Drug treatment of acute leukaemia. Current status

The drug treatment of acute leukaemia has changed considerably over the past years, offering the possibility of remission and, in some cases, cure. The broad outline of treatment schedules, the drugs in current use and newer approaches to therapy are discussed. Bone marrow transplantation is described in brief, as well as the role of support therapy.     

Pharmacoeconomic considerations in treating patients with acute leukaemia.

Whereas individual cost-effectiveness analyses of new agents for acute leukaemia should be performed in target populations, any meaningful pharmacoeconomic evaluation of treatment options for this condition should include the many types of costs and outcomes in unselected, representative groups of patients. Both direct costs (e.g. costs for medication and hospitalisation) and indirect costs (e.g. lost productivity costs and reduced quality of life) are important parameters to assess, as are the costs of chronic adverse effects, research and development costs for new agents, and costs of procedure-related deaths. Complete remission, cure and survival are the 'success' response criteria for acute leukaemia treatments, in addition to prolonged life with acceptable quality of life for patients with incurable acute leukaemia. Death is 'failure', caused either by resistant disease (relapse and progressive disease) inspite of optimal chemotherapy or, sometimes, by insufficient treatment. All of these parameters should be taken into account when a pharmacoeconomic evaluation is performed (either for administrative or scientific purposes) in order to ensure a comprehensive and reliable background for the evaluation in question. Treatment of acute leukaemia is expensive with a total cost of about $US3000 per patient per day during the induction. Although 80% of children with acute leukaemia are cured, only less than 50% of adults are cured. Thus, a great cost is associated with death during treatment and only optimal medical treatment with full-scale combination chemotherapy and full supportive treatment can keep the number of deaths to a minimum.     

Colony-stimulating factors in the treatment of older patients with acute myelogenous leukaemia

The treatment of acute myelogenous leukaemia (AML) in the elderly is a difficult and increasing problem. The elderly are generally less able to tolerate the intensive chemotherapy required to achieve a sustained remission, and there is an increased incidence of resistant disease in this age group. Granulocyte- and granulocyte-macrophage colony-stimulating factors have been demonstrated to shorten the duration of severe neutropenia following chemotherapy for solid tumours and after bone marrow/peripheral blood stem cell transplantation, and the effect of these growth factors in the treatment of AML has been investigated in a number of trials using 2 distinct strategies. Growth factors may be administered following chemotherapy in an attempt to accelerate neutrophil recovery, and they may be given before and during chemotherapy with the aim to increase the number of leukaemic blast cells in cell cycle and enhance their responsiveness to chemotherapy. Both of these approaches have proved safe despite initial theoretical concerns regarding the expression of receptors for these growth factors on leukaemic cells. The results of trials using these growth factors in the treatment of AML in the elderly generally show a significant reduction in the duration of neutropenia following induction chemotherapy. However, consistent benefits with respect to morbidity and early mortality together with improvements in long term disease outcome have not been observed. The 'priming' approach using growth factors before and during induction chemotherapy has proved equally disappointing in failing to improve response rates or survival. The routine use of these growth factors in the treatment of AML in the elderly population as a whole would, therefore, not seem to be cost effective.     

New therapeutic strategies for the treatment of acute lymphoblastic leukaemia

Although contemporary treatments cure more than 80% of children with acute lymphoblastic leukaemia (ALL), some patients require intensive treatment and many patients still develop serious acute and late complications owing to the side effects of the treatments. Furthermore, the survival rate for adults with ALL remains below 40%. Therefore, new treatment strategies are needed to improve not only the cure rate but also the quality of life of these patients. Here, we discuss emerging new treatments that might improve the clinical outcome of patients with ALL. These include new formulations of existing chemotherapeutic agents, new antimetabolites and nucleoside analogues, monoclonal antibodies against leukaemia-associated antigens, and molecular therapies that target genetic abnormalities of the leukaemic cells and their affected signalling pathways.     

Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review

Clofarabine, a synthesised adenosine nucleoside, has recently demonstrated single-agent activity in the acute leukaemias. Originally developed to capture the best qualities of cladribine and fludarabine, clofarabine contains halogenated carbons, rendering it resistant to inactivating enzymes and maintaining its stability in acidic environments. Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination. Clofarabine has also been shown to induce apoptosis in transformed cell lines, indicating that clofarabine results in cell death in both cycling and non-cycling cells. Interest in the development of clofarabine was initially hampered by the availability of other active nucleoside analogues for the treatment of haematological malignancies. However, the results of several early-phase trials evaluating the use of clofarabine in acute leukaemias in adults and children have rekindled enthusiasm for further investigation into its use. This article describes the development, pharmacology, toxicity and clinical activity of clofarabine, as well as discuss its potential role in the treatment of acute leukaemia.     

Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review

Clofarabine, a synthesised adenosine nucleoside, has recently demonstrated single-agent activity in the acute leukaemias. Originally developed to capture the best qualities of cladribine and fludarabine, clofarabine contains halogenated carbons, rendering it resistant to inactivating enzymes and maintaining its stability in acidic environments. Like other adenosine nucleosides, clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication and also resulting in premature DNA chain termination. Clofarabine has also been shown to induce apoptosis in transformed cell lines, indicating that clofarabine results in cell death in both cycling and non-cycling cells. Interest in the development of clofarabine was initially hampered by the availability of other active nucleoside analogues for the treatment of haematological malignancies. However, the results of several early-phase trials evaluating the use of clofarabine in acute leukaemias in adults and children have rekindled enthusiasm for further investigation into its use. This article describes the development, pharmacology, toxicity and clinical activity of clofarabine, as well as discuss its potential role in the treatment of acute leukaemia.     

Bronchiectasis in acute leukaemia.

Five children in remission from acute lymphoblastic leukaemia developed bronchiectasis when on chemotherapy. Persistent collapse or consolidation on chest radiographs was helpful in suggesting the diagnosis. Necropsy established the diagnosis in one child who died of massive haemoptysis when in complete remission, and bronchography confirmed the diagnosis in three. In a further child the diagnosis was based on clinical and chest X-ray findings alone. The surviving children were treated with prophylactic rotating antibiotics. Routine chest radiographs are recommended in children with acute lymphoblastic leukaemia, as bronchiectasis may otherwise be underdiagnosed.     

Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia.

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara-C in patients with newly diagnosed untreated AML, using a bioassay and GC-MS method to measure the plasma concentrations. 2 Most patients showed a bi- or tri-phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC-MS method, and terminal half-lives varied from 7--107 min. 3 There was poor correlation of the GC-MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara-C. 4 Plasma concentrations were measured by GC-MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara-C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara-C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.     

Cost analysis of 2 empiric antibacterial regimens containing glycopeptides for the treatment of febrile neutropenia in patients with acute leukaemia.

OBJECTIVE: Patients with cancer-associated neutropenia are at high risk of developing severe infections which can be fatal if treatment is not promptly administered. For this reason, fever is treated as soon as possible with broad spectrum antibacterial therapy. The objective of this study was to conduct a cost analysis in Italy comparing 2 empiric glycoprotein-containing antibacterial regimens for the treatment of febrile neutropenia in patients with acute leukaemia. DESIGN AND SETTING: A retrospective cost analysis was conducted, using the records of 527 febrile neutropenic patients with acute leukaemia who participated in an 18-month multicentre (29 Italian haematological units) randomised trial during 1991. All patients received either of the following 2 empiric intravenous regimens, each containing 3 antibacterial agents: ceftazidime (2 g, 3 times daily) and amikacin (15 mg/kg/day, in 3 separate doses) plus teicoplanin (6 mg/kg, in a single dose) or vancomycin (30 mg/kg/day, in 2 separate doses). Economic analyses were carried out from a hospital perspective. Only the direct costs per patient, i.e. mean antibacterial treatment and management cost, mean overall treatment failure cost and mean cost of adverse effects, were included. MAIN OUTCOME MEASURES AND RESULTS: No differences were found in the clinical response, defined as the improvement in the rate of fever or infection (if documented), between the 2 regimens. However, tolerability, defined as the incidence of adverse effects probably or definitely related to the assigned treatment, was reported to be better with the teicoplanin-rather than the vancomycin-containing regimen. CONCLUSIONS: Thus retrospective cost analysis showed that despite the higher acquisition cost of teicoplanin relative to vancomycin, the lower incidence of adverse effects associated with teicoplanin and its ease of administration (single daily dose) resulted in equivalent overall treatment costs between teicoplanin- and vancomycin containing regimens.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt's lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.