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

Home , Idarubicin

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 idarubicin 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 considered in morphologic CR when the bone marrow contained 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 cyclophosphamide 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. Idarubicin in ABMT for AML patients in first CR Sh Jerjis et al 15 tinuous intravenous infusion of idarubicin of 21 mg/m2 per not reach platelet counts of 50 × 109/l at 4.9 and 2.8 years day on days −12 and −11. after ABMT. One of these patients did not reach a platelet In an earlier study16 the cardiac ejection fraction was count of 20 × 109/l at 4.9 years. The other patients repopu- measured by a nuclear (isotope) method before and after lated successfully and reached leukocyte counts of 1 × 109/l anthracycline administration and this has not changed. For and platelet counts of 50 × 109/l. this study an ejection fraction was measured only when In the control group, one patient died 38 days after indicated (age above 60 years, excessive anthracycline ABMT without having reached a leukocyte count of administration or cardiac symptoms). A value below 50% 0.5 × 109/l and a platelet count of 20 × 109/l. A second was a contraindication for idarubicin administration. patient reached a leukocyte count of 0.5 × 109/l after 13 days, but he died 22 days after ABMT before having reached a platelet count of 20 × 109/l. The leukocyte count Suportive care of a third patient reached 0.5 × 109/l at day 17 and 1 × 109/l All transfused blood products were depleted of leukocytes at day 20, but he relapsed 53 days after ABMT and died in order to minimize the risk of alloimmunization. They 117 days after transplantation, while his platelet counts were also irradiated to prevent graft-versus-host disease. remained under 20 × 109/l. Oral infection prophylaxis consisted of ciprofloxacin The median number of days to reach a leukocyte count 2 × 500 mg per day, cotrimoxazole 2 × 960 mg per day of 0.5 × 109/l and 1 × 109/l were 20 days and 38 days, twice weekly, acyclovir 4 × 400 mg per day, amphotericin respectively, compared to 17 (P = NS) and 23 days B lozenges 4 × 400 mg per day and amphotericin inha- (P = NS) in the control group. The median number of days lations 2 × 10 mg per day. This prophylaxis was given until to reach a platelet count of 20 × 109/l were 152 and 251, the leukocyte counts had reached 1 × 109/l. Cotrimoxazole respectively, in the study group, compared to 57 (P = NS) was continued until 6 months after hospitalization. The and 183 in the control group. number of days with fever of more than 38.5°C and the The median interval from ABMT until the last platelet number of days of four main groups of medication were and erythrocyte transfusion in the study group was 72 days analyzed: antibiotics, antifungals, antivirals and morphine. (range 13–1025) and 159 days (range 12–1025) respect- During admission, blood, stool, and pharyngeal cultures ively, compared to 45 days (range 23–167; P = NS) and were routinely taken twice weekly. Indications for intra- 152 days (range 42–344; P = NS) in the control group venous antibiotics were as follows: fever 38.5°C with leu- (Table 3). kocyte counts less than 1 × 109/l, positive blood cultures, and positive stool cultures or cultures from pharynx with Toxicity and hospitalization duration signs or symptoms of infection. Intravenous acyclovir 3 × 500 mg daily was administered after diagnosis of her- Two of 13 patients in the control group died 38 and 22 days pes simplex. Intravenous fluconazol was used for proven after transplantation without repopulation, from pneumonia candidiasis infections. Intravenous amphotericin B or oral with bacteremia and veno-occlusive disease, respectively. itraconazol were used in suspected or proven aspergillosis. Two of 17 patients in the intensified group died from Painful oromucositis was treated with continuous intra- hemorrhage and pulmonary aspergillosis 37 and 208 days venous infusion of morphine. after transplantation, respectively. Cardiotoxic compli- cations were not observed in the patients of the two groups. Statistics Disease-free survival was defined as the time from ABMT Table 3 The median number of days of hospitalization and repopu- until the day of relapse, death or the date of analysis, 17 lation of leukocytes and platelets, and the median number of blood trans- October 1997. Overall survival was defined as the time fusions from ABMT until death or the date of analysis. Death Control Intensified P before repopulation was considered treatment-related mor- value tality whatever the cause of the death. Death after relapse Median Range Median Range was considered to be due to leukemia. Disease-free survival, OS and RR were evaluated by the Kaplan–Meier Days leukocytes 17 5–36 20 12–47 NS method. Differences between the curves were tested for у0.5 × 109/l statistical significance by the log-rank test. Categorical data Days leukocytes 23 11–55 38 14–148 NS were compared by the ␹2 test and continuous data by the у1.0 × 109/l Days thromb у20 × 109/l 57 33–172 152 21–1688 NS Mann–Whitney U test. Days thromb у50 × 109/l 183 44–291 251 47–1780 NS Days to last thrombocyte 45 23–167 72 13–1025 NS transfusion Results Days to last erythrocyte 152 42–344 159 12–1025 NS transfusion No. of thrombocyte 18 4–31 23 4–122 NS Hematopoietic recovery transfusions No. of erythrocyte 23 4–44 38 5–125 NS In the study group, two patients died 37 and 208 days after transfusions ABMT with leukocyte and platelet counts below 0.5 × 109/l Hospitalization (days) 39 25–52 42 28–97 NS and 20 × 109/l, respectively. Two patients in this group did Idarubicin in ABMT for AML patients in first CR Sh Jerjis et al 16 The TRM was 12% in the study group compared to 15% 1 in the control group. The number of days with fever more than 38.5°C and 0.8 P = 0.047 intravenous antimicrobial agents was calculated as an esti- Intensified mate of serious infections in both groups (Table 4). The 0.6 mean number of days on intravenous antibiotics was 29 in Control the group with intensified regimens vs 15 (P = 0.02) in the control group. Patients conditioned with the intensified 0.4 regimens received intravenous antifungal drugs (amphotericin B and fluconazol) for more days (12 days) 0.2 than in the control group (2 days) (P = 0.05). Intravenous acyclovir was administered for 5 and 6 days (P = NS) in 0 the intensified and control group, respectively. The mean 0 24 48 72 96 120 number of days of fever higher than 38.5°C in the study Months group was 14.8, vs 7.2 in the control group (P = 0.006). Figure 1 Disease-free survival (months) of patients with AML auto- Intravenous narcotic analgesics were routinely prescribed grafted in first CR. Patients who received standard conditioning regimens to treat pain due to severe oromucositis. The mean amount (control) are compared to patients conditioned with intensified regimens of morphine was significantly higher (P = 0.04) in the study (intensified). group (Table 4). Seven patients (41%) developed bleeding in the study group: three hematuria one of them with throm- 1 bosis; two hematoma one of them with petechia and the other with hemoptysis, one epistaxis and one vaginal bleed- 0.8 P = 0.074 ing. Only two patients (15%) developed gastrointestinal bleeding in the control group (P = NS). Twelve patients 0.6 (71%) on intensified regimens showed positive bacterial Control blood cultures, eight with staph epidermidis. Six patients in the historical group developed positive bacterial blood 0.4 cultures, five due to strep mitis, and one patient (54%) had a blood culture positive for candidiasis (P = NS). In the 0.2 study group one patient developed bilateral pulmonary Intensified infiltrates. A second one showed a unilateral infiltration and 0 the third patient developed unilateral sinus infiltration. Only 0 24 48 72 96 120 one patient developed unilateral pulmonary infiltration in Months the control group. Nine patients (53%) in the study group Figure 2 Overall survival (months) of patients with AML autografted in showed clinical features of mucositis in comparison to three first CR. Patients who received standard conditioning regimens (control) (23%) in the control group (P = NS). The mean number of are compared to patients conditioned with intensified regimens hospitalization days in the study group was 42 (range 28– (intensified). 97), compared to 39 (range 25–52) in the control group = (P NS) (Table 3). contrast, 13 of 17 patients in the study group survive without relapse between 1.04 and 5.15 years (median 3.1 years). Outcome The 2-year DFS and OS for all patients in the two groups of the study estimated by Kaplan–Meier analysis were 66% Six of 13 patients in the control group survive without cyto- (95% confidence interval (CI) = 49–83%). The 2-year DFS genetic or morphological evidence of relapse between 3.8 (Figure 1) in the group prepared with the intensive regi- and 9.8 years after transplantation (median 6.8 years). In mens was 82% (95% CI = 66–98%). This was significantly better compared to 46% (95% CI = 19–73%; P = 0.047) in Table 4 The mean duration of administration of intravenous anti- the historical group. There was a trend toward better OS microbial agents, morphine and days with fever more than 38.5°C (Figure 2) in the study group: 82% (95% CI = 65–99%) in comparison to 46% (95% CI = 19–73%; P = 0.074) in the Mean days P value historical group (Table 5).

Control Intensified Table 5 Two-year disease-free survival, overall-survival, relapse rate and treatment-related mortality in two groups Antibioticsa 15.2 28.9 0.02 Antifungalsb 2 11.6 0.05 Acyclovir 6.2 4.9 NS DFS % OS % RR % TRM % Morphine 4.3 9.4 NS Morphine dose (mg) 150 480 0.04 Control 46 ± 27 46 ± 27 45 ± 29 15 Days fever Ͼ38.5°C 7.2 14.8 0.006 Intensified 82 ± 16 82 ± 17 7 ± 11 12 P valuesa 0.047 0.074 0.035 NS aCeftazidime, vancomycin, teicoplanin and other i.v. antibiotics. bAmphotericin and fluconazol. aRelated to the overall curve. Idarubicin in ABMT for AML patients in first CR Sh Jerjis et al 17 Five of 13 patients in the control group relapsed 2, 3, 4, irradiation in different hematological malignancies treated 8 and 9 months after transplantation, compared to two of with allogeneic or autologous BMT appear to offer no 17 patients in the group treated with the more intensive advantages over other regimens.41–43 BCNU, etoposide, preparatory regimens who relapsed at 10 and 55 months high-dose cyclophosphamide and fractionated TBI as con- after transplantation. The 2-year relapse rate in the study ditioning for allogeneic BMT patients with advanced hema- group was 7% (95% CI = 0–18%). This was significantly tological malignancies carried a high antileukemic activity better (P = 0.035) compared to the 45% relapse rate (95% and an acceptable toxicity.44 The addition of etoposide to CI = 16–74%) in the control group (Figure 3). cyclophosphamide and busulphan increased non-hematological skin, pulmonary and hepatic toxicity.43,45 Idarubicin has been administered by our team as continu- Discussion ous infusions in various schedules to intensify BMT conditioning regimens for allogeneic BMT.16–20,46 In these Idarubicin has been evaluated extensively in induction ther- studies the data of two comparable cohorts of standard risk apy for AML and it has been found to be superior to other patients (AML CR1, ALL CR1/2, CML CP1) were com- anthracyclines in improving the overall survival3,28 and may pared. All patients were treated with bone marrow from increase the disease-free survival.29,30 Idarubicin also histocompatible siblings followed by a short course of induced a higher complete remisson rate4,29,31,32 in older immunosuppression for 3–6 months. The relapse rate was patients.33 Maintenance of complete remission after significantly reduced from 52 to 26% in the idarubicin- remission-induction therapy for AML can be achieved by treated group. This resulted in a significantly better disease- intensive consolidation therapy followed by allogeneic or free survival of 56%, compared to 36% in the traditionally autologous stem cell transplantation or by chemo- conditioned group.18 The addition of anthracyclines to con- 8,12–14 therapy. Allogeneic BMT usually results in the high- ditioning regimens caused more severe oromucositis and est disease-free survival, but its use is limited to younger slower repopulation in the schedule when idarubicin was 11,12 patients with HLA-identical siblings. Autologous BMT given as a continuous infusion until 24 h prior to the mar- for AML in CR1 did not improve overall survival compared row infusion.20 These side-effects and the low relapse rate to intensive consolidation therapy, mainly due to a more may be attributed to the low concentration of idarubicin effective salvage therapy for those patients who relapsed when it is given on days −12 and −11 similar to the regi- after chemotherapy. However, the disease-free survival 11–13 mens in this study, and to the presence of its cytotoxic after ABMT was significantly better. metabolite idarubicinol at the time of autograft infusion and Several approaches have been attempted to intensify the during the early post-transplant days. antileukemic activity of conditioning regimens for allo- We introduced this schedule in the autologous BMT set- geneic or autologous stem cell transplantation in different ting since the reported relapse rate was more than 50% after hematologic malignancies. Better results were not achieved conventional conditioning regimens. The 2-year disease- by adding busulphan to cyclophosphamide and total body free survival of 82% was significantly (P = 0.047) better irradiation in advanced MDS,34 and myeloid leukemia35,36 than the DFS of 46% in the control group. This resulted in treated by allogeneic BMT. Addition of high-dose vincris- = tine to the same conditioning regimen in children with ALL a trend towards (P 0.074) better overall survival: 82% in 37 38 the study group vs 46% in the historical group. This better treated by allogeneic or autologous BMT was feasible = and promising. Thiotepa, cyclophosphamide and busulphan survival was the result of a significantly (P 0.035) were tolerable as conditioning for allogeneic BMT39 and reduced relapse risk: 7% in the group on the intensified there was also a high response rate in ABMT patients40 regimens vs 45% in the traditionally treated group. with hemtologic malignancies at high risk for relapse. Eto- The differences for time to recovery, transfusion inde- poside combined with cyclophosphamide and total body pendence and for number of platelet and erythrocyte infusions were different between the two groups, although

1 this was not statistically significant. These differences may be significant in a sample with a large number of patients. Intravenous antibiotics and antifungals were administered 0.8 for longer duration in the study group. Duration of fever of more than 38.5°C was also longer in this group. The 0.6 increased incidence of severe oromucositis after condition- Control ing with idarubicin intensified regimens was substantiated 0.4 P = 0.035 by an increased usage of intravenous narcotic analgesics, and a higher usage of intravenous antibiotics and antifungal Intensified 0.2 agents. The TRM was almost as high as the historical group and an increased mortality from the addition of idarubicin 0 cannot be ruled out. 0 24 48 72 96 120 In an attempt to decrease the duration of hypoplasia and Months hence decrease requirement for supportive care and improve cost-effectiveness in the intensified group we Figure 3 Relapse rate (months) of patients with AML autografted in first CR. Patients who received standard conditioning regimens (control) are recently introduced autologous peripheral blood stem cells compared to patients conditioned with intensified regimems (intensified). instead of bone marrow47–52 as rescue. Autologous periph- Idarubicin in ABMT for AML patients in first CR Sh Jerjis et al 18 eral stem cells may also decrease treatment-related mor- remission: a prospective controlled trial. Br J Haematol 1989; tality rate. 72: 57–63. The two groups in this analysis were not randomized. 12 Zittoun RA, Mandelli F, Willemze R et al. Autologous or allo- Nevertheless, the only prognostic factor which was not bal- geneic bone marrow transplantation compared with intensive anced between the two groups was the distribution of WBC chemotherapy in acute myelogenous leukemia. European × 9 Organization for Research and Treatment of Cancer (EORTC) above and below 30 19 /l (Table 1). The 2-year disease- and the Gruppo Italiano Malattie Ematologiche Maligne dell- free survival and overall survival were not significantly dif- Adulto (GIMEMA) Leukemia Cooperative Groups (see ferent when the groups with WBC above and below comments). New Engl J Med 1995; 332: 217–223. 30 × 109/l were compared separately in all patients and in 13 Cassileth PA, Andersen J, Lazarus HM et al. Autologous bone the study group. marrow transplant in acute myeloid leukemia in first In conclusion, intensification of conditioning regimens remission. J Clin Oncol 1993; 11: 314–319. with a continuous intravenous infusion of 42 mg idarubicin 14 Lambertenghi Deliliers G, Annaloro C, Della Volpe A et al. per m2 over days −12 and −11 prior to marrow infusion is Single-institution results of autologous bone marrow trans- feasible and may result in a prolongation of DFS and OS. plantation in acute myeloid leukemia. Haematologica 1995; The low number of patients and the consecutive nature of 80: 136–141. 15 Meloni G, Vignetti M, Andrizzi C et al. ABMT for children this analysis warrants a cautious interpretation of the data. AML: Italian experience. GITMO-AIEOP Groups. Bone Mar- Future randomized studies with a larger number of patients row Transplant 1991; 3: 80–83. are needed to confirm the promising antileukemic proper- 16 Raemaekers J, De Witte T, Schattenberg A, Van der Lely N. ties of these intensified regimens. Prevention of leukemic relapse after transplantation with lym- phocyte depleted marrow by intensification of the conditioning regimen with a 6-day continuous infusion of anthracyclines. Bone Marrow Transplant 1989; 4: 167–171. References 17 Schattenberg A, Mensink E, de Witte T. Intensification of the conditioning regimen by the addition of anthracyclines results 1 Bishop JF. Etoposide in the treatment of leukemias. 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