Myron Karon

Prognostic factors and therapy in acute lymphoblastic leukemia of childhood: CCG‐141: A report from childrens cancer study group

From 1975 to 1978, 880 previously untreated patients with acute lymphoblastic leukemia (ALL) were entered on CCG‐141, a protocol designed to determine the importance of clinical predictors of remission‐induction, duration of complete continuous remission (CCR), and survival, and to determine the benefit of intensive therapy in patients with a poor prognosis. Patients with initial leukocyte count <20 × 109/1 received prednisone (PDN), vincristine (VCR), L‐asparaginase (LASP), cranial irradiation and intrathecal (IT) methotrexate (MTX), and were maintained on 6‐mercaptopurine (6‐MP), MTX, and monthly PDN and VCR. Patients with initial leukocyte count >20 × 109/1 were randomly assigned to this standard regimen or to a more intensive four‐drug regimen (PDN, VCR, LASP, and cyclophosphamide) and a maintenance program consisting of alternating cycles of PDN, VCR, 6‐MP, and MTX (POMP) and PDN, VCR, cytosine arabinoside, and Adriamycin (POCA). The overall rate of complete remission (CR) was 93%. Factors associated with a significantly lower rate of CR were: M3 bone marrow (BM) on day 14, CNS leukemia at diagnosis, L3, morphology, less than 40% PAS‐positive lymphoblasts, low IgG, age >10 years, and L2 morphology. The relapse rate in patients with an initial leukocyte count <20 × 109/1 was significantly lower than in patients with an initial leukocyte count >20 × 109/1. By multivariate analysis, adverse predictors of duration of CCR were leukocyte count >50 × 109/1, Hb >10 g/dl, low IgM, massive splenomegaly, age <1 yr, M3 BM on day 14 and male sex. More intensive maintenance therapy did not prolong the duration of CCR in patients with initial leukocyte count >20 × 109/1. By life table analysis, 80% of patients with good prognostic factors remain in CCR at four years. In patients with poor prognostic factors, the CCR rate at four years is 43%. This study demonstrates the utility of clinical prognostic factors in identifying subsets of patients at low and high probability of treatment failure. Intensive induction and maintenance therapy as used in this protocol did not benefit the poor prognosis group.

Treatment of acute leukemia with methylglyoxal-bis-guanylhydrazone (methyl GAG)

Methyl GAG was administered to 83 patients with acute leukemia. Significant antileukemic activity was identified in patients with acute myeloblastic leukemia who received the drug in an average daily dose of 126 to 160 mg. per square meter (4.5 per cent complete remissions). The remission rate is higher than that reported for other agents and is reflected by the median increlMe in survival from 2.5 to 6.5 months when compared to patients with myeloblastic leukemia treated with 6‐mercaptopurine. Adverse effects of methyl GAG are severe, and include mucosal ulcerations, diarrhea, phlebitis, desquamation of feet, furunculi tis, and marrow hypoplasia. The effective dose range is quite narrow; minor alterations in dose result in either greater toxicity or decreased antileukemic effect. Leukemic cells of patients with the highest response rate to methyl GAG (72 per cent) were characterized morphologically by Auer rods and/or significant granulation. Remissions lasted 4 months (median) and 4 patients had reinduction by a subsequent course. Methyl GAG has antileukemic activity which, although associated with substantial toxicity, is unique in the treatment of acute myelohlastic leukemia.

The role of vincristine in the treatment of childhood acute leukemia

In a study of 117 patients under the age of 20 with acute leukemia, vincristine (VCR), at 2 mg. per square meter body surface per week, produced complete remissions in 55 per cent and partial remissions in 15 per cent. The drug also induced second remissions. Patients entering complete remission with VCR were randomly allocated to maintenance therapy with VCR or placebo. The median duration of remission was short: 9 weeks for VCR compared with 6 weeks for placebo. The probability of serious neurological toxicity computed according to the time of exposure to VCR, based on the supposition that VCR was not used for maintenance therapy, indicated that the minimal theoretical risk of toxicity for the highest complete remission rate occurred at 4 weeks (38 per cent remissions with 5 per cent toxicity). At 6 weeks, the corresponding probabilities were 54 and 16 per cent.

THE METABOLISM OF RING-LABELED OROTIC ACID IN MAN

Considerable knowledge concerning purine metabolism has been obtained from chemical and isotopic studies of urinary uric acid. Corresponding information in man is lacking for the closely related field of pyrimidine metabolism. The availability of ring-labeled orotic acid as a specific pyrimidine precursor (1), together with the presence of pseudouridine (5-ribosyluracil) and uracil, as specific end products of pyrimidine metabolism in man, in conveniently assayable amounts in human urine (2-4), makes it possible to conduct certain kinetic studies. In the present investigation the metabolism of ring-labeled orotic acid and the time course of isotope incorporation into urinary *pseudouridine and uracil were studied in order to develop methods of measurement and to obtain values for the whole-body rate of pyrimidine synthesis as well as for the turnover rate of certain ribonucleic acid fractions.

Acid soluble components in RNA prepared from human leukemic white cells.

Summary Phenol-prepared RNA from human leukemic white cells contains degradation products. Interpretations regarding the significance of “unusual” RNA components from such sources, therefore, have to be made with great caution.