Prognostic factors and therapy in acute lymphoblastic leukemia of childhood: CCG-141. A report from childrens cancer study group.
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Biomedical subjects
Publications and source records attributed to D Hammond.
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Members of the Childrens Cancer Study Group treated 234 eligible patients in a randomized trial designed to study the relative effectiveness of two therapy programs for the treatment of childhood and adolescent non-Hodgkin's lymphoma. Two chemotherapeutic strategies were compared: a 4-drug regimen (COMP) and a 10-drug regimen (modified LSA2-L2). Failure-free survival for all patients was 60 per cent at 24 months. In patients with disseminated disease treatment success was influenced by both the histologic subtype of disease and the therapeutic regimen followed. The 10-drug program was more effective than the 4-drug program in patients with disseminated lymphoblastic disease (two-year failure-free survival rate, 76 vs. 26 per cent, respectively; P = 0.0002), whereas the 4-drug program was more effective than the 10-drug program in those with nonlymphoblastic disease (57 vs. 28 per cent, respectively, P = 0.008). The less toxic, more easily administered 4-drug regimen was as effective as the 10-drug regimen in patients with localized disease (89 vs. 84 per cent, respectively).
The prognostic significance of hand mirror cells (HMCs) in childhood acute lymphoblastic leukemia was determined by quantifying the percentage of these cells in the diagnostic bone marrow aspirates of previously untreated children entered on the Childrens Cancer Study Group protocol 141. Of 664 examinable patients, 39 (5.9%) had greater than 10% HMCs, and only four (0.6%) had greater than 30% HMCs. Compared with the entire study population, a greater proportion of children with more than 10% HMCs were older than 10 years of age, had hemoglobin levels greater than 10 g/dL, and had undifferentiated lymphoblast morphology. The children with more than 10% HMCs had a higher rate of bone marrow relapse, poorer disease-free survival, and shorter survival than patients with less than 10% HMCs. By multivariate analysis, HMC morphology was an independent, unfavorable prognostic factor.
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Major advances have been made in the past 10 yr in both the understanding of the biologic characteristics of acute nonlymphocytic leukemia and in the treatment of patients with this disease. Advances in the biologic characteristics include: a better understanding of the nature of leukemic cell proliferation and differentiation; a clearer description of the morphological, histochemical, and ultrastructural characteristics of leukemic cells; a recognition that a high percentage of patients may have specific cytogenetic abnormalities; and a recognition that biochemical differences exist between acute nonlymphocytic leukemia (ANLL) and acute lymphoblastic leukemia (ALL). Today, over 70% of children with ANLL can be induced into a complete remission and over 25% are remaining in a continuous remission for over 2 yr. In spite of these improved results, the best method of extending remissions is unknown. It is unlikely that better results of therapy will be achieved in the future by tailoring the treatment according to the biologic characteristics of the patient, since it appears that ANLL is a heterogeneous group of diseases.
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Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.
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The identification of important prognostic factors at diagnosis of childhood leukemia has been very useful in explaining the marked differences in disease outcome. After a complete remission is achieved, it is interesting to determine whether the ability to maintain a complete remission and the patient's survival continue to be influenced by the prognostic factors identified at diagnosis. If the maintenance of complete remission and survival continue to be influenced, it is important to determine the magnitude of this effect and its variations with time. Data from a study population of 936 children with newly diagnosed acute lymphoblastic leukemia were analyzed to determine the duration of effect for three variables showing strong prognostic influence: WBC, age at diagnosis, and sex. The strongest of these, WBC, showed a gradual attenuation of effect for children in progressively longer periods of complete continuous remission to a virtual disappearance at 24 months. Age and sex showed a similar reduction in prognostic effect with a negligible contribution at 15 months of continuous complete remission. However, sex becomes an important variables again with a late effect on recurrence results in patients who experience long periods of remission.
In the period 1968--78, 3161 children were enrolled in six studies of acute lymphoblastic leukaemia by participating institutions of the Childrens Cancer Study Group. In the first two studies, which did not include central-nervous-system (CNS) prophylaxis in the treatment programme, the outcome for male and female patients was very similar. In the following four studies, which included radiation prophylaxis to the CNS, a difference in outcome favouring females appeared consistently. This difference began about 6--12 months after initial remission and was further accentuated by withdrawal of therapy. Some of these studies also included a randomised trial of duration of therapy, studying 3 versus 5 years of maintenance treatment. Analysis of these studies suggests that sex group has implications both for duration of treatment and for optimum central-nervous-system prophylaxis.
Data from 119 patients with nasopharyngeal carcinoma who were under 30 years of age were retrospectively analyzed by the investigators of the Children's Cancer Study Group. The overall five-year survival and relapse-free survival rates from diagnosis were 51 and 36%, respectively. When the tumor was confined to the nasopharynx (1 + T2, 41 patients), the five-year survival was 75%. No significant correlation was found between survival or local recurrence and the radiation dose to the primary site. The five-year survival from relapse was 37% for 21 reirradiated patients with local and/or regional relapse compared with 11% for 45 patients with other forms of relapse. It is concluded that the optimal radiation dose for tumor eradication in young patients is now known.
Children and young adults less than 18 years of age with acute nonlymphocytic leukemia who remained in long term bone marrow and extramedullary remission for two years or longer since starting maintenance were compared to the remaining responders for the following characteristics: cell type, sex, age at diagnosis, race, pretreatment, white blood count, length of time from start to induction therapy to achievement of an M1 marrow, marrow rating at day 56 of therapy, marrow rating at the start of maintenance therapy, and specific study. Forty-eight patients of a group of 333 qualified as having long term remission (14.4%). Multivariant analysis indicated that patients between the ages of 3 and 10 years (p = 0.003) as well as the length of time to achieve an M1 marrow from the start of treatment (p = 0.03) were the only characteristics associated with achievement of a long term remission. Maintenance therapy was discontinued in 15 patients from 2.5 to 4.8 years after start of maintenance and all patients remained in bone marrow remission of periods from 0+ to 3.0+ years after stopping treatment. Of the 33 who have remained on a continuous maintenance therapy 12 have had bone marrow relapses. These data confirm the prognostic value of age and length of time to achieve remission during induction in acute nonlymphocytic leukemia and suggest that there may be no significant benefit from maintenance therapy continued beyond 2 years for patients in their initial remission.
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Plasmids in both Escherichia coli and Staphylococcus aureus contain an "operon" that confers resistance to arsenate, arsenite, and antimony(III) salts. The systems were always inducible. All three salts, arsenate, arsenite, and antimony(III), were inducers. Mutants and a cloned deoxyribonucleic acid fragment from plasmid pI258 in S. aureus have lost arsenate resistance but retained resistances to arsenite and antimony, demonstrating that separate genes are involved. Arsenate-resistant arsenite-sensitive S. aureus plasmid mutants were also isolated. In E. coli, plasmid-determined arsenate resistance and reduced uptake were additive to that found with chromosomal arsenate resistance mutants. Arsenate resistance was due to reduced uptake of arsenate by the induced plasmid-containing cells. Under conditions of high arsenate, when some uptake could be demonstrated with the induced resistant cells, the arsenate was rapidly lost by the cells in the absence of extracellular phosphate. Sensitive cells retained arsenate under these conditions. When phosphate was added, phosphate-arsenate exchange occurred. High phosphate in the growth medium protected cells from arsenate, but not from arsenite or antimony(III) toxicity. We do not know the mechanisms of arsenite or antimony resistance. However, arsenite was not oxidized to less toxic arsenate. Since cell-free medium "conditioned" by prior growth to induced resistant cells with toxic levels of arsenite or antimony(III) retained the ability to inhibit the growth of sensitive cells, the mechanism of arsenite and antimony resistance does not involve conversion of AsO2- or SbO+ to less toxic forms or binding by soluble thiols excreted by resistant cells.
The French-American-British (FAB) classification has been proposed as a useful and uniform method of defining morphologic subsets of acute leukaemias. As part of a prospective study designed to identify subsets of children with high risk of early relapse (CCG 141), submitted bone marrow slides from 765 of 883 patients entered on study were reviewed by two morphologists blinded as to prognostic factors and treatment regimen. L1, L2 and L3 acute lymphoblastic leukaemia (ALL) comprised 85.1%, 14.1% and 0.8%, respectively, of the total population. Children with greater than 25% L2 lymphoblasts had a significantly higher relapse rate and significantly poorer survival. Results of this study indicate that as a single variable, lymphoblast morphology is a very significant predictor of survival, haematologic remission, and complete continuous remission. Multivariate analyses show that lymphoblast morphology is again significant in determining duration of survival (P = 0.048), and is of borderline statistical significance (P = 0.089) in predicting length of complete continuous remission. The FAB classification, with minor modifications, is reproducible, useful, and prognostic in childhood ALL.
Eight-hundred ninety-five previously untreated acute lymphoblastic leukemia (ALL) patients were entered on a protocol designed to provide results of selected immunologic tests. At diagnosis, delayed hypersensitivity tests with four antigens (tetanus, diptheria, candida, and SKSD), immunoglobulin levels, tests for serum inhibition to phytohemagglutinin-stimulated lymphocyte blastogenesis, and HLA-A, B, and C typing were performed. Although delayed lymphocyte blastogenesis have been reported previously to be abnormal in ALL, we did not find them to be associated with disease outcome. Thirty percent of the patients had reduced levels of one or more immunoglobulins. The frequency of remission was less in those patients with decreased IgG and IgA. IgA and IgM showed prognostic importance in remission duration, and all three fractions appeared to have prognostic significance for survival duration. Although none of the HLA types appeared to be associated with significantly increased or decreased success in remission induction, patients with antigens A28 or B12 and patients bearing lymphocyte A11/B35 had shorter remissions. our results indicate that the immunologic factors studied, hypogammaglobulinemia and certain HLA antigens may be related to disease control and outcome in ALL.