1. Combinations of effective agents produce at least an additive increase in complete remission rates over that which can be achieved when the agents are used individually. 2. Patients who do not achieve complete remission with initial treatment have a significantly shorter survival. 3. Alternating MTX and 6-MP at 28-day intervals during remission does not prolong the duration of remission over that of combined concurrent 6-MP and MTX. 4. The administration of folic acid antagonists intrathecally at 28-day intervals during antimetabolite maintained remission did not prolong the duration of remission. Meningeal leukemia, however, occurred significantly less frequently in these patients. 5. The duration of combined 6-MP and MTX maintained remission is not greater than that of 6-MP maintained remission. 6. The toxicity of 6-MP and MTX in combination in patients in remission is additive. The above conclusions were drawn from this comparative study of combinations of chemotherapeutic agents in children with acute lymphocytic leukemia.
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.
Thirty-seven children with acute leukemia were treated with 5-azacytidine in 5-day courses given every 14 days. Six out of 14 children with acute myelogenous leukemia who were adequately treated achieved an M1 marrow. Five of these subsequently developed complete remissions lasting 8 mo, 6 mo, 3 mo, 2 mo, and 2 mo. Of 22 children with acute lymphocytic leukemia, one achieved an M1 marrow and one an M2 marrow. The former attained a complete remission which lasted 3 mo. The maximum tolerated dose is between 150 to 200 mg/sq m on a daily x 5 schedule given every 14 days. The impressive activity of 5-aza-C in patients with acute myelogenous leukemia resistant to cytosine arabinoside indicates that this drug will become an important addition to the therapeutic armamentaria against this type of leukemia.
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