Leukemia (2001) 15, 898–902 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Daunorubicin continuous infusion induces more toxicity than bolus infusion in acute lymphoblastic leukemia induction regimen: a randomized study M Hunault-Berger1, N Milpied2, M Bernard3, J-P Jouet4, M Delain5, B Desablens6, A Sadoun7, F Guilhot7, P Casassus8 and N Ifrah1 Division of Hematology of the University Hospital of 1Angers, 2Nantes, 3Rennes, 4Lille, 5Tours, 6Amiens, 7Poitiers and 8Bobigny, France We report the first randomized study assessing the efficacy Patients and methods and safety of daunorubicin (DNR) continuous infusion (CI) com- pared to the more conventional 30-min infusion (i.v.) in newly diagnosed adult acute lymphoblastic leukemia (ALL). Seventy- Treatment seven patients were initially randomized to receive either a 24- h CI DNR (60 mg/m2 days 2–4) (40 patients) or bolus DNR at Seventy-seven consecutive previously untreated patients with the same dosage (37 patients) with vincristine (2 mg i.v. days a non-Burkitt ALL, between the ages of 15 and 65 years, from 1, 8, 15) and oral prednisone (60 mg/m2 days 1–15), without nine hospitals, entered this study from May 1986 to May hematopoietic growth factor support, as an induction regimen. 1990. Patients with either a clinical history or electrical signs The distribution of adverse prognostic factors was comparable of coronary insufficiency or heart failure were not included. in the two-induction arm. Acute toxicity was more important 2 in the CI arm. Gram negative infection (9 vs 1 gram negative During the induction treatment, DNR (60 mg/m /day on days septicemia, P = 0.01) and infection-related deaths (6 vs 1 2 to 4) was delivered according to the initial randomization, deaths, P = NS) occurred more frequently in the CI arm during either by CI or by rapid 30-minute infusion (i.v.). DNR was the induction treatment than in the i.v. arm, leading to the study given with vincristine (2 mg administered intravenously on interruption. Neutropenia but not thrombopenia duration was days 1, 8, 15) and oral prednisone (60 mg/m2 on days 1 to significantly longer in the CI arm than in the i.v. arm (18 days vs 14 days, P . 0.05 and 16 days vs 12 days, P . 0.05, 15). Supportive care was performed according to each center respectively). Despite a similar CR rate according to the policy. Antibiotics were maintained up to neutropenia recov- method of DNR administration (68% in the CI DNR arm vs 76% ery. Patients did not receive hematopoietic growth factors. in the i.v. arm after the first course), there was a trend toward The complete treatment program is summarized in Figure 1. higher freedom from relapse (FFR) after DNR CI (48% vs 28% Bone marrow evaluation was carried out on day 21. At this = in the i.v. arm at 5 years, P NS), suggesting that despite this time, patients with significant bone marrow blasts cells high toxicity, DNR CI may improve the CR quality and decrease further the residual disease. Leukemia (2001) 15, 898–902. received a second induction cycle (named ADA containing 2 2 × Keywords: acute lymphoblastic leukemia; daunorubicin; continu- DNR 60 mg/m i.v. day 1, cytarabine 30 mg/m i.v. 2 days ous infusion; toxicity 3–7, asparaginase 1000 U/kg days 8–12) with DNR CI or i.v. according to the initial randomization. Patients who did not enter CR after the second induction cycle were considered as Introduction treatment failure and were taken off the study. Patients in CR, after one or two induction regimens, received a two-course Despite improvement in chemotherapy and supportive care consolidation therapy including an ADA course 10 days after over the past two decades, the prognosis of adults with acute CR, followed by a second course consisting of high-dose lymphocytic leukemia (ALL) is still poor. Complete remission methotrexate, l-asparaginase, prednisone and vincristine rates of 60% to 85% are reached with induction regimens (MAPO) (Figure 1). Late intensification by the BEAC regimen 2 2 including anthracycline. However, the toxicity of these induc- (BCNU 200 mg/m p.o. day 1, cytarabine 300 mg/m CI days 2 tion regimens is high, with 10% to 20% mortality rate during 1–4, cyclophosphamide 1.5 g/m i.v. days 2–3, etoposide 300 2 induction as a result of infections, and does not preclude a mg/m CI days 2–3) without stem cell support ended this high relapse rate, leading to 20–40% 5-year disease-free sur- intensive program. Patients under age 45 years, with an HLA- vival, depending in part on patient selection.1–3 Continuous identical donor were proposed for allogeneic bone marrow infusion (CI) of cancer chemotherapeutic agents may have transplantation after the first consolidation phase. In one insti- enhanced therapeutic effects because of an improved pharma- tution, patients under age 50 years received an autologous cological availability while the reduced peak plasma concen- bone marrow transplant (ABMT) after MAPO course. Six tration level seems to reduce some of their side-effects.4,5 weekly prophylactic intrathecal injections were followed, Studies with solid tumors have shown that anthracycline con- after completion of the chemotherapy, by cranial irradiation of tinuous intravenous infusion could reduce its dose-limiting the entire brain and the spinal cord above the second cervical cardiotoxicity.6 Few data concerning CI in ALL treatment are vertebra for a total midline dose of 18 Gy, performed over a available. In order to improve the remission rate and/or to 2-week period. decrease the toxicity of the ALL induction regimen, we com- pared in a randomized multicentric study, DNR CI during induction chemotherapy with the more conventional rapid Statistical methods infusion. The primary end-point of this study was the CR rate after the induction regimen while the secondary end-points were the induction toxicity, overall survival (OS) and freedom from Correspondence: N Ifrah, Me´decine D, CHU, 49033 Angers cedex relapse (FFR) duration. Differences among response rates and 01, France; Fax: 33 2 41 35 45 82 incidence of certain characteristics among subgroups were Received 23 October 2000; accepted 23 February 2001 analyzed by the ξ2 test for qualitative parameters, and the Stu- Safety and efficacy of daunorubicin continuous infusion in ALL M Hunault-Berger et al 899 Figure 1 Complete treatment program. dent’s t-test for quantitative parameters. Survival time was measured from the time of diagnosis to the death or last fol- low-up. FFR duration was measured from the time of remission until documented relapse. Global event-free sur- vival (EFS) was measured from day 1 of therapy until failure Table 1 Patients’ characteristics to achieve CR, death or relapse. Survival and remission curves were generated with Kaplan–Meier product limit method and Daunorubicin CI Daunorubicin i.v. = = compared by log rank test. (n 40) (n 37) Sex (M/F) 21/19 25/12 Median age (years) 36 36 Results Age ,35 17 18 Bulk diseasea 14 10 Patients’ characteristics Splenomegaly 15 12 Fever 12 8 Forty patients were initially randomized to CI DNR arm and Documented infections 7 3 37 to i.v. DNR arm. The distribution of clinical and laboratory LDH (n = 61) .2N 19/30 19/31 characteristics in the two induction groups (Table 1) was com- Median WBC (109/l) 18 18 parable and not significantly different, especially for adverse WBC .30 × 109/l 11 12 Hemoglobin (g/dl) 10 10 prognostic factors such as Philadelphia chromosome, leuko- 9 cytosis, non-T cell leukemia lineage. Platelets (10 /l) 45 44 Immunophenotype (n = 70) T-ALL 10 9 Disease response and toxicity according to Calla 17 18 Other pre-B ALL 5 5 randomization Tdt — 1 Myeloid antigen 2 1 Induction results are summarized in Table 2. Sixty-six patients Null ALL 2 — achieved CR, 11 of them after an ADA course leading to an Karyotype (n = 41) overall CR rate of 86% (66/77). Six patients died before their Normal 4 6 remission status could be ascertained while five failed to achi- Abnormal 11 11 eve CR. Remission rate was unaffected by the method of DNR Ph1 4 5 administration. CR was achieved after the first course in 27 patients allocated to CI DNR (68%) and 28 patients (76%) in aDefined by a mediastinal mass or an adenomegaly .5 cm. Leukemia Safety and efficacy of daunorubicin continuous infusion in ALL M Hunault-Berger et al 900 Table 2 Induction results Daunorubicin CI Daunorubicin i.v. P (n = 40) (n = 37) CR (first induction) 27 (68%) 28 (76%) CR of patients alive at day 21 27/35 (77%) 28/36 (77%) CR after first ADA 6 5 Overall CR 33 (82%) 33 (89%) Resistance after ADA1 2 3 Deaths 6 (15%) 1 (2%) 0.06 Time to reach CR (days) 25 (13–40) 21 (17–38) Median thrombopenia (,50 x 109/l) (days) 16 (0–31) 12 (0–26) Median red blood cells transfused (units) 8 (0–21) 8 (0–19) Median platelets transfused (apheresis) 5 (0–15) 5 (0–16) Median neutropenia (,0.5 x 109/l) (days) 18 (0–35) 14 (0–30) 0.05 Median duration of fever (days) 2 (0–27) 1 (0–13) Documented bacteriemia 19 10 NS Staphylococcus 6 7 Streptococcus 2 (mitis + B) 1 (D) Candida 1 1 Corynebacterium 1 0 Gram-negative 9 1 0.01 Pulmonary aspergillosis 1 0 Undocumented pneumopathia 1 1 Induction-related deaths 6 1 NS Gram – septicemia 4 (days 12, 13a, 15, 18) 0 NS Gram + septicemia 1 (day 22) 0 Candidemia 1 (day 26a) 1 (day 25) Aspergillosis 1 (day 40) 0 aThis patient developed a gram-negative septicemia and subsequently a candidemia.