We report the first randomized study assessing the efficacy and safety of daunorubicin (DNR) continuous infusion (CI) compared to the more conventional 30-min infusion (i.v.) in newly diagnosed adult acute lymphoblastic leukemia (ALL). Seventy-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 the same dosage (37 patients) with vincristine (2 mg i.v. days 1, 8, 15) and oral prednisone (60 mg/m2 days 1–15), without hematopoietic growth factor support, as an induction regimen. The distribution of adverse prognostic factors was comparable in the two-induction arm. Acute toxicity was more important in the CI arm. Gram negative infection (9 vs 1 gram negative septicemia, P = 0.01) and infection-related deaths (6 vs 1 deaths, P = NS) occurred more frequently in the CI arm during the induction treatment than in the i.v. arm, leading to the study interruption. Neutropenia but not thrombopenia duration was 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, respectively). Despite a similar CR rate according to the method of DNR administration (68% in the CI DNR arm vs 76% in the i.v. arm after the first course), there was a trend toward higher freedom from relapse (FFR) after DNR CI (48% vs 28% in the i.v. arm at 5 years, P = NS), suggesting that despite this high toxicity, DNR CI may improve the CR quality and decrease further the residual disease.
Despite improvement in chemotherapy and supportive care over the past two decades, the prognosis of adults with acute lymphocytic leukemia (ALL) is still poor. Complete remission rates of 60% to 85% are reached with induction regimens including anthracycline. However, the toxicity of these induction regimens is high, with 10% to 20% mortality rate during induction as a result of infections, and does not preclude a high relapse rate, leading to 20–40% 5-year disease-free survival, depending in part on patient selection.1,2,3 Continuous infusion (CI) of cancer chemotherapeutic agents may have enhanced therapeutic effects because of an improved pharmacological availability while the reduced peak plasma concentration level seems to reduce some of their side-effects.4,5 Studies with solid tumors have shown that anthracycline continuous intravenous infusion could reduce its dose-limiting cardiotoxicity.6 Few data concerning CI in ALL treatment are available. In order to improve the remission rate and/or to decrease the toxicity of the ALL induction regimen, we compared in a randomized multicentric study, DNR CI during induction chemotherapy with the more conventional rapid infusion.
Patients and methods
Seventy-seven consecutive previously untreated patients with a non-Burkitt ALL, between the ages of 15 and 65 years, from nine hospitals, entered this study from May 1986 to May 1990. Patients with either a clinical history or electrical signs of coronary insufficiency or heart failure were not included. During the induction treatment, DNR (60 mg/m2/day on days 2 to 4) was delivered according to the initial randomization, either by CI or by rapid 30-minute infusion (i.v.). DNR was given with vincristine (2 mg administered intravenously on days 1, 8, 15) and oral prednisone (60 mg/m2 on days 1 to 15). Supportive care was performed according to each center policy. Antibiotics were maintained up to neutropenia recovery. Patients did not receive hematopoietic growth factors. The complete treatment program is summarized in Figure 1. Bone marrow evaluation was carried out on day 21. At this time, patients with significant bone marrow blasts cells received a second induction cycle (named ADA containing DNR 60 mg/m2 i.v. day 1, cytarabine 30 mg/m2 i.v. × 2 days 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 treatment failure and were taken off the study. Patients in CR, after one or two induction regimens, received a two-course consolidation therapy including an ADA course 10 days after CR, followed by a second course consisting of high-dose methotrexate, L-asparaginase, prednisone and vincristine (MAPO) (Figure 1). Late intensification by the BEAC regimen (BCNU 200 mg/m2 p.o. day 1, cytarabine 300 mg/m2 CI days 1–4, cyclophosphamide 1.5 g/m2 i.v. days 2–3, etoposide 300 mg/m2 CI days 2–3) without stem cell support ended this intensive program. Patients under age 45 years, with an HLA-identical donor were proposed for allogeneic bone marrow transplantation after the first consolidation phase. In one institution, patients under age 50 years received an autologous bone marrow transplant (ABMT) after MAPO course. Six weekly prophylactic intrathecal injections were followed, after completion of the chemotherapy, by cranial irradiation of the entire brain and the spinal cord above the second cervical vertebra for a total midline dose of 18 Gy, performed over a 2-week period.
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 relapse (FFR) duration. Differences among response rates and incidence of certain characteristics among subgroups were analyzed by the χ2 test for qualitative parameters, and the Student's t-test for quantitative parameters. Survival time was measured from the time of diagnosis to the death or last follow-up. FFR duration was measured from the time of remission until documented relapse. Global event-free survival (EFS) was measured from day 1 of therapy until failure to achieve CR, death or relapse. Survival and remission curves were generated with Kaplan–Meier product limit method and compared by log rank test.
Forty patients were initially randomized to CI DNR arm and 37 to i.v. DNR arm. The distribution of clinical and laboratory characteristics in the two induction groups (Table 1) was comparable and not significantly different, especially for adverse prognostic factors such as Philadelphia chromosome, leukocytosis, non-T cell leukemia lineage.
Disease response and toxicity according to randomization
Induction results are summarized in Table 2. Sixty-six patients achieved CR, 11 of them after an ADA course leading to an overall CR rate of 86% (66/77). Six patients died before their remission status could be ascertained while five failed to achieve CR. Remission rate was unaffected by the method of DNR administration. CR was achieved after the first course in 27 patients allocated to CI DNR (68%) and 28 patients (76%) in the other group. In addition, the CR rates were also similar (77% in both arms) when only patients alive at day 21 were taken into account (27 out of 35 patients treated by CI as compared to 28 out of 36 patients in the i.v. arm). Neutropenia (<0.5 × 109/l) duration but not thrombopenia (<50 × 109/l) duration was significantly longer in the CI arm than in the i.v. arm (18 vs 14 days, P < 0.05 and 16 vs 12 days, P > 0.05, respectively). This could account for the severity of infections observed during the induction treatment: 19 patients in the CI arm and 10 patients in the i.v. arm experienced documented bacteriemia, with an excess of gram-negative infections in the CI arm (three Escherichia coli, four Klebsiella pneumoniae, two Enterobacter in the CI arm vs one Moraxella infection in the i.v. arm) (P = 0.01). Infection-related deaths tended to be more frequent in the CI arm (four gram-negative septicemia followed for one patient by a Candida tropicalis septicemia, one cocci gram-positive septicemia and one invasive aspergillosis) (15%) than in the i.v. arm (one from candidemia) (2%). No difference in terms of platelets or red blood cells transfusion were observed. No patients’ experienced grade 3 or 4 mucositis or requiried i.v. treatment. While cardiac toxicity was assessed by weekly EKG, only one patient in the CI arm experienced chest pain without any EKG modification. Echocardiograms were not routinely available. However, 10 years later, none of the living patients have clinical cardiac dysfunction.
Out of the 66 patients alive in CR, only 53 entered the late intensification phase (18 received HLA genoidentical allogenic BMT, eight autologous BMT and 27 BEAC regimen) due to early relapse or toxic deaths. Late intensification type was equally distributed in the two randomization arms. Two patients, one with hemorrhage pancreatitis and one with acute renal insufficiency were withdrawn from the study. At the time of analysis, 21 patients remained in CR, 36 relapsed, and nine died in CR. With a mean follow-up of 47 ± 6 months (0–158), overall survival is 32% at 47 months with EFS and FFR of 27% and 38% at 44 months, respectively (20 patients at risk). EFS and survival were higher after allogenic BMT (66% and 71% at 44 months respectively, 11 patients at risk) than after late intensification (18 and 26% respectively) (P = 0.0071 and 0.002). The EFS and survival were 37.5% with 43% FFR for the eight patients who underwent autologous BMT in first CR. OS and EFS were not influenced by the method of DNR administration. However, although not significant, FFR tended to be higher after DNR CI (48% in the CI arm vs 28% in the i.v. arm at 5 years, P = NS) (Figure 2).
The increase effectiveness in terms of complete remission of ALL induction regimens containing DNR has been demonstrated.7 However the best DNR administration modality remains to be established. Pharmacokinetic data seem to favor CI both in terms of efficacy and toxicity.8 DNR CI produced a more rapid cytoreduction than DNR bolus in ALL9 and, when performed over 4 h, reduced the peak plasma levels of DNR compared to bolus infusion without significant change in ALL cells concentrations or difference in acute toxicity.10 The absence of DNR peak serum concentration when administered as 24-h CI5 is considered as a major reason why the risk of side-effects such as cardiomyopathy is relatively low in multiple myeloma treated by the VAD regimen.11
Despite these theoretical advantages, few randomized data on acute leukemia are available. In AML, DNR CI, used at 45 or 30 mg/m2/day days 1–3, seems to be efficient without increased toxicity, in association with either cytosine arabinoside CI (100 mg/m2/day days 1–10) and 6-thioguanine (100 mg/m2 every 12 h orally for 8 days) or carboplatin (200 mg/m2/day days 3–7) respectively in non-randomized studies.12,13 In ALL, among 44 children, reduction in leukemic cell population is more rapid after 2 days DNR CI infusion (60 mg/m2/day) than after bolus and has a lower acute cardiac toxicity (0/18 patients after DNR CI vs 4/18 patients after bolus DNR).9 The safety and efficacy of other anthracycline CI in ALL have been reported. Epirubicin, as a 4-day CI course followed by a vincristine 4-day CI course, induced 52% of response in 23 refractory or relapsed acute leukemia including four ALL with minimal extrahematologic toxicity, particularly cardiac and gastrointestinal toxicity.14 Idarubicin (24 mg/m2/day days 1–2 CI) induced 49% response in 51 children with prognostically poor recurrence of ALL but long intervals of myelosuppresion and high rates of systemic infection.15 CI or bolus mitoxantrone (10 mg/m2 days 1–3) were equally effective and well tolerated in 39 patients with newly diagnosed ALL.16 Low doses of adriamycin in the VAD program (vincristine 0.4 mg/day days 1–4 CI, adriamycin 12 mg/m2/day days 1–4 CI and dexamethasone 40 mg/day on day 1 to 4, 9 to 12 and 17 to 20 followed at day 24 by a second VAD cycle plus 1 g/m2 of cyclophosphamide on day 1 of the second course) induced a CR rate of 84% (88/105) with three deaths from infection.17 However, in a subsequent publication among 268 ALL, the CR rate was lower (58%) among elderly patients with an increased mortality rate during induction (12%).18
In our randomized study, continuous infusion of DNR (60 mg/m2/day x 3 days) resulted in a higher gram-negative infection rate (9 vs 1, P = 0.001), more toxicity-related early deaths (15% vs 2%), especially from gram negative septicemia (4 vs 0) and longer neutropenia (18 vs 14 days, P = 0.05). Such an high rate of gram-negative sepsis has also been reported in relapse ALL with lower doses of DNR CI (60 mg/m2/day x 2 days).19 Other toxicities such as cardiotoxicity or thrombocytopenia were not increased. The excess infection is not related to the presence of a central venous catheter, as all patients had such venous access. The increased incidence of gram-negative bacteriemia suggests that DNR continuous infusion increases bacterial translocation from the gastrointestinal tract although an excess of mucositis or gastrointestinal toxicity was not reported. Because of this high morbidity in the CI arm observed at a planned interim analysis, without any benefit in terms of CR, the study was prematurely interrupted. Nevertheless, after a long follow-up, we observed a trend toward an improved FFR in the CI arm (48% vs 28%) suggesting that CI DNR might improve the quality of the remission and decrease the residual disease. We strongly believed that this should be reported despite the low statistical power due to the small number of randomized patients. Indeed, although data are still conflicting, supportive care such as the addition of hematopoietic growth factor20 or quinolone prophylaxis21 might decrease the high morbidity and mortality related to gram-negative sepsis. Therefore, additional studies using route of administration designed to improve the tolerability of the anthracyclines and increase the antitumor activity such as liposomal DNR22 should be done.
The results of our randomized study are disappointing as DNR CI at this dosage not only did not improve the response rate but also increased chemotherapy-related toxicity. However, the trend toward a better FFR in the CI arm would suggest that the quality of the CR in term of residual disease might be improved.
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Hunault-Berger, M., Milpied, N., Bernard, M. et al. Daunorubicin continuous infusion induces more toxicity than bolus infusion in acute lymphoblastic leukemia induction regimen: a randomized study. Leukemia 15, 898–902 (2001). https://doi.org/10.1038/sj.leu.2402130
- acute lymphoblastic leukemia
- continuous infusion
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