The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2- chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DNA extension by human DNA polymerase alpha in an in vitro model system was conducted. In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DNA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone. Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3′-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen.

No abstract

Background. There have been published reports on cytogenetic, immunophenotypic, and molecular changes at relapse in childhood acute lymphoblastic leukemia (ALL) including lineage switch and secondary leukemia. There are limited data, however, on the cytogenetic, immunophenotypic, and molecular parameters of adult ALL at relapse. Because, as in children, the cytogenetic and/or immunophenotypic changes observed in adult ALL at relapse may have prognostic significance, the authors investigated the significance of such changes. Methods. Fifty‐three patients with relapsed adult ALL for whom cytogenetic, immunophenotypic, and/or molecular analyses were performed at diagnosis and at relapse were studied. Changes in any of the parameters at relapse were correlated with total survival and survival from the time of relapse. Results. Of the 32 patients for whom cytogenetic studies were performed at relapse, 21 (66%) showed clonal cytogenetic changes, 40% of which were clonal evolution. None of these cases, however, showed two entirely different abnormal karyotypes at diagnosis and at relapse. The immunophenotypes showed occasional gain or loss of one or two surface markers, and the molecular genetic configurations for JH, JK, and the T‐cell receptor beta were stable throughout the evolution of the disease. Patients with clonal evolution had a shorter overall survival than the rest of the group (P = 0.02). This difference, however, was not significant with respect to survival measured from the time of relapse. Conclusions. The most frequent changes in the biologic profile of adult ALL at relapse are shifts in the karyotype, with or without clonal evolution. Clonal evolution detected at relapse is associated with a higher frequency of unfavorable karyotypes at diagnosis and with a worse overall prognosis. However, survival from the time of relapse is similar in patients with and without clonal evolution. Cancer 1995;76:985–91.

The French-American-British (FAB) classification of acute leukemias is based on the light microscopic detection of myeloperoxidase (MPO) activity in blast cells. Cells with MPO activity in > 3% of cells are classified as acute myeloid leukemia (AML) and usually express myeloid cell surface antigens. We describe a case of acute leukemia in which the blast cells have lymphoid morphology, ultrastructure, immunophenotype, and molecular rearrangements, but express significant amounts of MPO. We discuss the incidence, features, and outcome of MPO-positive acute lymphoblastic leukemia (ALL).

The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical modulation strategies to increase the accumulation of ara-CTP in leukemia blasts, a clinical protocol was designed combining 2- chlorodeoxyadenosine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and continued for 5 days. Identical doses of ara-C were administered on days 3, 4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA and ara-C during therapy were investigated. To complement these studies, molecular actions of the triphosphate of ara-C and CdA on DNA extension by human DNA polymerase alpha in an in vitro model system was conducted. In the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP pharmacokinetics showed a median 40% increase in the rate of ara-CTP accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on accumulation of ara-CTP in AML blasts was similar to that during therapy except that the enhancement was less. The DNA synthetic capacity of the circulating blasts was inhibited to a greater extent by administration of CdA and ara-C in combination than by either one alone. Additionally the lowered level of DNA synthesis was maintained until the next infusion of ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C infusion. Administration of CdA in general lowered the concentrations of all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity in a DNA primer extending over an oligonucleotide template of defined sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA monophosphate (CdAMP) at its 3′-end by incorporating ara-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly complete inhibition of DNA primer extension. The insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion may be responsible for sustained inhibition of DNA synthesis in the circulating leukemia blasts during therapy with this combination regimen.