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Letter to the Editor |
Division for Hematology, Department of Medicine; Haukeland University Hospital and The University of Bergen, Bergen, Norway
Øystein Bruserud, M.D., Medical Department, Haukeland University Hospital, N-5021 Bergen, Norway. Telephone 47-55-29-80-60; Fax 47-55-97-29-50; e-mail: oystein.bruserud{at}haukeland.no
In our recent review in STEM CELLS we suggested that the combination of repeated courses of high-dose Ara-C (HIDAC; defined as single doses of 3 g/m2) and autotransplantation with peripheral blood stem cells (PBSC) should be investigated in future clinical studies [1]. In contrast, the title of a recent study reported by Cahn et al. on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation stated, "No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukemia in first remission" [2]. Thus, according to this title our ideas seem to be old-fashioned even before they are published.
The use of HIDAC in AML therapy is mainly based on two large randomized studies [3, 4]. In the study reported by Mayer et al. [3], four courses with HIDAC alone were used as consolidation therapy. In Bishop's study [4], HIDAC was used in combination with daunorubicine and etoposide for remission induction, one or two courses were then given depending on whether residual disease could be detected 28 days after start of therapy. This last approach is the basis for our conclusion that optimal AML therapy probably should include at least two courses of HIDAC.
The present EBMT study probably included both marrow and PBSC transplantation, although the numbers for each group are not presented. Furthermore, the study defined HIDAC as Ara-C doses of 1.5-3.0 g/m2 (whereas HIDAC was defined as 3 g/m2 in [1, 3, 4]), and the possible importance of one cycle versus repeated cycles with HIDAC was not examined. Due to this heterogeneity in autografts, Ara-C dose, and number of HIDAC cycles, we think that the data in the EBMT study should be interpreted with care.
The EBMT study concluded that HIDAC should be avoided prior to autotransplantation because this treatment had "a major disadvantage of prolonging the delay to platelet recovery compared with standard-dose Ara-C." This delay was observed by Bishop et al. [4] who combined HIDAC with etoposide and daunorubicine but, despite the delay, HIDAC was associated with a significantly higher AML-free survival. In the study reported by Mayer et al. [3] HIDAC was used alone, and no major difference in the percentage of courses requiring platelet transfusions was detected when comparing Ara-C 3 g/m2 (86%) and 400 mg/m2 (80%). The time until platelet recovery was not given in a randomized study by Kern et al. [5], but these authors also reported that recovery from critical cytopenia did not differ between patients treated with mitoxantron combined with Ara-C 3 g/m2 and 1 g/m2. Furthermore, hematopoietic reconstitution is usually observed within an acceptable time period for most patients transplanted with PBSC mobilized by HIDAC plus growth factors, although the initial studies suggest that late platelet reconstitution remains a problem for a minority of patients [1]. Thus, in our opinion the question of platelet reconstitution should not be decisive when considering the use of HIDAC together with autotransplantation in future clinical trials.
We think it is premature to conclude "increasing the dose of Ara-C before stem cell transplantation does not give any advantage" [2]. In our opinion additional clinical studies are required before this question can be answered, and it is therefore justified to further investigate this therapeutic approach in future clinical studies.
References
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