytic leukemia using high-dose cytosine arabinoside combined with low-dose L-asparaginase

A 41-year-old male was diagnosed as acute lymphocytic leukemia (ALL) in November, 1982 and partial remission was obtained by a combination chemotherapy of LVP, DVP ABOP and VAMP. In January, 1983, peripheral blood showed an increasing number of leukemic cells and he was readmitted to our hospital. WBC count in the peripheral blood was 13,200/mm3 and an 82% ratio of leukemic cells was observed. Bone marrow aspiration showed a hypercellularity of 89.4% leukemic cells. High-dose Ara-C therapy was started at a dose of 3 g/m2 i.v. every 12 hours for 6 days. Leukemic cells in peripheral blood were rapidly decreased in number, and the nucleated cell count of bone marrow was also reduced after 3 weeks of treatment, however 95% of leukemic cells remained. Low-dose L-asparaginase was then supplemented at a dose of 2000 U for 3 days, and 2 months later complete remission was achieved. The side effects associated with this high-dose Ara-C therapy were nausea, vomiting, diarrhea, fever and conjunctivitis, although these were tolerable. These observations suggest that high-dose Ara-C combined with L-asparaginase should be added to the treatment of leukemia which is refractory to conventional chemotherapy.     

Induction of differentiation in human myeloid leukemia cells with cytosine arabinoside

Normalization of granulocyte counts was obtained with low-dose cytosine arabinoside (Ara-C) in a patient with acute myelogenous leukemia (AML, FAB-M2) who had relapsed on maintenance therapy containing conventional doses of Ara-C and was clinically resistant to high-dose Ara-C treatment. The patient's leukemic cells exhibited an abnormal karyotype (45, X-Y, t[8q; 21q]). To determine whether the response to low-dose Ara-C was a result of induced leukemic cell differentiation, the mature peripheral blood granulocytes were isolated and fused with mitotic chinese hamster ovary (CHO) cells to induce premature chromosome condensation. Karyotypic evaluation of the granulocyte prematurely condensed chromosomes (PCC) during response to low-dose Ara-C demonstrated the presence of cells with 45 chromosomes. This result strongly suggests that part of this patient's response to low-dose Ara-C was a result of induced maturation of the leukemic clone.     

中等剂量阿糖胞苷用于急性非淋巴细胞白血病的毒副反应观察

用中等剂量阿糖胞苷（ＩＤＡｒａ－ｃ）１ｇ／ｍ２．每１２小时１次，共用６或１０次，治疗１０例急性非淋巴细胞白血病病人，其毒副反应为发热、恶心、呕吐、脱发、血细胞减少和阿糖胞苷综合征，均为可逆住，并可耐受。血细胞减少期平均在治疗起始７～２１天之间。无早期死亡，未见中枢神经系统的毒副反应。结果提示，中等剂量阿糖胞苷比高剂量阿糖胞苷更具优越性。     

Low-dose cytosine arabinoside treatment for acute nonlymphocytic leukemia in elderly patients

Thirty patients older than 65 years of age with acute nonlymphocytic leukemia were treated with low-dose cytosine arabinoside (10 mg/m2 subcutaneously every 12 hours for 15 to 21 days). Fifteen achieved complete remission and five had partial remission. Treatment was more effective when initial bone marrow cellularity was low (P = 0.007). Four of six patients with secondary leukemia entered complete or partial remission. Therapy was well tolerated with reduced myelosuppression and few number of early deaths. Sixteen patients followed the whole treatment as outpatients. Six of 12 patients who achieved complete remission showed no evidence of post-therapeutic bone marrow aplasia. These data are consistent with the view that low-dose cytosine arabinoside acts on leukemic cells as a differentiating agent.     

Chemotherapy of chronic myelogenous leukemia in blastic crisis--vindesine, cytosine arabinoside prednisolone combination therapy

Twenty patients with chronic myelogenous leukemia in terminal transformation were treated with regimen incorporating vindesine, prednisolone and additional cytosine arabinoside. Of the 19 patients in blastic crisis, complete remission was achieved in 13 (68.4%). All four patients with lymphoid morphology, and nine of the eleven patients with myeloid morphology, achieved complete remission (81.8%); the four with monocytoid morphology did not. One patient in accelerated phase also attained complete remission. The present results indicate that the regimen incorporating vindesine-cytosine arabinoside-prednisolone should be treatment of choice in CML-BC with lymphoid morphology and myeloid morphology as well.     

High-dose cytosine arabinoside remission induction for acute myelogenous leukemia: comparison of two regimens of remission maintenance.

We report a single institution sequential trial of two maintenance treatment regimens for patients with acute myelogenous leukemia (AML). A total of 175 consecutive patients with AML received initial remission induction therapy with high-dose cytosine arabinoside (ara-C) and glucocorticoids. For the initial 63 patients (group A), the control population, planned maintenance treatment was with conventional-dose ara-C given over 4 days for up to 18 months. The subsequent 107 patients (group B) had planned maintenance therapy of up to 6 courses of daunorubicin, ara-C and prednisone and daily cis-retinoic acid for up to two years. The presenting features of group A and B patients were similar as were the response to remission induction, 60 and 52%, respectively. Severe neurological toxicity was encountered once after high-dose ara-C; no drug-related deaths occurred during maintenance treatment. Median duration of remission for group B patients was 9.9 months compared with 5.5 for group A (p = 0.0685). Median survival duration for the two groups was similar, 9.1 months for group A and 10.4 for group B. Survival of patients in group B who attained a complete remission was significantly better than that of patients in group A (p = 0.0439). The studies confirm our initial experience with remission induction using single agent high-dose ara-C and suggest a positive role for maintenance therapy in AML.     

Behenoyl cytosine arabinoside, daunorubicin, 6-mercaptopurine, and prednisolone combination therapy for acute myelogenous leukemia in adults and prognostic factors related to remission duration and survival length

Fifty-one consecutive previously untreated adult patients with acute myelogenous leukemia (AML) were treated with BHAC-DMP (N4-behenoyl-I-beta-D-arabinofuranosyl-cytosine, daunorubicin, 6-mercaptopurine, and prednisolone) therapy. Forty-two patients (82.4%) achieved complete remission (CR). The Kaplan-Meier analysis revealed a probability for remaining in remission of 14% and for survival of 23% at 6 years. Pretreatment factors related to the achievement of CR, such as age, French-American-British (FAB) classification and WBC at the start of treatment, were not identified. Factors related to the CR duration and survival time of the patients who had achieved CR were first analyzed by a univariate analysis with the generalized Wilcoxon test. WBC count at the start of treatment, percent of blasts in the marrow at 1 and 2 weeks after the initiation of therapy, days required until CR, number of courses of induction therapy required until CR, and days required for the disappearance of circulating blasts were identified as statistically significant prognostic factors. When these characteristics were further analyzed by the Cox multivariate regression model, the percent of blasts in the bone marrow at 2 weeks was the most important prognostic factor with a statistical significance, and WBC count at the start of treatment and days required until CR (or number of courses required to achieve CR) were also important factors, with borderline significance.     

Cytokinetic changes after cytosine arabinoside in acute non-lymphocytic leukemia

Changes in the S-phase compartment of blasts were measured after intravenous push-injections of cytosine-arabinoside (Ara-C, 100 mg/m², 380 mg/m² or 1000 mg/m² body surface) in 11 patients with acute non-lymphocytic leukemia. At several intervals after Ara-C injection blood and bone marrow samples were taken for autoradiography, DNA-flowcytometry and ³H-thymidine incorporation.The data obtained from the bone marrow aspirates were corrected for peripheral blood admixture. In untreated patients the three methods correlated very well. The perturbation of the cell-cycle after Ara-C administration shows for each method a specific pattern. Labelling indices reached, after an initial decrease, pretreatment levels at about 24 h after injection. Recruitment of cells into the cycling compartment could not be demonstrated. DNA-flowcytometry reveals a significant increase in the percentage of cells with > 2n < 4n DNA, with a maximum after about 30h. The discrepancy between autoradiography and DNA-flowcytometry after Ara-C injection may be due to the presence of cells arrested in S-phase. ³H-thymidine incorporation increased after an initial inhibition to about twice pretreatment values at 30 to 40 h after injection. This observation suggests partial synchronization. Incorporation of ³H-thymidine in peripheral nucleated cells correlated well with the corrected values of ³H-thymidine incorporation in the bone marrow. The perturbation of the cell-cycle appeared identical in the three different dosages used. The observations suggest that 24 h scheduling might be optimal for Ara-C given by push-injections.     

Intermediate- and high-dose cytosine arabinoside therapy in acute refractory leukemia

Seven patients with refractory and/or relapsed acute leukemia were treated with intermediate- or high-dose cytosine arabinoside (ara-C). One patient obtained complete remission and two achieved partial remission. We advocate intermediate ara-C in combination with anthracyclines for the treatment of patients with refractory and/or relapsed acute leukemia, because the toxicity is less severe than that of high-dose ara-C and the therapeutic results are not inferior to those obtained with high-dose ara-C. Kinetic differences in leukemic cells should be considered in order to obtain the maximum effect in intermediate- and high-dose ara-C therapy.     

Improved survival in young children with acute granulocytic leukemia treated with combination therapy using cyclophosphamide, oncovin, cytosine arabinoside, and prednisone.

Seven of 17 children (41%) under 5 years of age with acute granulocytic leukemia (AGL) treated with either cytosine arabinoside-cytoxan (CA-CYT) or Mini-COAP (CA-CYT with vincristine sulfate [VCR] and prednisone) have been in continuous complete remission 4 years or more. CA and CYT were each given in the dosage of 120 mg/m2 intravenously, daily in 3 divided doses, for 4 days. Induction consisted of two courses given at intervals of 2 weeks; during maintenance the courses were repeated at intervals of 4 weeks. In the Mini-COAP regimen, standard 28-day VCR-prednisone therapy was superimposed on CA-CYT induction and 4-day VCR-prednisone pulses were superimposed on CA-CYT maintenance. Transient moderate to severe myelosuppression was frequent; other manifestations of toxicity were mild. Administration of drugs at home was feasible in many instances. Mini-COAP was proved to be an effective therapeutic regimen for young children with AGL and should be considered as initial therapy.     

Concomitant chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. Complete remission of CLL achieved with high-dose cytosine arabinoside.

The concomitant presentation of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare with so far only eleven cases reported. In addition, the achievement of complete remission (CR) in CLL is exceptional and generally not assessed by immunophenotypical investigations. We report a case with a simultaneous occurrence of AML and CLL in which, in addition to the complete remission of AML, an eradication of the CLL clone was obtained following high-dose cytosine arabinoside. The immunophenotypic investigation of minimal residual disease showed that less than 1 x 10(-3) CD19+/CD5+ B-cells remained in bone marrow.     

A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes

We reviewed 53 publications reporting 751 patients with hematologic malignancies treated with low doses (5 to 20 mg/m2/d) of cytosine arabinoside (LoDAC). Of 507 patients evaluable for response, complete remission (CR) rates varied from 32% for patients with primary acute non-lymphoblastic leukemia (1 degree ANLL) to 16% for patients with hematologic malignancies secondary to previous chemotherapy or following a myelodysplastic syndrome (MDS) (2 degrees ANLL), and 16% for MDS. Median duration of CR was 9.5 months for 1 degree ANLL, and 10.5 months for both 2 degrees ANLL and MDS. Based on limited available survival data, overall median survival for these groups was 9 months, 3 months, and 15 months, respectively. Only three CRs were reported of 31 evaluable patients treated for a variety of other hematologic malignancies. CR rates for patients with 1 degree ANLL greater than or equal to 50 years old was 56%, compared with 29% less than 50 years old (P = .10). While prior chemotherapy was more common in 1 degree ANLL patients less than 50 years of age (86% v 21%; P less than .001), it did not influence response rates in those greater than 50 years of age, suggesting other biases. Hematologic toxicity was mentioned in only 33 of 53 publications, affecting 254 of 289 patients (88%), with at least 15% treatment-related deaths. LoDAC hypothetically acts as a differentiating agent; however, correlative laboratory studies were rarely performed. Cytogenetic data were available for only 15%, and in vitro studies for 10% of all patients with marked discrepancies in the interpretation of results. LoDAC is clearly cytotoxic for both malignant and normal hematopoietic cells. While large numbers of patients have been reported, the lack of well-designed clinical trials prohibits definitive conclusions as to its role as a differentiating agent. Future LoDAC studies should determine optimal dose and schedule, with clinical laboratory correlates to assess differentiation. Trials in ANLL comparing LoDAC with conventional chemotherapy, and in MDS with supportive care alone, may help identify the role of LoDAC. Until appropriate indications can be identified, LoDAC should not be routinely used in clinical practice.