Prednimustine and vincristine compared with cytosine arabinoside and thioguanine for treatment of elderly patients with acute nonlymphoblastic leukemia

Summary Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine+vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 patients randomized to prednimustine and vincristine (15 adequately treated), three entered a complete remission and one a partial remission. Four further patients went into complete remission after a switch to other treatment modalities. Of 34 patients randomized to cycles of ARA-C and thioguanine (22 adequately treated), four entered a complete remission and three a partial remission with the correct program. One patient entered a remission with intermittent cytosine arabinoside+thioguanine (wrong program) and one further patient entered a complete remission after a switch to prednimustine and vincristine. Prednimustine+vincristine did not appear to be superior to treatment with cytosine arabinoside thioguanine cycles for elderly patients with ANLL.     

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.     

The role of timing of high-dose cytosine arabinoside intensification and of maintenance therapy in the treatment of children with acute nonlymphocytic leukemia

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.     

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.     

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.     

Seizures following intrathecal cytosine arabinoside in young children with acute lymphoblastic leukemia.

Two young children (3 1/2 years and 19 months) developed seizures within 24 hours of receiving intrathecal cytosine arabinoside. Both had previously received intrathecal cytosine and methotrexate as well as cranial irradiation without untoward effect. Possible mechanisms of causation are discussed and caution is stressed for use of intrathecal cytosine arabinoside in young children.     

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.     

Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia

One hundred three relapsed leukemia patients were treated with high-dose cytosine arabinoside (Ara-C); 3 g/m2 intravenously over 2 hours every 6 to 12 hours for a total of nine to 12 doses or 3 g/m2 intravenously over 2 hours for two doses 12 hours apart followed by a continuous infusion of 1.5 g/m2 over 24 hours daily for 3 to 4 days. Thirteen of them developed adult respiratory distress syndrome (ARDS) without having any recognized reason for the development of pulmonary edema. This problem showed no correlation with age or prior chemotherapy. Four of the patients recovered, but in nine this complication was fatal. The authors have reviewed the clinical course of these 13 patients and the postmortem findings of the seven patients who had an autopsy performed. The pulmonary tissue from six patients showed massive edema and one had diffuse alveolar damage. Histologic examination revealed a highly proteinaceous intraalveolar infiltrate without any inflammatory reaction in all cases. Intestinal tissue from all patients revealed changes compatible with cytotoxic damage, and pleura and/or pericardium from six of the seven patients showed an extensive fibrinous exudate suggestive of capillary leakage. The time sequence of the clinical events and the histologic findings indicate that high-dose Ara-C treatment in leukemia may cause a capillary leakage syndrome with ARDS that may progress to fatal respiratory failure.     

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 in myelodysplasia and acute myelogenous leukemia: a review

We analyzed clinical trials of low dose cytosine arabinoside (LDARA-C) in 324 patients with acute myelogenous leukemia (AML) and 129 patients with myelodysplasia (MDS). Complete and partial remission rates were 31% and 18%, respectively, in patients with AML, and 24% and 27% in patients with MDS. Toxicity was primarily hematologic. Although in vitro data suggested that LDARA-C acts as a differentiating agent, clinical data generally indicate a cytotoxic mechanism. Given the lack of effective therapeutic options in MDS and high risk AML (patients greater than 65 years old, secondary AML), these data are encouraging. LDARA-C warrants further study, comparing continuous infusion with intermittent subcutaneous administration and comparing LDARA-C to conventional dose therapy.     

Etoposide and cytosine arabinoside combination chemotherapy for refractory acute lymphocytic leukemia in childhood

Eighteen children with refractory acute lymphocytic leukemia (ALL) who had been heavily pretreated, were treated with combination etoposide and cytosine arabinoside (ara-C) chemotherapy. Seventeen of these 18 patients were in their first to third relapses; the remaining patient had never responded to induction therapy. The drug combination of etoposide followed by ara-C was administered as an intravenous (IV) infusion twice a week for two consecutive weeks, a total of four doses. The dosage was 150 mg/m2/dose for each drug. Seven (39%) of the 18 patients attained a complete remission (CR) and three (17%) attained a partial remission (PR). Complete response was obtained in two of eight patients in first marrow relapse, and in five of nine patients in second and third relapse. Five patients achieved a CR after one course of therapy and two achieved a CR after two courses of therapy. Of three patients who had previously received teniposide, two attained a CR with this combination. The duration of these responses was brief with a median of 1 month, ranging from 0.5 to 3 months, with the exception of one case, which has been in remission for 2.5 + months. Although myelosuppression was observed, none of the patients died from infection or bleeding. Allergic reaction with fever and rash was observed in two patients. The efficacy of the etoposide and ara-C combination for refractory childhood ALL is encouraging in several current reinduction regimens.     

Combination of rubidazone and cytosine arabinoside in the treatment of first relapse in acute myelocytic leukemia.

This study tested the efficacy of rubidazone and cytosine arabinoside in 35 patients (13 children and 22 adults) with acute myelocytic leukemia in first relapse. Induction consisted of 1-2 courses of rubidazone 200 mg/m2 days x 4 days plus cytosine arabinoside 100 mg/m2 x 7 days in CI followed by 2 consolidation courses of 3 days and 5 days. Nineteen patients (54%) achieved complete remission, 8 failed to respond, and 8 died. Twelve patients relapsed after 1 to 9 months, at a median of 4 months, 1 patient died of cardiac failure and 1 remains in complete remission at 12 months. Five patients underwent bone marrow transplantation, 3 of them autologous, 1 was still in complete remission at 29 months, 1 relapsed, and 1 died of sepsis. Two received allogeneic marrow transplants and died at 3 and 4 months afterwards of VOD and graft failure. The main toxicity was severe and prolonged myelosuppression.     

Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.     

Idarubicin and standard-dose cytosine arabinoside in adults with recurrent and refractory acute lymphocytic leukemia

BACKGROUND: Drug resistance and early disease recurrence were major contributing factors in the limited survival of patients with acute lymphocytic leukemia (ALL). New chemotherapeutic agents and drug combinations were employed in refractory patients to overcome drug resistance. METHODS: The current study evaluated the efficacy of a regimen comprising intravenous bolus injections of idarubicin, 12 mg/m2 daily x 3, and a continuous 7-day infusion of cytosine arabinoside (ara-C), 100 mg/m2 daily, in adults with refractory or recurrent ALL. Twenty patients aged 14-75 years were treated. RESULTS: Six patients (30%) achieved complete remission (CR), 5 (25%) had a partial response (PR), and 9 (45%) did not respond. Recovery of blood counts occurred at a median of 20 days. One patient who achieved CR and one who achieved PR survived 1.5 and 2 years, respectively, after receiving this treatment. The median response and overall survival periods were 2.75 and 6.3 months, respectively. There was no relation between remission duration and previous chemotherapy. Neither leukocyte count at study entry nor patient karyotype was associated with attainment of CR. All patients experienced profound myelosuppression. Gastrointestinal toxicity was mild to moderate, with the exception of one case of World Health Organization Grade 3 mucositis. CONCLUSIONS: The regimen of idarubicin and ara-C achieved a 55% overall response rate in patients with recurrent or refractory ALL. This response rate compared favorably with other regimens and was achieved with acceptable toxicity. Response duration was disappointing, however.