Donald J. Fernbach

Toxicity of L‐asparaginase in children with advanced leukemia

A total of 105 patients with advanced acute leukemia in relapse received 123 trials of L‐asparaginase. Three different schedules were used, two of which involved simultaneous administration of vincristine and prednisone. Treatment was temporarily interrupted because of toxicity in 14 patients, and permanently discontinued in an additional 31. In 13 patients, this occurred before 10 doses of L‐asparaginase were given, while in the remaining 18 patients, therapy was stopped after remission was attained. The major toxicities were pancreatitis (fatal in four patients), hypersensitivity reactions, disturbances of liver function (fatal in two patients), and clinical and laboratory manifestations of central nervous system (CNS) dysfunction. Diabetic keto‐acidosis was encountered in two patients and was fatal in one. Severe leukopenia ascribed to L‐asparaginase occurred in two patients, in one of whom it was the contributory cause of death. Toxicity was not clearly different with any of the three treatment schedules. Most of the patients with only laboratory evidence of toxicity had no associated clinical manifestations, and this did not appear to decrease the likelihood of obtaining a remission.

Typhlitis. An 18‐year experience and postmortem review

A review of pediatric autopsy results at the Texas Childrens Hospital, Baylor College of Medicine from 1970 through 1987 was conducted. Thirty‐three cases of typhlitis were identified in patients with acute leukemia and two cases each in patients with lymphoblastic lymphoma and aplastic anemia. Patients ranged in age from 10 months to 17 years. Fifty‐seven percent were male and 43% were female. All were myelosuppressed. A postmortem incidence rate of 24% was determined for patients with acute leukemia. Common symptoms included abdominal pain and distention in 78% of patients and acute lower gastrointestinal bleeding in 35%. Abdominal radiographs varied in spectrum from a nonspecific bowel gas pattern to frank right colonic pneumatosis intestinalis. Thirty‐three patients received chemotherapy within 30 days before onset of abdominal symptoms. All patients were febrile (> 38.5°C), and 33 received broadspectrum antibiotics. Three patients received amphotericin B. Premortem, 84% of organisms cultured from blood were bacterial whereas 16% were fungal. Fungal pathogens accounted for 53% of new microorganisms seen at autopsy. Postmortem examination showed typhlitis in the following anatomic distributions: (1) confined to the cecum; (2) involving the cecum and ileum; (3) involving the cecum, ileum, and ascending colon; or (4) involving the cecum, with sporadic ulcers throughout the intestine. This review includes clinical and postmortem features of typhlitis and current strategies for diagnosis and management.

Factors influencing survival in pediatric acute leukemia. The SWCCSG experience, 1958–1970

From 1958 through 1970 a total of 1,024 patients was entered on the 7 clinical studies of the Southwest Cancer Chemotherapy Study Group for newly diagnosed cases of acute leukemia. A review of these cases was undertaken to determine the important factors, other than therapy, influencing survival. The most important variables in terms of survival prognosis were found to be age at diagnosis, histologic type of leukemia, and initial peripheral blood leukocyte count. The influence of these variables appeared to persist for at least 5 years following diagnosis. Based on these variables, a simple heuristic approach was taken to define prognostic groups of patients. The patients race, initial platelet count, hemorrhagic status, and enlargement status of liver, spleen, and nodes were of additional prognostic value, but there appeared to be no prognostic significance in the patients sex, initial hemoglobin value, or percent of blast cells in the bone marrow.

Adjuvant chemotherapy in primary treatment of osteogenic sarcoma.A southwest oncology group study

A four‐drug adjuvant chemotherapy regimen (CONPADRI‐I) was utilized in the primary treatment of 18 children with osteogenic sarcoma. All patients had surgical amputation for the primary lesion. The children then received cyclophosphamide, vincristine, melphalan, and adriamycin in defined combinations intermittently over a 72‐week period. Of the 18 patients, 10 (55%) remain free of disease 24 months or longer from time of amputation.

Malignant rhabdoid tumor of the extremity

Two cases of malignant rhabdoid tumor (MRT) involving the sciatic nerve are described. Despite the close affiliation of the tumor with neural tissue, staining characteristics in these patients do not suggest a neural origin of MRT. Survival in patients with renal and extrarenal MRT has been poor. Our patients were treated with an aggressive chemotherapy program using cisplatin, Adriamycin (doxorubicin), vincristine, cyclophosphamide, actinomycin D, and DTIC. One child died of progressive disease; the other is well 35 months after diagnosis.

Treatment intensity and outcome for children with acute lymphocytic leukemia of standard risk: a pediatric oncology group study

Four hundred thirty‐four children, with good‐risk acute lymphocytic leukemia (ALL), were assigned randomly to receive intensive or less intensive maintenance therapy with 6‐mercaptopurine and methotrexate, plus vincristine and prednisone pulses in such a way that patients on treatment 1 had their leukocyte counts maintained between 1500 and 3000/mm3. Patients on treatment 2 had leukocyte counts maintained between 3000 and 4500/mm3. Absolute granulocyte counts were maintained above 500/mm3 on both groups. All children received induction treatment with vincristine, prednisone and L‐asparaginase and had central nervous system (CNS) prophylaxis with cranial irradiation and intrathecal methotrexate. The overall remission rate was 94%. Event‐free survival at 8 years was 44% (SE, 5.6%). There was no significant difference in outcome between treatments 1 and 2 (P = 0.83). The incidence of infection was similar overall and not significantly different between treatment arms.

A fatal X-linked recessive reticuloendothelial syndrome with hyperglobulinemia: X-linked recessive reticuloendotheliosis

In the past two generations of a Latin American family, 17 preschool-age boys died following a brief illness characterized by fever, hepatosplenomegaly, lymph node enlargement, purpura, hyperglobulinemia, and anemia. All were related through their mothers, and the disorder occurred in the pattern of an X-linked recessive trait. Postmortem examination of 12 boys revealed widespread infiltration by immature mononuclear cells and mature plasma cells. Results of extensive studies in the most recently affected boy are described.

Wilms tumor with aniridia/iris dysplasia and apparently normal chromosomes.

Two patients with Wilms tumor, iris dysplasia (complete aniridia in one and subtle iris defects in the other), normal karyotypes, and no gene loss demonstrable by enzyme marker and direct DNA analyses are presented. The findings indicate that aniridia and less severe iris defects define a risk for Wilms tumor even in the absence of del (11p13), and that there is as yet no consistent biochemical genetic marker for the aniridia-Wilms tumor association.

Vincristine in acute leukemia of childhood.

Ninety‐four children with acute leukemia refractory to other forms of chematherapy were treated by three dosage regimens of vincristine. Complete remission occurred in 21.8% of the children experiencing adequate drug trial, with partial remission in 25.4% and bone marrow remission in 37.4%. Rapidity of response was variable with bone marrow remission occurring between the fourteenth and eighty‐fifth day of therapy and optimum response between the twenty‐first and one hundred and thirteenth day. Remissions, lasting only 20‐154 days, on maintenance therapy with vincristine tended to be relatively short‐lived, compared with those maintained by other agents. Toxicity of vincristine proved to be a limiting lactor, requiring alteration of therap in over 25% of the children treated. Vincristine, nevertheless, is firmly established as a valuable agent for the induction of remission in acute leukemia. Continuing studies indicate that the rate of remission reinduction is markedly increased by the combination of vincristine with prednisone.

Interrupted vs. continued maintenance therapy in childhood acute leukemia

A total of 313 patients with childhood acute leukemia received a combination of vincristine (2 mg/m2/week) and prednisone (60 mg/m2/day); 86% of 276 evaluable patients achieved a complete bone marrow remission in a median of 35 days. When a complete bone marrow remission was achieved, patients were randomized to one of three oral maintenance therapies: 6‐mercaptopurine (6MP) (75 mg/m2/day), methotrexate (MTX) (25 mg/m2/twice weekly), or cyclophosphamide (CYC) (100 mg/m2/day). Patients receiving maintenance therapy were further randomized at 2 and 6 months after the start of maintenance either to continue or discontinue therapy. The median lengths of subsequent bone marrow remission for patients randomized at 2 months to continue vs. discontinue therapy were: 37 vs. 19 weeks for 6‐MP patients; 25 vs. 14 weeks for MTX patients; and 29 vs. 13 weeks for CYC patients. The median lengths of subsequent marrow remissions for patients receiving maintenance therapy for 6 months and randomized to continue vs. discontinue were: 57 vs. 17 weeks for 6‐MP patients; 60 vs. 40 weeks for MTX patients; and 23 vs. 10 weeks for CYC patients. Results indicate a significant advantage for continuing maintenance therapy at 2 and 6 months after the start of complete bone marrow remission.