Ralph Vogler

Relationship between plasma adriamycin levels and the outcome of remission induction therapy for acute nonlymphocytic leukemia

SummaryPlasma adriamycin and adriamycinol levels were masured in 45 patients with acute nonlymphocytic leukemia 3 h after the drug was administered. A wide range of levels was found. Plasma levels increased after the administration of each of three daily doses of the drug. High plasma levels were associated with both death during remission induction therapy and, for patients who entered remission, long remissions.

Prediction of response of patients with acute nonlymphocytic leukaemia to remission induction therapy: use of clinical measurements

Two hundred patients with acute nonlymphocytic leukaemia received remission induction therapy consisting of cytosine arabinoside and an anthracycline antibiotic. Analysis of the pretherapy characteristics of the patients demonstrated that patient age was the most important factor in determining whether or not the patient would survive remission induction therapy. Assessment of the characteristics of the bone marrow after 6 d of therapy permitted the recognition of patients who were likely to fail to enter remission because of persistent leukaemia. Taken together, these observations demonstrate that it is possible to identify patients for whom conventional chemotherapy is not likely to be of benefit either because it is too intensive or because it is not intensive enough to produce a complete remission.

The treatment of patients with newly diagnosed poor prognosis acute myelogenous leukaemia: response to treatment and treatment failure

The failure of poor prognosis patients with newly diagnosed AML to enter remission is usually due to two phenomena: a high mortality rate and resistance of the leukaemia to chemotherapy. We conducted a pilot study of a regimen designed to overcome these two types of treatment failure. Patients were carefully selected for therapy on the basis of their likelihood of surviving. Chemotherapy consisted of high dose cytosine arabinoside (HDaraC) with the doses modified on the basis of patient age so as to reduce the risk of toxicity. Finally, daunorubicin was administered only to those patients for whom HDaraC was not likely to produce sufficient antileukaemia effects to produce a remission.

Biological significance of cell cycle kinetics in 128 standard risk newly diagnosed patients with acute myelocytic leukaemia

Bromodeoxyuridine (BrdU) was administered to 128 newly diagnosed patients with standard risk acute myelocytic leukaemia (AML) for cell cycle measurements. Labelling indices (LI) were obtained from both the bone marrow aspirate (BMasp) and biopsies (bx) and durations of S‐phase (Ts) and total cell cycle time (Tc) were measured by double‐labelling the S‐phase cells in vitro with tritiated thymidine. Median LI BMasp was 8% and from BMbx was 25%. The median Ts was 12 h (range 3·1–35 h) and Tc was 48 h (range 11·5–211 h). All patients received induction therapy with a combination of cytosine arabinoside and an anthracycline. Outcome of therapy or FAB type were not related to cell cycle characteristics. Patients with above median LI BMasp, however, had longer remission durations (P= 0·03) as did patients with above median Ts (P= 0·03) and Tc (P= 0·03). Upon longer follow‐ups, even some of the patients with slowly cycling myeloblasts have relapsed (log rank P= 0·453 and 0·203 for Ts and Tc respectively). We conclude that patients with rapidly cycling cells tend to relapse faster; however, slowly cycling nature of myeloblasts is not associated with curability.

The selective use of AMSA following high-dose cytarabine in patients with acute myeloid leukaemia in relapse: a Leukemia Intergroup Study

Summary. This clinical trial was designed to evaluate the role of high‐dose cytarabine (ara‐C) in the treatment of adults with acute myeloid leukaemia (AML) in first relapse. We also tested the hypothesis that the selective use of AMSA (100 mg/m2/d on days 7, 8 and 9) would increase the complete remission (CR) rate when leukaemia cells remained in the bone marrow immediately following 6 d of Ara‐C (2–3 g/m2/12 h) alone. Of 155 patients evaluable for response, 115 (74%) experienced marked cytoreduction by day 6 and received no further induction chemotherapy; 53 (45%) of these patients achieved CR after one course and 45 (38%) had resistant disease. The 36 patients (23%) with inadequate cytoreduction after the 6 d of ara‐C alone were randomly assigned either to no further chemotherapy (21 patients) or to 3 d of AMSA (15 patients). The CR rates after one course were 14% and 53%, respectively (P= 0001). and the fractions with resistant disease were 76% and 40%, respectively. The fractional reduction of leukaemia cells in the day 6 bone marrow aspirate specimen (P<0.0001) and the reduction in the leukaemia cell mass measured in the day 6 marrow biopsy (P= 0.001) were the strongest predictors for achieving CR versus having residual disease in univariate analyses. The median duration of remission was 5 months, but seven patients (10%) remain in CR after 30–92+ months. Among the 140 patients who received only the 6 d of ara‐C, the pretreatment albumin (P= 0.002) and lactate dehydrogenase (P= 0.01) levels were the strongest predictors of response in univariate analyses, but only the albumin remained significant (P= 0.01) in a stepwise logistic regression analysis. Those patients with albumin >4.0 mg/dl and LDH <125% of normal had a 71% CR rate, and only 16% had resistant disease. Among patients lacking both of these favourable characteristics, only 38% had a CR and 39% had resistant disease. Thus, pretreatment characteristics and rapid cytoreduction in the day 6 bone marrow sample identified a favourable subset of patients with AML in first relapse, some of whom responded quite well to 6 d of ara‐C alone and have had long disease‐free remissions.

Inhibition of DNA synthesis by cytosine arabinoside: Relation to response of acute non-lymphocytic leukemia to remission induction therapy and to stage of the disease

The sensitivity of leukemic marrow cell DNA synthesis to cytosine arabinoside (araC) exposure in vitro was studied in specimens obtained from patients with acute non-lymphocytic leukemia. Cells from patients who had been treated with araC in the past were more likely to be resistant to the effect of araC on DNA synthesis than cells obtained from patients who had not been so-treated previously. Resistance to the effects of araC on DNA synthesis was associated with the failure of high-dose araC therapy to induce remissions in relapsed patients, whereas remission induction failure in previously untreated patients was not associated with araC resistance.

Cell cycle and clinical characteristics of patients with acute myeloid leukemia and myelodysplasia whose biopsies are reactive with anti-factor VIII antibody

Abstract Presence of megakaryocytic cells in patients with myeloid disorders were investigated by staining plastic embedded biopsy sections with an anti-Factor VIII antibody (AFA). Two hundred and fifty cases were studied, 207 of whom had acute myeloid leukemia (AML) while 43 had myelodysplastic syndromes (MDS). Abnormal clusters of AFA positive cells indicating multilineage disease were identified in 17% with primary AML ( 30 175 ), 38% with secondary AML ( 12 32 ) and 42% cases of MDS ( 18 43 ). Biological characteristics of these 60 AFA positive cases were investigated. No unique differences in cell cycle characteristics following bromodeoxyuridine (BrdU) were identified. We confirm several recent reports that the incidence of multilineage involvement in AML is substantial.

Limited efficacy of a four-day course of high-dose cytosine arabinoside in the treatment of poor-risk patients with acute nonlymphocytic leukemia

SummaryHigh-dose cytosine arabinoside therapy was administered to 29 patients with poor-prognosis acute nonlymphocytic leukemia. In an attempt to reduce toxicity, therapy was divided into an initial 4-day course of therapy, followed by a 3-day course if the marrow aspirate examined 1 week after the end of treatment contained substantial numbers of leukemic cells. Of the 29 patients, 5 entered complete remission, 2 of them after the initial 4-day course of therapy. The toxicity of split-course therapy was the same as that of conventional 6-day high-dose cytosine arabinoside therapy. This study demonstrates that the modification of high-dose cytosine arabinsoide therapy used in this study failed to reduce toxicity and produced a lower remission rate than that obtained with the 6-day course of therapy.