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The Hematology Journal (2001) 2, 214 ± 219 2001 The European Haematology Association All rights reserved 1466 ± 4680/01 $15.00 www.nature.com/thj

High-dose idarubicin and busulphan as conditioning for autologous stem cell transplantation in acute myeloid leukemia: a feasibility study Felicetto Ferrara*,1, Mario Annunziata1, Ettore Mariano Schiavone1, Carolina Copia1, Mariacarla De Simone1, Filiberto Pollio1, Salvatore Palmieri1, Assunta Viola1, Consiglia Russo1 and Giuseppina Mele1 1

Division of Hematology and Stem Cell Transplantation Unit, Cardarelli General Hospital, Naples, Italy

Introduction: Between 30 and 50% of patients with acute myeloid leukemia still relapse after autologous stem cell transplantation. We investigated the feasibility of a new conditioning regimen consisting of high dose IDA plus oral busulphan in patients undergoing autologous transplantation. Materials and methods: Patients (n=13) were given three days continuous infusion IDA, followed by four days conventional dose oral busulphan as conditioning. Peripheral blood stem cells were used in all cases. Eleven patients were in CR1. Patients with t(8;21) and inv(16) as well as those with acute promyelocytic leukemia were excluded from the study. The median of CD34+ cells infused was 6.26106/l (2.6 ± 16.1). Results: No case of transplant-related mortality occurred. The median number of days to neutrophil (40.56109/l) and platelet (4206109/l) recovery was 10 (7 ± 21) and 20 (9 ± 26), respectively. Patients needed a median of 3 platelet units (1 ± 6) and 3 blood units (0 ± 12), respectively. Left ventricular ejection fraction remained unmodi®ed after ASCT. Twelve out of 13 patients (92%) had variable grade of mucositis (two grade 2, ®ve grade 3 and ®ve grade 4). Total parenteral nutrition was needed in nine patients (69%). After a median follow-up of 14 months from ASCT, 11 patients out of 13 (85%) are alive in continuous CR; the other two patients experienced relapse at 12 and 14 months. Conclusion: Our data demonstrate the feasibility of a conditioning regimen based on highdose IDA plus Busulphan in AML. Results concerning antileukemic ecacy are promising, but need con®rmation on larger series with longer follow-up. The Hematology Journal (2001) 2, 214 ± 219 Keywords:

acute myeloid leukemia; stem cell transplantation; conditioning; idarubicin

Introduction The induction regimens currently used to treat newly diagnosed young/adult patients with acute myeloid leukemia (AML), achieve a complete remission (CR) rate of 60 ± 80%.1 ± 3 However, most patients require further intensive chemotherapy to avoid relapse. Autologous stem cell transplantation (ASCT) is increasingly used for treatment of AML following CR1 achievement and consolidation. Some studies claim that ASCT is superior to intensive chemotherapy,1 ± 4 yet a substantial proportion of patients (30 ± 50%) still relapse after transplantation.4 Therefore, di€erent strategies including in vivo purging with highdose cytarabine before ASCT, bone marrow (BM) or

*Correspondence: F Ferrara, Via NiccoloÁ Piccinni 6, 80128 - Napoli, Italy; Tel/Fax: +39 0817472241; E-mail: [email protected] Received 5 February 2001; accepted 20 March 2001

peripheral blood stem cells (PBSC) ex vivo purging, intensi®cation of conditioning regimen, PBSC instead of BM, and immunotherapy after ASCT have been attempted with the aim of reducing the relapse rate.5 ± 16 Conditioning regimens, such as the Busulphan-Cyclophosphamide combination as originally designed by the Baltimore team17 (BuCy) and then its modi®cation by the Columbus team18 (BuCy2), have been most frequently used for ASCT in AML. However, both these regimens are speci®cally proposed for allogeneic SCT, with the role of cyclophosphamide component serving to induce marked immunosuppression and allow marrow engrafment. In the autologous setting, alternative chemotherapy combinations have been designed with the aim of inducing a superior antileukemic activity.9,10 Previous observations have shown promising results of regimens intensi®ed with idarubicin (IDA) in the allogeneic transplant setting.19 ± 21 Favorable results have been obtained with IDA as part of conditioning regimens for ASCT.22 On this

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basis, we investigated the feasibility and ecacy of a new conditioning regimen, termed I-Bu, consisting of a combination of three days continuous infusion (c.i.) IDA at a dose of 20 mg/m2 followed by standard dose busulphan (Bu) for patients with AML in ®rst or subsequent CR. Here we describe the disease characteristics and treatment results from a series of 13 consecutive patients who were given the I-Bu regimen as conditioning for ASCT.

Material and methods Diagnosis of AML was based on the FAB classification criteria using standard morphology and cytochemistry.23 Immunophenotypic analysis24 was carried out in all cases. At least 20 fully evaluable metaphases were analysed by RHG cytogenetic techniques from BM collected at diagnosis prior to treatment.25 Karyotypic analysis was successful in 12 out of 13 patients (92%): 50% of patients had a normal karyotype while the others had a complex karyotype (n=4), trisomy 11 (n=1) or a t(1;11) (n=1). Patients were subdivided into groups according to the cytogenetic pattern of their AML.26 Patients were considered in CR when BM blast cells were less than 5% and blood counts had recovered to normal values, in the absence of extramedullary leukemia. Relapse was diagnosed when BM analysis showed more than 5% blasts. Patients with core-binding-factor AML, ie those with t(8;21) and inv(16) as well as those with acute promyelocytic leukemia were excluded from the therapeutic programme when in CR1. Thirteen patients treated by ASCT between January 1999 and October 2000 were included in this evaluation. There were eight males and ®ve females with a median age of 50 years (range 16 ± 64). Induction treatment consisted of ICE (IDA 10 mg/ m2 on days 1,3,5; cytarabine (ARA-C) 100 mg/m2 as c.i. on days 1 ± 7; etoposide 100 mg/m2 on days 1 ± 4). Following achievement of CR, patients were consolidated with the NOVIA regimen (ARA-C 500 mg/m2 q12h on days 1 ± 6 and mitoxantrone 10 mg/m2 on days 4 ± 6). G-CSF (450 mcg/m2) was added at day 15 from the beginning of NOVIA to induce mobilization of CD34+ cells. In one patient, who failed to mobilize after NOVIA, PBSC were collected after further consolidation with one cycle of high-dose ARA-C (3 g/m2 q12h on days 1,3,5). One patient (64 years) was refractory to ICE and achieved CR with the FLAG regimen (¯udarabine, ARA-C and G-CSF), used as salvage treatment.27 PBSC were collected after consolidation with FLAG in combination with IDA (10 mg/m2 on days 1,3,5). Two patients were transplanted in CR2; both achieved CR2 by FLAG administration and received consolidation with IDAFLAG, which was also successfully used as mobilization regimen. The median interval between CR achievement and ASCT was three months (range 2 ± 8). The median number of CD34+ cells infused was 6.26106/kg (2.6 ± 16.1). Clinical and hematological characteristics of patients are summarized in Table 1.

Table 1

Characteristics of patients

No. of patients Age, median (range) Sex (M/F) FAB M1 M2 M4 M5 Cytogenetics Poor Intermediate Not available Courses to CR1 1 2 Patients transplanted in CR1 Patients transplanted in CR2 Interval CR1/2-ASCT (months) Infused CD34+ cells (6106/kg)

13 50 (16 ± 64) 8/5 4 2 5 2 6 6 1 11 2 11 2 3 (2 ± 6) 6.2 (2.6 ± 16.1)

The conditioning regimen consisted of three days c.i. IDA (20 mg/m2 from day 713 to 711) followed by oral Bu (4 mg/kg daily) for four days (from day 75 to 72). To prevent seizures, phenytoin (100 mg) was administered orally three times daily beginning 24 h before the ®rst dose of Bu and continued until 24 h after the last dose. All transfused blood products were depleted of leukocytes to minimize the risks of alloimmunization and graft-vs-host-disease. Infection prophylaxis was based on oral nor¯oxacin when neutrophils were less than 16109/l. Neither antiviral nor antifungal prophylaxis was performed. Indications for antibiotic therapy included fever 4388C with leukocyte count 516109/l, as well as signs or symptoms of infection. Intravenous ¯uconazol was used for proven candidiasis infection, while amphotericin B was given for aspergillosis when suspected (fever persisting for more than seven days while on treatment with broad-spectrum antibiotics). In all patients left, ventricular ejection fraction (LVEF) was evaluated before and after ASCT by echocardiogram and, at the time of transplant, all patients showed a value over 50%. Disease free survival (DFS) was de®ned as the time from ASCT until the month of relapse, death or the date of last analysis. Overall survival (OS) was de®ned as the time from ASCT until death or last analysis. DFS and OS were calculated by Kaplan-Meier method.28

Results Transplant-related mortality (TRM) was not observed and 12 out of 13 (92%) patients achieved full hematological recovery. One patient, who received ASCT while in CR2, has not yet reached a platelet count 41006109/l at 10 months from infusion of CD34+ cells, however BM examination shows no persistence of leukemia and platelet infusion is no longer required. The median number of days to stable neutrophil count of 0.56109/l was 10 (range 7 ± 21). The Hematology Journal

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The median number of days to stable platelet count of 206109/l and 1006109/l was 20 (range 9 ± 26) and 26 (18 ± 90), respectively. Transfusion support consisted of a median number of 3 (range 1 ± 6) platelet units and 3 (range 0 ± 12) blood units (Table 2). Cardiotoxic complications were not observed in any patient, LVEF remaining substantially unmodi®ed after ASCT as showed in Figure 1. There were no documented infections, while all patients experienced fever of unknown origin (FUO). There were no central venous catheter-related complications. The median number of days with fever 438.58C and i.v. antimicrobial agents was 11 (range 5 ± 20) and 14 (range 7 ± 23), respectively. In addition, eight out of 13 patients needed intravenous antifungal drugs (two ¯uconazole and six amphotericin B); in all cases amphotericin B was added because of persistence of FUO for more than seven days in absence of documented aspergillosis. Finally, the median period of hospitalization was 30 days (range 27 ± 36). Extrahematological toxicity included variable grade of mucositis in all but one patient (92%); according to WHO scale,29 grade 2 mucositis (two patients), grade 3 (®ve patients), grade 4 (®ve patients) occurred. Narcotic analgesics were used only in two patients to treat pain due to severe mucositis. In the other patients non-steroid analgesic drugs were sucient. Total parenteral nutrition (TPN) was needed in nine patients (69%) for a median of nine days (range 3 ± 14). Data summarizing antibiotic, antifungal and TPN requirement are shown in Table 3.

After a median follow-up of 16 months from ASCT (range 6 ± 18), 11 patients out of 13 (85%) are alive in continuous CR and median survival has not yet been reached. Two relapses occurred at 12 and 14 months; one patient had AML with complex karyotype and secondary to refractory anemia with excess of blasts, the second patient (64 years) failed to achieve CR1 following ICE regimen and received FLAG/IDAFLAG as salvage therapy. DFS and OS are shown in Figure 2. Table 3 Days of fever, antibiotics, antifungal, TPN and hospitalization Days Days Days Days Days a

of i.v. antibiotics of antifungal administrationa of TPNb of fever 438.5 of hospitalization

Median

Range

14 6 9 11 30

5 ± 20 4 ± 11 4 ± 16 5 ± 17 27 ± 46

Needed in eight patients (61%); bNeeded in nine patients (69%).

Table 2 Hematological recovery and transfusion requirements for patients receiving I-Bu as conditioning to ASCT Days to leukocyte recovery Days to platelet recovery No. of platelet transfusions No. of erythrocyte transfusions

Median

Range

10 20 3 3

7 ± 21 9 ± 26 1±6 0 ± 12

Figure 1 LVEF before and after ASCT for each patient receiving I-Bu as conditioning regimen to ASCT. The Hematology Journal

Figure 2 Disease-free survival and overall survival of patients conditioned with I-Bu regimen.

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Discussion Currently, ASCT is almost exclusively used to consolidate AML patients in CR. However, results from largest series report an incidence of relapse ranging from 40 ± 50%.4 Di€erent approaches including in vivo or ex vivo purging, immunotherapy after ASCT and intensi®cation of conditioning regimen have been investigated in an attempt to reduce this relapse rate.5 ± 15 In particular, preliminary data suggest that the addition of IDA, an intercalating agent with powerful antileukemic activity,30 ± 32 may result in a consistent reduction of relapse rate either in autologous or in allogeneic SCT.19 ± 22 Furthermore, encouraging results have recently been reported for ASCT in multiple myeloma after intensi®cation of busulphan-melphalan or cyclophosphamide-melphalan associated with two days c.i. high-dose IDA.33,34 In the present study the choice of high-dose IDA, given as continuous infusion, was supported by previous data demonstrating a signi®cant reduction in relapse rate for patients treated with IDA-BuCy or IDA-TBICy group when compared with historical controls conditioned with classical regimens (BuCy or TBI-Cy).22 However, the particularity of the regimen used in our series relies on the speci®c increase of the dose of IDA, which was given as c.i. for 72 h at 20 mg/m2/day in combination with classical dose of oral Bu, as well as on the removal of cyclophoshamide. It should be considered that either BuCy or BuCy2 regimens were proposed for the allogeneic setting, the role of cyclophosphamide being to determine immunosuppression rather than a speci®c antileukemic activity. As a matter of fact, cyclophosphamide is not included in most induction or consolidation regimens for AML; in addition, experience derived from conditioning regimens not including cyclophosphamide, such as BAVC or others, demonstrates a relapse rate at least comparable to BuCy.9,10

Finally, the removal of cyclophosphamide was expected to signi®cantly reduce the hematological and extrahematological toxicity as well as the posttransplant immunosuppression. On this basis, we treated 13 consecutive AML patients with a median age of 50 years. Worthy of note, three patients with favorable cytogenetics, two with t(8;21) and one with inv(16) were excluded from the study, our policy being to consolidate core-bindingfactor AML with high-dose cytarabine.35 In addition, more than 50% of patients showed unfavorable characteristics at diagnosis and median age was 50 years. Nonetheless, they achieved full engraftment with fast hematopoietic recovery, and no TRM was observed. Obviously, the use in all patients of PBSC as well as the relatively high median number of CD34+ cells infused may consistently shorten the duration of neutropenia and thrombocytopenia.12,13 Worthy of note, no patient needed hospitalization in the postASCT period because of FUO or documented infection. One patient, with AML secondary to MDS, relapsed at 12 months and a second (64 years), with complex karyotype and refractory to ®rst line treatment, relapsed at 14 months. Eleven patients (85%) are alive and in continuous CR at the time of writing. Toxicity was mild, with only the grade 3 ± 4 episodes consisting of mucositis, which was reversible in all patients and resolved with hematological reconstitution. Despite the small size of the series studied, our results demonstrate the feasibility of high-dose IDA in association with Bu as a conditioning regimen for AML patients who will undergo ASCT. While the observed reduction in relapse rate is encouraging, longer follow-up will be required to verify if the I-Bu regimen is actually superior to the standard Bu-Cy combination. A randomized study would provide more de®nitive information about the clinical ecacy of such an approach.

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