Use of idarubicin in pre-transplant conditioning in children with high-risk acute leukaemia

Abstract

Summary:The major cause of treatment failure following allogeneic bone marrow transplantation for acute leukaemia is disease relapse. In an attempt to reduce posttransplant relapse in 33 children with high-risk acute leukaemia who received a related or unrelated bone marrow transplant, the pre-transplant conditioning regimen was intensified by the addition of idarubicin. Its toxicity and effects on survival were evaluated over a 57-month period. Toxicity, largely gastrointestinal, was increased but acceptable, and there was no specific regimen-related toxicity. Relapse rates were low (24%) in this high risk group, but mortality was increased in those receiving unrelated donor grafts, largely due to sepsis. Idarubicin does appear to have a role to play in the conditioning regimen of patients with high-risk acute leukaemia undergoing BMT, and may reduce relapse rates without increasing transplant-related mortality. Keywords: childhood acute leukaemia; idarubicin; BMT Acute leukaemias are rare in children, and represent onethird of all childhood malignancies. In children with high-risk acute leukaemia in either first or other remission, prognosis is poor. Intensive treatment including allogeneic bone marrow transplantation may offer the best chance of long-term disease-free survival.1-13 Leukaemic recurrence however, continues to play a major role in treatment failure.One possible way of reducing the probability of relapse is to further intensify the conditioning regimen prior to transplantation using anthracyclines which have proven anti-leukaemic activity, provided this approach is not associated with unacceptable toxicity and increased procedurerelated mortality. [14][15][16] Two pilot studies have demonstrated a reduction in relapse rates, improved disease-free and actuarial survival with comparable transplant-related mortality in patients receiving intensified conditioning with idarubicin prior to sibling T cell-depleted grafts when compared with historical controls. sified conditioning regimens in a heterogeneous population of patients with malignant haematological disease. They also demonstrated reduced relapse probability, increased overall and disease-free survival without increased transplant-related mortality in comparison with historical controls receiving cyclophosphamide and total body irradiation (TBI) alone, prior to a T cell-depleted graft. The toxicity of the intensified regimen was schedule-dependent and was reduced by administration of idarubicin earlier in the conditioning regimen.We report the use of an intensified conditioning regimen containing idarubicin in 33 children considered to be at high risk of leukaemic relapse. We discuss the toxicity of the regimen and its success with respect to relapse and mortality.

Autologous stem cell transplantation for elderly patients with acute myeloid leukaemia conditioned with continuous infusion idarubicin and busulphan

“…Such a regimen was specifically designed for AML, with the aim of reducing relapse rate which, differently from toxicity, remains substantially unmodified in patients autografted with PBSC. The choice of high-dose IDA, given as c.i., was supported by previous data demonstrating a significant reduction in relapse rate for patients treated with IDA-BuCy or IDA-total body irradiation (TBI)-Cy group when compared with historical controls conditioned with classical regimens, such as BuCy or TBI-Cy [37][38][39][40]. Furthermore, the uniqueness of the regimen used in our series lies with the specific increase of the dose of IDA, which was given as c.i.…”

Continuous infusion idarubicin and oral busulfan as conditioning for patients with acute myeloid leukemia aged over 60 years undergoing autologous stem cell transplantation

“…26 Preliminary data suggest that the addition of IDA may result in a reduction of relapse rate either in autologous or in allogeneic SCT. [27][28][29] In the present study, the choice of high-dose IDA given as continuous infusion was supported by previous data demonstrating a significant reduction in relapse rate for patients treated with IDABuCy or IDA-TBI-Cy when compared with historical controls conditioned with classical regimens including BuCy or TBI-Cy. 30 However, our regimen relies on the specific increase of the dose of IDA, which was given as CI for 48 h at 20 mg/m 2 /day in combination with oral Bu at 4 mg/kg for 3 days, as well as on the removal of cyclophosphamide.…”

High‐dose idarubicin and busulphan as conditioning to autologous stem cell transplantation in adult patients with acute myeloid leukaemia

“…Different approaches, including in vivo or ex vivo purging, immunotherapy after ASCT and intensification of conditioning regimen have been investigated in an attempt to reduce recurrence of AML in patients undergoing ASCT (Gorin, 2002;Linker, 2003;Stein et al, 2003;Nathan et al, 2004 ). In particular, preliminary data suggest that the addition of IDA, an intercalating agent with powerful antileukaemic activity (Vogler et al, 1992;Wiernik et al, 1992;Reiffers et al, 1996), may result in a consistent reduction of relapse rate either in autologous or in allo-SCT (Schaap et al, 1997;Jerjis et al, 1998;Lawson et al, 1999;Mengarelli et al, 2000). Furthermore, encouraging results have been recently reported with the adoption of an intensified preparative regimen of Bu 16 mg/kg p.o.…”

“…In most studies comparing ASCT versus chemotherapy, a significant reduction in the relapse rate has been observed in favour of ASCT, yet a substantial proportion of patients (30–50%) still relapse after transplantation (Zittoun et al , 1995; Harousseau et al , 1997; Burnett et al , 1998; Cassileth et al , 1998; Nathan et al , 2004). Promising results, in terms of reduction of relapse rate, have been reported following the adoption of conditioning regimens specifically designed for AML (Meloni et al , 1996; Linker et al , 1998); in particular, the addition of idarubicin (IDA), a powerful antileukaemic agent, has been shown to be potentially useful in inducing a superior antileukaemic activity as compared with the combination of busulphan and cyclophosphamide (BuCy) (Schaap et al , 1997; Jerjis et al , 1998; Lawson et al , 1999; Mengarelli et al , 2000), which still remains the most frequently used conditioning regimens for ASCT in AML. However, neither BuCy (Santos et al , 1983) nor its modification, BuCy2, introduced by the Columbus team (Tutschka et al , 1987), were specifically developed for allo‐SCT, with cyclophosphamide component serving to induce marked immunosuppression and allow marrow engraftment.…”