High-dose cytosine arabinoside and L-asparaginase therapy for poor-risk adult acute nonlymphocytic leukemia. A retrospective study

The effectiveness and toxicities of high-dose cytosine arabinoside with L-asparaginase (HiDAC-ASNase) were evaluated in 41 patients with "poor risk" acute nonlymphocytic leukemia (ANLL). Twenty-four patients had either refractory or relapsed primary ANLL, and 17 had ANLL secondary to prior cytotoxic chemotherapy or an underlying hematologic disorder. The overall complete remission (CR) rate was 37%. The CR rates for primary and secondary ANLL were almost identical. Furthermore, advanced age alone did not adversely influence the CR rate. The median CR duration was 302 days with no differences between primary and secondary ANLL. The induction death rate was 24%. Predictors for induction deaths included poor initial performance status, fever at the time of presentation, low cholesterol and/or albumin, and an initial bone marrow aspirate with greater than 50% blasts. These data indicate that HiDAC-ASNase is a moderately effective regimen for patients with poor prognosis ANLL including secondary ANLL.     

Preventive central nervous system irradiation in children with acute nonlymphocytic leukemia.

In this study of children with acute nonlymphocytic leukemia an attempt was made to prevent central nervous system relapse and to determine whether this therapy, coupled with multiagent chemotherapy, would be successful in prolonging durations of complete remission. Central nervous system relapses were prevented by irradiation, although patients who received this therapy did no better than those who did not receive irradiation. A small group of patients received irradiation to the liver and spleen, but this modality also failed to improve the duration of remission. Control of extramedullary leukemia, in this study, failed to improve remission duration because bone marrow relapse was not prevented or delayed. It is unlikely that focal therapy will have a significant impact in acute nonlymphocytic leukemia until longer marrow remissions are achieved.     

Antibody response in patients with acute nonlymphocytic leukemia.

Lymphocytotoxic (LCT) and anti-red blood cell (ABO) antibodies were measured serially in adult patients with acute nonlymphocytic leukemia (ANLL) receiving induction chemotherapy. The antigenic stimulus was provided by multiple platelet transfusions, many of which were ABO incompatible. Comparison of pretherapy titers 4-6 weeks into therapy shows that 50% (19/38) of patients became LCT positive (cytotoxicity against greater than 10% of panel of cells) and 54% (19/35) had increases in ABO titers (greater than 2 tube dilution). A total of 66% of patients had significant rises in at least one antibody. ABO and LCT titers tended to vary in parallel although exceptions were noted. The development of anti) remission rate or duration, 3) type of therapy, 4) number of platelet transfusions, 5) time relationship between the antigenic stimulus and the initiation of cytotoxic therapy, and 6) skin test reactivity. Antibody responders tended to have higher pretreatment lymphocyte counts. The ability to develop a secondary antibody response does not appear to be a major prognostic factor in ANLL.     

Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide

In order to test the toxicity and efficacy of intensive postremission therapy with high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide in adults with acute nonlymphocytic leukemia (ANL), 100 adults (ages 19 to 75) with previously untreated ANL were entered into a study using six sequential cycles of chemotherapy. Cycles 1 (induction), 3, and 5 included conventional doses of daunomycin, cytosine arabinoside, 6-thioguanine, vincristine (VCR), and prednisone. Cycle 2 was cytosine arabinoside 3 g/m2 intravenously (IV) every 12 hours for four doses, followed by L-asparaginase 10,000 U intramuscularly (IM) at hour 42; this combination was repeated 1 week later. Cycle 4 included amsacrine 120 mg/m2/d and etoposide 100 mg/m2/d, both IV for five days, and cycle 6 was three monthly courses of VCR on day 1, and prednisone, mercaptopurine, and methotrexate each for five days. Seventy-four patients (74%) achieved complete remission (CR) (51 with cycle 1 and 23 after cycle 2). The overall disease-free survival (DFS) for patients achieving CR is 27% at 3 years by Kaplan-Meier analysis, while for patients achieving CR with cycle 1 it is 34%. The actuarial probability of being free from relapse at 3 years for patients achieving CR is 34%. Sixteen of the 74 CR patients (22%) died in CR while continuing to receive intensive chemotherapy, including 12 (18%) who succumbed to infection (nine bacterial, three fungal). After a median follow-up of 20 months, 36 patients have relapsed and 21 remain alive in CR. Intensive consolidation with high-dose cytosine arabinoside, amsacrine, and etoposide can modestly prolong DFS compared with historical controls. However, relapse continued to be a major problem and, in addition, with more aggressive consolidation therapy, infection during marrow aplasia resulted in a significant number of deaths.     

Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.     

Acute nonlymphocytic leukemia in children

Acute nonlymphocytic leukemia (ANLL) is a heterogeneous group of hematologic malignancies caused by a clonal proliferation of primitive myeloid cells. 30 Infiltration of the bone marrow by these cells causes impairment of normal hematopoiesis and results in anemia, granulocytopenia, and thrombocytopenia. Recent progress in bone marrow culture techniques, cytogenetics, and immunology have contributed to a better understanding of the pathophysiology of ANLL. Major therapeutic advances have also occurred because of improved supportive care and carefully designed prospective and randomized clinical trials. This article presents the current knowledge of the diagnosis and management of ANLL.     

Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood.

Two groups of children with refractory acute lymphoblastic leukemia were treated with a regimen of methotrexate (MTX) and asparaginase (Asn'ase) based on studies of the effect of MTX in vitro on human lymphoblasts exposed to Asn'ase. Induction therapy in 12 children produced 4 complete remissions, 3 partial remissions, and 5 failures. Responsiveness to Asn'ase seemed necessary for successful induction with the drug combinations. Maintenance therapy in 18 children produced a median hematologic remission of 31 weeks (range 3-85 weeks). During remission, 2 children developed central nervous system leukemia and 2 died of infection. The mean maximally tolerated dose of MTX was 361 mg/m2. The results of this trial suggest therapeutic synergy in maintenance therapy and the capability of Asn'ase to attenuate MTX toxicity.     

DA方案骨髓腔给药诱导缓解急性非淋巴细胞白血病的临床研究

 目的 比较柔红霉素联合阿糖胞苷骨髓腔给药诱导缓解急性非淋巴细胞白血病（简称急非淋）的疗效和毒副反应。方法 用随机对照的方法将40例初治急非淋患者分为骨髓腔给药组（A组,20例）和静脉给药组（B组,20例）,观察两组的疗效和毒副反应。结果 A组与B组完全缓解率分别为70 %,35 %。总有效率分别为85 %,50 %。两组比较,差异均有统计学意义（P＜0.05）。两组心脏毒性、胃肠道反应发生率比较,差异有统计学意义（P＜0.05）。两组骨髓抑制发生率比较,差异无统计学意义（P＞0.05）。结论 骨髓腔给药诱导缓解急非淋具有较好的治疗效果,毒副反应小。     

Improvement in outcome for children with acute nonlymphocytic leukemia. A report from the Childrens Cancer Study Group

The Childrens Cancer Study Group conducted four therapeutic studies on a total of 1006 children with acute nonlymphocytic leukemia from 1972 to 1983. This report describes the therapeutic strategies of these studies and examines trends in induction rates and long-term outcome over this period. The remission induction rate has changed from 58% in 1972 to 1975 to 80% for the period 1980 to 1983, and the induction mortality dropped from 20% to 6%. Four-year survival probabilities from time of diagnosis have almost doubled from 19% to 36%. Few deaths occurred more than 5 years after diagnosis: children surviving in first remission beyond 5 years had a 92% survival rate and an 86% relapse-free survival rate over the next 5 years. In contrast, median survival after a marrow relapse was less than 6 months and the 6-year survival probability was 4%. The leukocyte count was a significant prognostic factor, and although the mortality for infants was high initially, long-term survival was not decreased.     

Hypersensitive reactions and antibody formation during L-asparaginase treatment of children and adults with acute leukemia.

One hundred and fourteen patients with acute leukemia, 57 children (10 AML and 47 ALL) and 57 adults (37 AML and 20 ALL) were treated with L-asparaginase (Asnase) 200 or 1000 IU/kg daily for 30 days unless withdrawn on account of side effects. Combinations with other cytotoxic drugs were used in all but eight patients. Hypersensitive reactions, decrease in Asnase activity in plasma, and bivalent antibodies to Asnase appeared more frequently in adults (28%, 46%, and 79%, respectively) than in children (16%, 17%, and 25% respectively). There was a clear association between these three parameters. Thus hypersensitive reactions generally developed at the time of or after the decrease in plasma Asnase activity. Antibodies were detected only where Asnase activity had disappeared from the plasma. This time sequence, and in vitro experiments, suggest the formation of antigen-antibody complexes which might be responsible for inactivation of Asnase and for the development of hypersensitive reactions. However in many cases antibodies were found without concomitant enzyme inactivation or hypersensitive reactions. Antibodies to Asnase of IgE type (reagins) were found in only 10 children and 6 adults. There was no correlation between hypersensitive reactions, decrease in Asnase activity, and IgE antibodies. The frequency of remission among patients developing bivalent antibodies to Asnase was 68% (13/19) in contrast to 27% (3/11) among patients whose sera contained no detectable antibodies to Asnase, but the difference was not statistically significant.     

L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemia

BACKGROUND: The objective of the current study was to compare chemotherapy dose modifications in obese (a body mass index [BMI] > 95%) and nonobese (a BMI < or = 95%) pediatric patients with acute lymphoblastic leukemia (ALL). METHODS: The study cohort was comprised of 199 pediatric patients diagnosed with ALL who were treated at 1 of 2 South Texas pediatric oncology centers between 1990-2000. The relative chemotherapy dose modification during the induction phase of chemotherapy was calculated as the ratio of 1) the actual administered dose of L-asparaginase and 2) the protocol-calculated dose of L-asparaginase. The extent to which the chemotherapy dose modification varied according to obesity status was assessed using stratified Student t tests and an ordinary least-squares regression analysis. RESULTS: Obese ALL patients were found to exhibit a 7% decrease in the mean relative modification of L-asparaginase during induction chemotherapy compared with their nonobese counterparts. This finding was statistically significant (P = 0.009), even after adjustment for gender, age, ethnicity, and clinical institution. CONCLUSIONS: To the authors' knowledge, the current study is the first published report of an obesity-associated chemotherapy dose modification in pediatric patients with ALL, the most common childhood malignancy. It will be important to examine whether these findings are consistent with those observed in future studies, and ultimately to assess the association between obesity-related dose modifications and long-term cancer outcomes.     

Intermediate-dose cytosine arabinoside and amsacrine. An effective regimen with low toxicity in refractory acute nonlymphocytic leukemia

Results of remission induction therapy in refractory acute nonlymphocytic leukemia (ANLL) has been improved since the introduction of high-dose cytosine arabinoside. However, the toxicity of these regimens attributes to an early death rate of about 20% to 30%. The authors treated 37 poor-risk patients with ANLL with intermediate-dose cytosine arabinoside and amsacrine for remission induction. One consolidation course and no maintenance therapy was given. Eleven of 19 patients with a first relapse entered complete remission (58%); ten of 15 patients in this group older than 50 years were complete responders (67%). Median duration of second remission was 8.2 months (range, 2-14). Three of 13 patients with primarily resistant disease had a complete remission (23%), but there was no response in five patients with a myeloid blastic phase of chronic myelogenous leukemia. Side effects of this remission induction regimen were mild; no cardiac, pulmonary, or central nervous system toxicity was observed. Five patients (14%) died during the remission induction phase, three from complications during aplasia and two from refractory leukemia.