Lois W. Dow

Pharmacokinetics of teniposide (VM26) and etoposide (VP16-213) in children with cancer

SummaryThe clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography—electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDc, VDss, and Cls all being smaller for VM26. Systemic clearances determined by model-independent methods were 5.2±1.0 ml/min/m2 (mean±SD) for VM26 and 17.8±11.2 ml/min/m2 for VP16-213. The major metabolites detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.

Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia

The therapeutic efficacy and toxicity of alpha‐interferon (α‐IFN) (Roferon, Hoffmann‐La Roche, Inc., Nutley, NJ) were determined in 15 children (age range, 6 to 20 years) with Philadelphia chromosome‐positive chronic myelocytic leukemia (Ph+ CML). All patients had received cytoreductive therapy with either hydroxyurea (n = 13) or busulfan (n = 1) or both (n = 1) for 6 weeks to 46 months (median, 7 months) before beginning α‐IFN therapy at a dose of 5 × 106 U/m2/d intramuscularly. This dose was escalated to 10 × 106 U/m2/d if leukemia was inadequately controlled. Ten children had a hematologic response, with nine showing a reduction in the percentage of Ph+ marrow cells, including four who had no detectable Ph+ cells in marrow samples collected 48 to 204 weeks after the initiation of therapy. Two of 15 patients remain free of Ph+ cells. Therapy was discontinued before week 104 in ten patients because of the following: (1) early hematologic responses without a decrease in Ph+ cells (three patients); (2) early resistant disease (one patient); (3) blast crisis (one patient); (4) progressive disease (two patients); (5) seizure attributed to high‐dose α‐IFN (one patient); or (6) an inadequate trial of α‐IFN caused by aseptic necrosis or poor compliance (two patients). The most common side effects were mild and have included fever, malaise, headache, myalgias, and pain at the injection site. Adverse events causing interruption of therapy were seizures, aseptic necrosis, and myelofibrosis. α‐IFN stabilizes the chronic phase of Ph+ CML in some children, is adequately tolerated when administered at a dose of 2.5 to 5 × 106 U/m2/d intramuscularly, and results in a significant decrease in the proportion of Ph+ metaphases in some patients. α‐IFN in combination with an effective cytoreductive agent or agents appears worthy of further clinical testing in this disease.

Unexpectedly severe toxicity from intensive early treatment of childhood lymphoblastic leukemia.

In early 1984, we treated 13 consecutive patients with acute lymphoblastic leukemia (ALL) using an induction regimen of rapidly rotated combinations of prednisone, vincristine, asparaginase, teniposide (VM-26), cytosine arabinoside, and high-dose methotrexate (MTX) followed by leucovorin rescue. The intent of this clinical trial, designated Total Therapy Study XI, is to test the hypothesis that greater initial leukemia cell kill will decrease opportunities for the development of drug-resistant mutants, with resultant improvement in the length of disease-free survival. Five patients experienced life-threatening gastrointestinal toxicity within three weeks of the start of treatment. One died. Three other patients had severe abdominal pain, abdominal distention, diarrhea, and weight loss, but not gastrointestinal bleeding. In the remaining five patients, toxicity was rapidly reversible, and each child was able to complete the planned course of chemotherapy. The study was then amended to switch high-dose MTX from the induction phase to the consolidation phase, allowing at least one week for mucosal recovery. Among the next 28 patients who were treated, none showed evidence of severe gastrointestinal toxicity. Patients now receive high-dose MTX alone as consolidation therapy and are tolerating it adequately. Drug timing should be examined critically when intensified multiple-agent regimens are being devised for initial treatment of ALL.

Cell differentiation antigens versus tumor-related antigens in childhood acute lymphoblastic leukemia (ALL). Clinical significance of leukemia markers.

Acute lymphocytic leukemia is the most common malignancy of childhood. In spite of recent advances in treatment, about half of children with ALL become refractory to treatment. A current challenge is to define the differences between poor and good re-ponders and to develop different modalities of treatment for children with a high risk for relapse. In order to understand the interactions between tumor and host cells that might influence these differential responses we have concentrated our investigations on the cell surface characteristics of bone marrow lymphoblasts from children with ALL.

Ultrastructural cytochemistry of basophils in chronic myelocytic leukemia

Abstract Cytochemical methods were used to determine the ultrastructural distribution of antimonate precipitable cations, anionic complex carbohydrate, acid phosphatase, and peroxidase in blood basophils from patients with chronic myelocytic leukemia and markedly elevated basophil counts. The morphology of these basophils varied but was generally similar to that reported for normal basophils. Antimonate precipitable cations were sparse in specific granules but more abundant in extra-granular cytoplasm and in vesicular structures of many basophils and, although varying with the fixation method, were distributed atypically in nuclei in a pattern similar to that seen in mast cells. The dialyzed iron technique diffusely stained anionic complex carbohydrate in the specific granules of basophils, and high iron diamine staining disclosed a sulfated mucosubstance in these granules. Acid phosphatase and peroxidase were distributed in a pattern similar to that of the acid mucosubstance in the basophil granules, and their presence suggested a lysosomal function for these granules

Limiting Toxicities During Intensified Remission Induction Chemotherapy for Childhood Acute Lymphocytic Leukemia

The leukemias of childhood have provided an excellent model with which to test novel therapeutic strategies for human neoplasias [1]. In 1984, we devised an intensive multi-drug regimen for treatment of newly diagnosed patients with acute lymphocytic leukemia (ALL). This therapy is being evaluated in Study XI of the Total Therapy series at St. Jude Children’s Research Hospital, and features drug combinations and scheduling that differ radically from those tested in previous studies. Our rationale follows predictions of the somatic mutation theory of Goldie and Coldman [2] that early and repeated use of nonspecific but intensive combination chemotherapy should decrease the likelihood of drug resistance and, therefore, improve the end results of treatment. However, we encountered unexpectedly severe toxicity from early intensification of therapy that led to amendment of the protocol [3]. In this article, we review the toxic effects of the original treatment regimen and its subsequent modifications, emphasizing the potential hazards of intensive combination chemotherapy for ALL.

Recent Results from Total Therapy Study X for Standard and High Risk Acute Lymphoblastic Leukemia in Children: Recognition of New Clinical and Biologic Risk Features *

The initiation of Total Therapy Study X in 1979 marked important new directions for leukemia studies at St. Jude, since for the first time treatment for Standard and high risk forms of lymphoblastic leukemia differed radically. Furthermore, recognizing the heterogeneity of childhood ALL, the blast cell characteristics of each new patient were prospectively investigated by Standard methods [1–3], and the independent impact of various clinical and biologic features on the outcome of therapy was thoroughly investigated. This report will present highlights of our recent results.