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One-hundred-fifty-four patients with acute leukemia and extensive prior chemotherapy were treated with 5-Azacytidine and evaluated according to five different schedules. One-hundred-twenty patients received adequate trials; 34 patients died within 14 days of onset of treatment. Nine patients achieved a complete remission (CR) and two achieved a partial remission. Although two of the treatments have a higher remission rate, the data were not statistically significant. The median time to CR was 48 days (range 21-173). The median duration of CR was 65 days (range 39-369). There was no difference in response rate according to cell type. The median age of responders was 31 years, and 39 years for nonresponders. Proportionately there were more women among responders (5M/6F) and more men (70M/39F) among nonresponders. At onset of therapy the median leukocyte counts were similar between responding (5.4 X 10(3)) and nonresponding (5.7 X 10(3)) patients, but the proportion of leukemic cells was significantly higher among nonresponding patients (46% vs. 7%). Toxicities included nausea, vomiting, diarrhea, skin rash, myalgias, prolonged myelosuppression, hypotension, and central nervous system stupor and/or coma. Lower dose continuous infusion schedules of five-, seven-, and ten-days duration appear effective and were associated with less toxicity.

Five hundred forty three adult patients with acute leukemia were entered on the study designed to: (1) test efficacy of vincristine and prednisone used as primary drug therapy in patients with good prognosis as judged by a circulating blast cell count less than 30,000 cm2; (2) investigate the use of either simultaneously or sequentially administered Adriamycin plus cytosine arabinoside plus vincristine and prednisone; and (3) to assess the use of bacillus Calmette-Guerin (BCG) in the maintenance phase on both the response and duration of response. Complete remissions were seen in 21% of patients with the vincristine and prednisone arm. Complete remission rates were similar in both the simultaneously and sequentially administered chemotherapy with overall complete remission rates of 55%. Median durations of complete remission and survival were 35 and 62 weeks, respectively, for patients with AML; and 47 and 75, respectively, for patients with ALL. Toxicity was within acceptable limits. BCG administered during the maintenance phase of therapy caused no differences in duration of complete remission and survival. These results demonstrate an improved response and duration of response over previous studies done by this group.

In this Southwest Oncology Group (SWOG) study, 216 adults with acute leukemia were treated with ten-day chemotherapy consisting of vincristine sulfate (Oncovin), cytarabine (ara-C) (100 mg per square meter of body area per day by 24-hour infusion), and prednisone (ten-day OAP). The results were compared with those of a previous SWOG study in which cytarabine (200 mg per square meter of body area per day) was given for five days (five-day OAP). Patients entering complete remission (CR) were given three consolidation courses of five-day OAP and randomized to maintenance chemotherapy alone (32 patients) or combined with BCG vaccine (24 patients). For 160 previously untreated patients with acute myelogenous leukemia, there was no difference in remission rates (53% vs 43%) or median survival times (48 vs 47 weeks) between ten-day and five-day OAP. The difference in duration of CR (74 vs 54 weeks, respectively) between the two maintenance arms was not statistically significant. However, 14% of evaluable patients with acute myelogenous leukemia and 26% of those achieving CR were alive and in remission more than five years.

101 patients with acute leukemia in relapse were treated with 5-azacytidine according to three schedules: Regimen A--300 mg/m2(day divided intravenously at 8 hour intervals for 5 days; Regimen B--750 mg/m2 as a single iv pulse dose administered at 2 to 3 weeks intervals; and Regimen C--300 mg/m2/day by continuous infusion daily for 5 days. Twelve patients achieved a complete remission (CR) and six achieved a partial remission (PR) for an overall 18% response rate. Of 78 patients receiving an adequate trial the response rate was 23%. An average of 1.5 courses and a median of 5 weeks were necessary to achieve a response. The median duration of CR patients was 21 weeks and for PR patients it was 5 weeks. Response rates were 24% for Regimen A, 0 for Regimen B, and 1 of 8 for Regimen C. The CR rate for AML and AMML was 13%. Two of eight AMoL patients achieved a CR. Only 2 of 23 ALL patients responded, one of whom achieved a CR. Toxicity included moderate to severe nausea and vomiting, diarrhea, stomatitis, skin rash, and prolonged myelosuppression. 5-azacytidine has significant activity in the acute nonlymphoblastic leukemias.

Adults (274) with acute leukemia (AML) were randomly assigned to one of three treatment regimens: vincristine, prednisone, cytarabine--(1) 100 mg/sq m/day with cyclophosphamide (COAP); (2) 100 mg/sq m/day with daunorubicin (DOAP); and 200 mg/sq m/day (OAP). Cytarabine was infused continuously for five days. Patients entering complete remission randomly received maintenance treatment with COAP or OAP. For 197 previously untreated AML patients given COAP, DOAP, or OAP, remission rates were 37%, 35%, and 43%, respectively; median lengths, 40, 45, and 90 weeks; median survival, 7, 11, and 8 weeks. No statistically significant difference was found among treatments. Therefore, adding cyclophosphamide or daunorubicin, or using the COAP regimen with continuously infused cytarabine, produced no significant improvement over previously reported regimens. There was no significant difference in remission lengths in previously untreated AML patients maintained on OAP (median 81 weeks) or COAP (median 65 weeks).

The Southwest Oncology Group did a limited institutional pilot study of the combination of doxorubicin and ifosfamide in the treatment of previously treated adult patients with acute leukemia. Thirty-four patients received one or two courses of the combination. All patients had received prior chemotherapy and 32 had received prior anthracycline chemotherapy. Three patients died before their responses could be fully evaluated. Fourteen patients achieved complete remission (41%) and one patient achieved partial remission. The complete remission rate was 27% for patients with acute myeloblastic leukemia (myelomonoblastic leukemia, monoblastic leukemia, and erythroleukemia) and 89% for patients with acute lymphocytic and undifferentiated leukemia (ALL). Toxic effects included severe hematologic reactions in 33 of 34 patients, hematuria in six patients, altered sensorium in one patient, and congestive heart failure in one patient. The safety of the combination was established and toxic side effects of this therapy were tolerable. The 89% complete remission rate for previously treated patients with ALL suggests that the combination of doxorubicin and ifosfamide may be particularly effective in ALL.