Purpose A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days. Patients and Methods Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting >7 days. Pharmacokinetic studies were performed during the first infusion course. Results The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma. two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for >6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myelosuppression was observed. Conclusions In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSK. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.
Purpose: The frequency and cost of varicella and varicella exposure were determined in children receiving maintenance chemotherapy for acute lymphoeytie leukemia, and the cost of a preventative strategy using the varicella vaccine was estimated. Patients and Methods: Retrospective analysis of clinic and hospital records for 472 children at 12 sites who were receiving maintenance chemotherapy on Protocol 105 of the Childrens Cancer Group. Results: During a mean maintenance period of 21/2 years there were 120 exposures to varicella among susceptible children (10/100 patient-years). During the same period there were 60 cases of varicella (4.6/100 patient-years). Half of the eases of varicella occurred without a known exposure. Exposures and varicella resulted in significant omission or delay in chemotherapy. Total medical charges for varicella-related events were $492,000 ($470 per varicella exposure; $7,450 per case of varicella). A proposed preventative strategy using varicella vaccine after 6 months of maintenance therapy would theoretically reduce varicella-related charges by 80%. Conclusions: Varicella exposure and varicella are common in this patient population. The use of varicella vaccine during the early maintenance period should be considered to prevent these events. This strategy is likely to be safe, and will save significant medical charges, drug omission, disease-related morbidity, hospitalization. and work and school disruption.
Eight otherwise healthy male chronic marijuana smokers were hospitalized for a period of 30 days. Initially they received placebo, then a sustained dose of 210 milligrams of Δ9-tetrahydrocannabinol (Δ9-THC) per day for 18 days, followed by placebo. Lymphocyte responses to phytohemagglutinin were examined during each of these periods. Neither the daily ingestion of marijuana extract containing 210 milligrams of Δ9-THC for 18 days nor the history of chronic marijuana smoking had a depressive effect on the lymphocyte responses of these subjects to phytohemagglutinin.
Peripheral blood lymphocyte size distribution curves in normal children and adults revealed a very constant pattern with a modal class size of 9.5μ to 10.4μ and a curve slightly skewed to the right. In acute infections characterized by abnormal lymphocytes an irregular alteration in the size distribution curve was seen. This pattern returned to normal following recovery. In children with immunologic defects abnormal distribution curves were seen. These abnormalities were unrelated to absolute lymphocyte count or to the clinical condition at the time measurements were determined. Patients with combined immunodeficiency states showed a biphasic abnormality with two distinct peaks at 13μ and 15μ. This was most pronounced in ten patients with the Wiskott-Aldrich syndrome. In one of these patients the curve became normal following successful bone marrow transplantation.
Abstract Fifty‐one children with acute lymphoblastic leukemia on a common protocol of treatment were classified according to presence or absence of chromosomal abnormalities found at the time of diagnosis in bone marrow and/ or blood. Twenty‐two or 43% had normal karyotypes while 29 (57%) had clonal abnormalities using the Giemsa‐trypsin banding technique. Thirteen of the 29 (45%) chromo‐somally abnormal patients relapsed while only three of 21 (14%) with normal karyotypes have relapsed with a median follow‐up of 49.5 months (42‐76 months). (One child with a normal karyotype did not respond to therapy.) Several hypotheses have been offered to attempt to explain the significantly better prognosis of patients with no observable initial chromosomal aberrations.
A newborn with graft-vs-host (GVH) disease following an exchange transfusion was treated by attempting to eradicate the incompatible graft and to reconstitute the child hematologically and immunologically with a bone marrow transplant. The patient was a female term infant (blood group B, Rh+ Coombs test positive) who received a one-unit group O, Rh- exchange transfusion from an unrelated female donor for hyperbilirubinemia due to ABO incompatibility on day 2. Signs of acute GVH disease began on day 8 and the clinical diagnosis was supported by skin biopsy. With antithymocyte globulin and high dose dexamethasone, the GVH reaction improved somewhat. Cyclophosphamide, 200 mg/kg total dose, was given over four days followed by a marrow graft from a brother who was HLA-A, B identical, and probably also D locus compatible in mixed lymphocyte culture. All signs of GVH resolved with cyclophosphamide treatment and hematologic reconstitution was evident by 14 days after transplant. Two weeks later the GVH reaction and aplastic anemia recurred and Y chromatin was detected in only 6% of marrow cells. The infant died on day 80. Autopsy showed disseminated candidiasis, disseminated cytomegalovirus infection, thymic dysplasia, hypoplastic marrow, and other histopathologic changes consistent with GVH disease. The persistence of female cells in blood and bone marrow and the destruction of the reconstituted marrow suggest that the original incompatible transfusion-derived graft was not eliminated and that it ultimately rejected the histocompatible marrow graft.
Pharmacodynamic measures of neutropenia, such as absolute neutrophil count at nadir and neutrophil survival fraction, may not reflect the overall time course of neutropenia. We developed a pharmacokinetic-pharmacodynamic model to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutropenia. Topotecan was administered as a 30-min infusion daily for 5 days, repeated every 21 days. As part of a Phase I Pediatric Oncology Group study, topotecan was administered at 1.4 and 1.7 mg/m(2)/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m(2)/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m(2)/day without filgrastim. A pharmacokinetic-pharmacodynamic model was fit to profiles of topotecan lactone plasma concentrations and neutrophil survival fraction from cycle 1 and used to calculate topotecan lactone area under the plasma concentration-versus-time curve from 0 to 120 h (AUC(LAC)) and the area between the baseline and treatment-related neutrophil survival fraction (ABC) from 0 to 700 h. The mean +/- SD neutrophil survival fraction at nadir for the POG, POG+G, and NHP groups was 0.12 +/- 0.09, 0.11 +/- 0.17, and 0.09 +/- 0.08, respectively (P > 0.05). The mean +/- SD for the ratio of ABC to AUC(LAC) for the POG and NHP groups was 1.02 +/- 0.38 and 0.16 +/- 0.09, respectively (P < 0.05). The model estimate of ABC and the ratio of ABC to AUC(LAC) in children and NHPs may better reflect sensitivity to chemotherapy-induced neutropenia.
If there are two words which describe Archie's trek through science and medicine they have to be “eclectic” and “energetic.” From bench to bedside, from neglected causes to international administration he has shown enviable skills and tireless energy. This award truly reflects his major contributions to the field of pediatric hematology/oncology, many of which go beyond our specialty. Archie's journey began with a B.S. in Life Sciences, from the Massachusetts Institute of Technology and his medical degree in 1969 from the University of Rochester School of Medicine and Dentistry, New York, where he graduated “with honor and with distinction in research.” Already expressing the “pharmacology—CNS” research gene Archie, as a medical student, had published studies of meperidine and effects on the EEG in a guinea pig model. He also received the Collier Prize for “compassionate and understanding care of the sick.” These were clearly predictors of his career to follow. The University of Washington, the Children's Orthopedic Hospital and Medical Center (COHMC) as the children's hospital in Seattle was then known, and the Fred Hutchinson Cancer Center became his primary “medical home” through the 70s and 80s as he rapidly ascended the academic tree and established his credentials as an international leader in our field. This period was interrupted only by a 3-year sojourn courtesy of the US Public Health Service, but a very important sojourn, as a Clinical Associate in the Laboratory of Chemical Pharmacology and attending physician at the Pediatric Oncology Branch of the National Cancer Institute. Here, he developed and honed his skills in pharmacokinetic studies of anti-neoplastic agents used to treat childhood cancer. During the early phase of his career Archie made major contributions in understanding the pharmacology of drugs in the newborn. But it was his studies, initially performed in collaboration with David Poplack, of the use of methotrexate, both in the laboratory in murine and primate studies, and in clinical trials that constituted a body of research which has had major impact on our understanding of the prevention and treatment of CNS leukemia. As a small but important example is the fact that Archie almost single-handedly defined intrathecal drug doses based on age, rather than on weight or surface area. His focused research on methotrexate, both given intrathecally and in high dose intravenously with citrovorum factor rescue defined the use, effectiveness, and toxicity of this drug so fundamentally important in the treatment of acute lymphoblastic leukemia in children. The treatment of ALL in infants and other children at high-risk of relapse also became areas of his research interest as did the broad spectrum of childhood cancers in general. Not content with these contributions, and emblematic of Archie's inquisitiveness, he also completed a fellowship in radiation oncology at the same time when he was on the attending staff of COHMC and a professor at the University of Washington, so that ultimately he held a professorship in three departments: pediatrics, medicine, and radiation oncology. Archie arrived in Houston in 1990 where he became the Chairman of Pediatrics at the University of Texas, MD Anderson Cancer Center, and held the Mosbacher Chair. With the enthusiasm and gift for multitasking that is so characteristic of his efforts, his impact was soon apparent in a number of areas. In the clinical area, patient registrations substantially increased, new inpatient facilities were designed and occupied and a modern outpatient chemotherapy and transfusion area were established, as he led an emphasis on the outpatient management of treating children with cancer. In the environment of managed care, he led efforts to put the Division on a stable financial base. Archie's deep commitment to advancing the science of pediatric oncology was apparent in a number of areas. As he emphasized and developed the infrastructure to support clinical trial participation, the percentage of patients enroled on therapeutic trials increased threefold. Extramural funding, and faculty publications in peer reviewed journals increased dramatically. The division conducted the initial pediatric trials with several diverse therapeutic and supportive agents including GM-CSF, lipo-amphotericin, navelbine, doxorubicin infusions, lipo-vincristine, MTP-PE, and fluconazole. Initial trials were conducted to demonstrate the utility of chemotherapy for infants with brain tumors, thus sparing the patients from the toxicity of radiation to the immature central nervous system. The safety and utility of fine needle aspirations and sentinel node biopsies were also established in pediatric patients as the Division built upon the creative efforts of colleagues in the adult specialties at MD Anderson. While encouraging academic activities, excellence in clinical care, and providing the infrastructure to enhance success, Archie also found the time and energy to help organize and co-host a series of international pediatric neuro-oncology conferences and two United States–Japan pediatric oncology conferences. Archie's most broad and long lasting contributions came from his work within the Children's Cancer Group (CCG), as well as his role in the subsequent merger of the four pediatric oncology groups to form the Children's Oncology Group (COG) in the late 1990s. As a first year Assistant Professor, Archie was tapped to lead CCG-161, the Phase III trial for newly diagnosed patients with low-risk ALL. This study documented that one could reduce CNS leukemia with pharmacokinetically/age-derived IT methotrexate, as noted above (Bleyer WA, et al.: J Clin Onc 1: 317–325, 1983). In 5 short years, he was an Associate Chair of CCG in charge of all leukemia and lymphoma studies, personally chairing the ALL Strategy Group from 1982 to 1986. It was during this reign that CCG adopted a BFM backbone for leukemia studies, with a series of randomized trials which dissected the German approach to show that, in intermediate risk children, delayed intensification was more important than aggressive upfront therapy in improving survival. Archie also played major roles in developmental therapeutics and treatment of children with brain tumors, chairing the Brain Tumor Strategy Group from 1978 to 1982. He recognized that as the survival in children with ALL was rapidly improving, brain tumors would be the “next frontier” for trying to lower childhood cancer mortality. In 1989, Archie was asked to be Vice-Chair of the CCG, became the PI of the NCI grant in 1990, and then Chaired CCG for a 10-year period of time from 1992 to 2002. This was a period of time for CCG when many ideas came out of the trenches in various diseases, and Archie appropriately saw his job as “getting out of the way” to let the next generation build on the scientific foundation that had previously been laid. The number of patients put on clinical trials increased from 3,613 to 8,979. Most importantly, the overall mortality of cancers in patients aged less than 20 years continued its fall from an annual rate of over 50 per million in 1975 to 25 per million in 2002. In the late 1990s, the NCI was struggling with its adult co-operative group programs, as well as with trying to increase the accrual rates of adults onto NCI sponsored clinical trials. They pushed the “adults” to merge groups or re-think how they interacted. Although no specific actions were required by the four childhood co-operative groups, Archie, along with Sharon Murphy, Dan Green, and Bill Crist recognized the value that might be obtained by increased pediatric unity. They then developed a blueprint for merging the four pediatric groups into one single group, the COG, which has been unified under a single leader, Greg Reaman, since 2001. The adult groups have yet to merge, and their challenges continue. However, in the pediatric arena, the world's largest pediatric group maintains it vibrancy; and is poised to grapple with the challenges ahead, continuing to lower childhood cancer mortality despite approaching optimum use of traditional cancer chemotherapeutic agents. Archie refuses to go “silently into the night.” Recently, he developed a new passion for adolescents and young adults with cancer and what he described as the “clinical trial gap” for these individuals. Archie was the first Chair of the Adolescent and Young Adult (AYA) Committee for COG, and has helped set up national fellowships for studying this particular age group. This program could ultimately lead to recognition of AYA issues, including transitioning of care of children with cancer and other chronic diseases into the adult world, as its own specialty. Moving cross-country has been a recurring theme in Archie's career and he has now returned to the Northwest, this time on the sunny side of the mountains to Bend, Oregon, where he is in “semi-retirement” as a medical advisor at the St. Charles Medical Center and director of an AYA cancer research program. Archie's curriculum vitae reflects an incredibly productive career and publication record in pharmacology and pediatric hematology–oncology including “too-many-to-count” invited distinguished lectureships across the US and around the world, and many awards and honors from the American Cancer Society and the Leukemia Society of America. He has made major contributions to the American Society of Clinical Oncology and many national and international societies dedicated to the care of children with cancer. A superb clinician, teacher, investigator, and advocate, Archie Bleyer is a very worthy recipient of this year's American Society of Pediatric Hematology/Oncology (ASPHO) Distinguished Career Award.
