Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Phase II study of 13-cis-retinoic acid in pediatric patients with acute nonlymphocytic leukemia--a Pediatric Oncology Group study.

Forty-one patients with refractory acute non-lymphocytic leukemia (ANLL) in relapse were treated with 13-cis-retinoic acid (cRA) as salvage therapy. The cRA was given as a single oral dose of 100 mg/m2/day for 4 weeks. One patient achieved a complete remission and two patients achieved a partial remission with reduction of the bone marrow blast count from 40 to 20% after the first course. We recommend further study of cRA in combination with other agents in the treatment of ANLL in children.

Metastasis of adenocarcinoma of the lung to optic nerve sheath meningioma.

A 71-year-old woman developed chronic progressive visual loss in the right eye and computed tomographic scan showed enlargement of the intraorbital optic nerve consistent with optic nerve sheath meningioma. Over 12 years, the contralateral optic nerve was not clinically affected, and serial neuroradiologic imaging showed no evidence of intracranial tumor extension. Death occurred from metastatic adenocarcinoma of the lung 14 years after initial visual loss. Examination of the postmortem specimen of optic nerve and chiasm revealed extradural extension of meningioma with spread to the region of the optic chiasm and hypothalamus. A large focus of metastatic adenocarcinoma was present within the intraorbital portion of the meningioma. Carcinoma metastatic to intracranial meningioma is rare; to our knowledge, this is the first reported case in an optic nerve sheath meningioma. Neuroimaging may be inadequate to predict the value of tumor excision in preventing intracranial spread of optic nerve sheath meningioma.

An isozyme of erythrocyte pyruvate kinase (PK-Los Angeles) with impaired kinetics corrected by fructose-1, 6-diphosphate.

A mutant isozyme of erythrocyte pyruvate kinase was found in a family of French-Canadian ancestry in association with hemolytic anemia. The isozyme was characterized by normal maximal activity, pH optimum, heat stability, and fructosediphosphate activation constants, but had markedly reduced affinity for the substrate, phosphoenolpyruvate. This kinetic defect was corrected almost entirely in vitro by low concentrations of fructosediphosphate.

Biphasic reaction kinetics in an anomalous isozyme of erythrocyte pyruvate kinase.

A mutant erythrocyte isozyme of pyruvate kinase (PK) (ATP: pyruvate phosphotransferase, EC 2.7.1.40) has been found in associatin with chronic hemolytic anemia in two siblings who were doubly heterozygous for the isozyme and for quantitative PK deficiency of the usual form. The isozyme was characterized by approximately normal maximum reaction velocities but had markedly decreased affinity for the substrate, phosphoenolpyruvate (PEP), with 5-fold to 10-fold increases in half-saturation constants and decreased interaction between substrate binding sites. Two distinctly separable kinetic patterns for PEP were observed with multiple specimens. Concentrations of fructose 1,6-diphosphate (FDP) required for half-maximal activation were two orders of magnitude greater than controls, and optimal pH was lowered to 6.5. stability at 4 degrees C was markedly decreased, but the lost enzyme could be reactivated by fdp for periods even longer than normal controls.

Unique phenotypic expression of glucosephosphate isomerase deficiency.

Studies of a Mexican kindred present evidence for a unique phenotype of erythrocyte glucosephosphate isomerase, GPI Valle Hermoso. The proband was apparently the homozygous recipient of a mutant autosomal allele governing production of an isozyme characterized by decreased activity, marked thermal instability, normal kinetics and pH optimum, and normal starch gel electrophoretic patterns. Unlike previously known cases, leukocyte and plasma GPI activities were unimpaired. This suggested that the structural alteration primarily induced enzyme instability without drastically curtailing catalytic effectiveness, thereby allowing compensation by cells capable of continued protein synthesis. Age-related losses of GPI, however, were not evident by density-gradient fractionation of affected erythrocytes.

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission.

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.