RR Ellison

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.

In a randomized study of acute myelocytic leukemia (AML), 352 patients of all ages were treated for remission induction by one of the four regimens: 7 days of cytosine arabinoside (ara-C) by continuous intravenous (i.v.) infusion or bolus injection every 12 hr, together with daunorubicin (DNR) by rapid i.v. injection on days 1, 2, 3; or 5 days of ara-C by infusion or bolus injection and DNR for 2 days only. The regimen of 7 and 3 infusion was significantly superior to the other 3 regimens, resulting in 56% complete remission (CR). For remission maintenance, ara-C was given for 5 days every month and each month one of the following four drugs added on a cyclic rotational basis: thioguanine, cyclophosphamide, CCNU, or DNR. Although ara-C dosage each month was the same, the route of ara-C administration by random allocation was either rapid i.v. bolus or subcutaneous (s.c.) injection. The median duration of CR was significantly longer for s.c. ara-C group: 14 mo for patients less than 60 yr old (versus 8 mo for i.v.) and 31 mo for 60 or older age group (versus 9 mo for i.v.). Patients who received a combination of the best of the four induction regimens (7 and 3 infusion) and the better of the two maintenance schedules (s.c. ara-C) had a median remission duration of 22 mo and a median survival of 35 mo (the longest reported in a prospective randomized trial of therapy for AML). These results establish the validity of an intensive chemotherapy to produce rapid marrow aplasia followed by a sequential maintenance therapy for achieving prolonged disease-free survival in AML.

The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)

The efficacy of the addition of intensive therapy with daunorubicin (45 mg/m2 IV on days 1, 2, 3) to an otherwise identical induction program consisting of vincristine, prednisone, and L-asparaginase was assessed in 177 previously untreated adults (greater than or equal to 20 years of age) with acute lymphocytic leukemia (ALL). In the prospectively randomized phase of the investigation, 46 patients received daunorubicin in induction, whereas 53 did not. The two groups were otherwise comparable for pretreatment variables. A complete response was observed in 38/46 patients (83%) treated with daunorubicin, compared to 25/53 (47%) induced with vincristine, prednisone, and L-asparaginase alone (P = .003). The high response rate attributable to the use of the anthracycline was confirmed by the nonrandomized treatment of 78 subsequent patients, in whom a complete response rate of 76% was attained. A common program for central nervous system therapy and for maintenance therapy was employed in 103 patients achieving complete response. Maintenance consisted of cycles of 6-mercaptopurine (6-MP) and methotrexate with periodic reinforcement with vincristine and prednisone. Maintenance therapy proved to be minimally toxic. The average duration of complete response was 15 months and was not affected by the induction program employed. Approximately 25% of responders are projected to remain in continuing complete response for 36 months. The failure of the daunorubicin-containing programs to produce a higher percentage of long-term survivors, despite the higher complete response rates achieved, was thought to be due to the use of a maintenance program that was weak in intensity and dependent on reinforcement with vincristine and prednisone. These data clearly establish the increased effectiveness of vincristine, prednisone, L-asparaginase, and daunorubicin, as compared to this combination without daunorubicin, in the induction of complete response in adults with ALL. The results support the concept of an intensive, rather than a conservative, chemotherapeutic approach as the most appropriate strategy for the treatment of adult ALL.