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Idarubicin to Intensify the Conditioning Regimens of Autologous Bone Marrow Transplantation for Patients with Acute Myeloid Leukemia in first Complete Remission

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Idarubicin to Intensify the Conditioning Regimens of Autologous Bone Marrow Transplantation for Patients with Acute Myeloid Leukemia in first Complete Remission Bone Marrow Transplantation, (1998) 22, 13–19 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Idarubicin to intensify the conditioning regimens of autologous bone marrow transplantation for patients with acute myeloid leukemia in first complete remission Sh Jerjis, E Roovers, P Muus, N Schaap and T de Witte Department of Internal Medicine, Division of Hematology, University Hospital St Radboud, Nijmegen, The Netherlands Summary: and high-dose cytarabine (HiDAC)6,7 have improved the remission percentage of conventional regimens based on 3 In an effort to reduce the relapse rate after unpurged days of daunorubicin and 10 days of standard-dose cytara- autologous bone marrow transplantation (ABMT) in bine.8 Without further treatment almost all patients are patients with acute myeloid leukemia (AML) in first expected to relapse. Only 10–15% of patients will be cured complete remission (CR1), the standard conditioning by using standard-dose consolidation and maintenance ther- regimens (cyclophosphamide/busulphan and apy. A higher DFS of 25–45% may be achieved after inten- cyclophosphamide/TBI) were intensified by adding ida- sive consolidation chemotherapy.9,10 rubicin. Seventeen patients received a continuous Allogeneic BMT as well as ABMT in de novo AML infusion of 21 mg idarubicin/m2/day for 2 consecutive patients when performed during CR1 results in better DFS days in addition to the standard preparative regimen. than intensive consolidation therapy11–13 and greater anti- Thirteen patients served as a historical control group. leukemic activity when performed in CR2.14,15 Relapse is The 2-year disease-free survival (DFS) of 82% in the the main cause of death in hematologic malignancies after study group was significantly (P = 0.047) better com- BMT, and even more so after ABMT. Combining the stan- pared to 46% DFS in the control group. The relapse dard conditioning regimens (cyclophosphamide/busulphan rate (RR) was also significantly lower (7% vs 45%; and cyclophosphamide/TBI) with non-cross-resistant P = 0.035) in the study group. The median time to reach agents and selecting agents without overlapping toxicity a white cell count (WCC) of 0.5 × 109/l was 20 days in may improve its efficacy. In this study we evaluated the the study group vs 17 days (P = NS) in the control antileukemic activity and the toxicity of the two standard group. The median time until recovery of the platelet conditioning regimens after intensification by the addition counts to 20 × 109/l was 152 days in the study group vs of a continuous infusion of idarubicin. Regimens intensified 57 days (P = NS) in the control group. The hypolasia in with idarubicin have shown promising results in the allo- the study group resulted in a trend towards a higher geneic transplant setting.16–20 need for transfusions: a median number of 38 units of erythrocytes vs 23 units in the control group (P = NS) and 23 units of platelet vs 18 units in the control group Patients and methods (P = NS). This pilot study suggests that addition of ida- rubicin to the standard conditioning regimens may Diagnosis and treatment of acute myeloid leukemia improve DFS and overall survival (OS) of patients with AML treated with ABMT in CR1. These results should Diagnosis of AML was based on the FAB classification be confirmed in a prospective randomized study. criteria using standard morphology and cytochemistry. In Keywords: idarubicin; conditioning regimens; autolog- addition, at least 32 marrow metaphases were analyzed by ous bone marrow transplantation; acute myeloid leukemia; standard cytogenetic banding techniques from bone marrow first complete remission obtained before initiation of treatment. Patients were con- sidered in morphologic CR when the bone marrow con- tained less than 5% blasts and the blood counts had reco- vered to normal values, and in cytogenetic remission when A complete remission (CR) rate of 70–80% can be achieved the cytogenetic abnormality disappeared. Relapse was diag- in patients with newly diagnosed acute myeloid leukemia nosed when the bone marrow contained more than 5% (AML) by currently used remission-induction regimens. blasts. Cytogenetic relapse was diagnosed when the original 1,2 Addition of a third drug such as etoposide, replacement of cytogenetic abnormalities had re-emerged. 3–5 daunorubicin by new anthracyclines such as idarubicin, Bone marrow was harvested after completion of one or two consolidation courses. For a successful repopulation after transplantation at least 2 × 106 CD34 cells/kg body Correspondence: Dr Sh Jerjis, Division of Hematology, University Hospi- × 4 tal St Radboud, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The weight (b.w.) and/or 20 10 CFU-GM/kg b.w. were col- Netherlands lected. No marrow purging was attempted. Marrow cells Received 24 October 1997; accepted 14 February 1998 were processed, cryopreserved, and thawed as described Idarubicin in ABMT for AML patients in first CR Sh Jerjis et al 14 before.21 No growth factors were administered after subdivided into bad prognostic (M4 and M5) and good ABMT. Informed consent was obtained according to the prognostic (others) subtypes, and the difference in distri- rules of Dutch law. bution between these subtypes was not significant. Patients were also subdivided into cytogenetic risk groups according to Keating et al.27 No significant difference was observed Patients between the two groups (Table 1). Four patients (24%) in Thirty consecutive patients who had been treated by ABMT the study group had leukocyte counts above 30 × 109/l at for AML in CR1 between August 1984 and August 1996 diagnosis, compared to eight patients (62%) in the control in the Nijmegen University Hospital were included in this group (P = 0.03). The median number of infused CFU- evaluation. As a historical control group 13 patients were GM/kg b.w. was similar in both groups (Table 2). Four treated with the standard regimens and 17 with the intensi- patients in the control group (31%) received two remission- fied regimens. The patients were treated with remission induction courses to achieve CR1 compared to three induction and consolidation courses according to the cur- patients (18%) in the study group (Table 1). Two patients rent European Organization for Research and Treatment of in the control and one in the study group received two con- Cancer protocols (EORTC-LCG AML-6,22 EORTC-LCG solidation courses prior to the marrow harvest. The interval AML-823 and EORTC-LCG/GIMEMA AML-1024), only between CR1 and ABMT was not significantly different three patients who had been referred from abroad were between the two groups (Table 2). given remission induction and consolidation courses according to the TAD regimen (thioguanine, cytarabine and daunomycin).25 Six of these patients participated in a pro- Conditioning regimens spective, placebo-controlled study with linomide26 after Two types of standard conditioning regimens were used ABMT. Three patients received placebo and three patients in this study. The first regimen (Bu/Cy) consisted of oral linomide. Since the number of patients was small we did busulphan 4 × 1 mg/kg b.w. daily for 4 days from day −8 not analyze the influence of linomide on the outcome of until day −5, followed by intravenous cyclophosphamide the patients in this analysis. Patient characteristics are 60 mg/kg b.w. daily on days −3 and −2. To prevent seizures detailed in Table 1. The median age of the patients in the phenytoin was administered orally at a dose of 100 mg control group was 38 years (range 20–60), while in the three times daily from 24 h before the first dose of busul- study group it was 43 years (range 29–58). phan until 24 h after the last dose. To prevent veno-occlus- Four patients were classified as M1, 14 as M2, one as ive disease intravenous heparin was administered at a dose M3, eight as M4, one as M5, and two as M6. Patients were of 100 U/kg b.w. until day +14. The second regimen (Cy/TBI) consisted of intravenous cyclophosphamide 60 mg/kg b.w., daily on days −7 and −6 followed by total Table 1 Patient characteristics body irradiation 4.5 Gy per day on days −2 and −1. Several prophylactic procedures were used to prevent hemorrhagic Control Intensified P cystitis after cyclophosphamide infusion. Hyperhydration (n = 13) (n = 17) value started 20 h before infusion of cyclophosphamide, with No. % No. % 3 l/day until 4 days after completion of the cyclophospha- mide infusion. This was combined with alkalinization of Sex male 4 31 10 59 NS urine by 1000 ml NaHCO3 (4.2%) per day and infusion of female 9 69 7 41 intravenous mesna 20 mg/kg b.w. in 10 ml NaCl 0.9% FAB classification during the cyclophosphamide infusion and 3, 6 and 9 h M4 and M5 5 39 4 24 NS thereafter. others 8 61 13 76 Cytogenetics Fifteen patients were treated with the Bu/Cy regimen: poor 2 15 2 12 NS six patients in the control group and nine in the study group. intermediate 5 39 11 65 Fifteen patients received the Cy/TBI regimen: seven in the good 3 23 2 12 control group and eight in the study group (Table 1). The unknown 3 23 2 12 standard preparative regimens were intensified by a con- Secondary disease yes 2 15 1 6 NS no 11 85 16 94 WBC below 30 5 38 13 76 0.03 Table 2 Patient characteristics (continued) above 30 8 62 4 24 Courses to CR1 Control Intensified P 1 9 69 14 82 NS value 2 4 31 3 18 Consolidation course Median Range Median Range 1 11851694NS 221516Age (years) 38 20–60 43 29–58 NS Conditioning regimen Interval CR1 and ABMT 112 79–180 142 76–252 NS Cy/TBI 7 54 8 47 NS (days) Bu/Cy 6 46 9 53 Infused CFU-GM (106/kg 0.079 0.03–0.27 0.06 0.02–0.35 NS b.w.) CY = cyclophosphamide; Bu = busulphan; TBI = total body irradiation.
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