Standard myeloablative allogeneic SCT (allo-SCT) is a well-established therapy for patients with AML. However, because of the high incidence of transplant-related mortality, this procedure is limited to younger patients in good medical condition.1 Reduced-intensity conditioning (RIC) regimens have emerged as an attractive modality to decrease transplant-related mortality.2, 3 However, toxicity might represent only one aspect of the problem, as AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen may have a negative impact on long-term leukemic control.4, 5 Thus, investigators are currently faced with a dilemma on how to optimize the potential role of RIC allo-SCT in patients with AML while minimizing myeloablation-related toxicity and maximizing allogeneic immunotherapy. The aim of this report was to analyze retrospectively the outcome of 31 AML patients in first complete remission (CR1), who were treated according to two RIC allo-SCT approaches that differed in the intensity of chemotherapy delivered prior to and during the RIC regimen.
Between 2001 and 2006, 31 patients with AML in CR1 received an RIC allo-SCT in two different institutions (Institut Paoli-Calmettes, Marseille; FB2A1 group; n=18; and CHU de Nantes, Nantes; FB1A2 group; n=13). In the FB2A1 group, the post-remission strategy was to administer one course of high-dose Ara-C and an autologous SCT followed by RIC allo-SCT. In contrast, in the FB1A2 group, the post-remission therapy usually consisted of a single course of high-dose Ara-C followed by RIC allo-SCT. All 31 patients were contraindicated for a standard myeloablative allo-SCT because of age (>50) and/or comorbid conditions. All patients received allogeneic PBSCs mobilized with G-CSF from an HLA-identical sibling donor. The FB2A1 regimen consisted of fludarabine (30 mg/m2/d for 5–6 days), oral BU (total dose 8 mg/kg) and antithymocyte globulins (thymoglobulin; total dose 2.5 mg/kg). GVHD prophylaxis included CsA alone.6 On the other hand, the FB1A2 RIC regimen comprised fludarabine (30 mg/m2/d for 4 days) and lower doses of BU (4 mg/kg total dose) but higher doses of ATG (total dose 5 mg/kg). GVHD prophylaxis included both CsA and corticosteroids (methylprednisolone, 2 mg/kg/d from day −5 until day 30 post-allo-SCT).7 Supportive care is detailed elsewhere.8 Relapse, transplant-related mortality and GVHD incidences were calculated using the cumulative incidence method. Comparisons between subgroups were estimated by the Gray test. All data were computed using the R Package (R Development Core Team (2006). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org). Patients' AML characteristics and transplant characteristics are summarized in Table 1. Except for age, there was no significant difference between the FB2A1 and the FB1A2 groups.
In the FB2A1 group (n=18), 13 patients were still alive at the time of this analysis. Causes of death were relapse (n=2), acute GVHD (n=1) and extensive chronic GVHD (n=2). In the FB1A2 group (n=13), six patients are still alive. One patient died from chronic GVHD and one patient died after graft rejection and prolonged myelodysplasia. In the FB1A2 group, six relapses occurred, five of which were fatal. One patient with disease recurrence is still alive in CR after donor lymphocyte infusion (DLI). Transplant-related mortality was not statistically different between both groups (17 and 26% for FB2A1 and FB1A2, respectively; P=0.85). Acute GVHD incidence was also comparable in both groups, whereas chronic GVHD and extensive chronic GVHD occurred more often in the FB2A1 group (70 versus 31%; P=0.02). Leukemia-free survival, overall survival, relapse incidences and transplant-related mortality are shown in Figure 1. With a median follow-up of 48 months (range, 21–65), leukemia-free survival was significantly higher in the FB2A1 group as compared to the FB1A2 group (72 versus 31%; P=0.03; Figure 1a). In addition, there was a trend toward a better overall survival in the FB2A1 group (72 versus 36%; P=0.07; Figure 1b). The improved outcome in the FB2A1 group was most likely due to a significantly higher relapse rate in the FB1A2 group (46 versus 11%; P=0.02; Figure 1c).
This analysis suggests that in the context of RIC allo-SCT for CR1 AML, leukemia-free survival might be improved when using a more ‘intensive’ strategy as it was applied in the FB2A1 group. Despite its limited size and the classical limitations of this kind of analyses, the results are in line with an ever-growing body of evidence, demonstrating that the absence or excessive reduction of myeloablation within the conditioning regimen may hamper disease control, at least in the short term after allo-SCT. In contrast, some form of reduced myeloablation in the RIC regimen (that is, 8 mg/kg of BU, in contrast to a truly non-myeloablative regimen) may provide better early leukemic control and therefore improve long-term outcome. In addition to conditioning intensity, the better leukemia-free survival observed in the FB2A1 group may be also related to the increased intensity of the pre-SCT chemotherapy (one course of high-dose Ara-C and autologous SCT), which may eradicate residual leukemia more efficiently. Another reason may be linked to the ‘aggressive’ GVHD prophylaxis used in the FB1A2 group (higher doses of ATG and corticosteroids+CsA). The latter translated toward a significantly higher rate of chronic GVHD in the FB2A1 group, with its well-established protective impact against leukemia relapse.9
In conclusion, this study highlights the need to prospectively define the role of dose intensity in the context of RIC allo-SCT for AML.10 A comprehensive comparison of different RIC regimens should appropriately also take into account the comparison of the different consolidation strategies applied after achieving CR1.
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We thank the nursing staff for providing excellent care for our patients. MM and DB thank the ‘Association pour la Recherche sur le Cancer (ARC)’ (Pole ARECA), the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fugain’ for their generous and continuous support for our clinical and basic research work. Our groups are supported by several grants from the French Ministry of Health as part of the ‘Programme Hospitalier de Recherche Clinique (PHRC)’.
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Cahu, X., Mohty, M., Faucher, C. et al. Outcome after reduced-intensity conditioning allogeneic SCT for AML in first complete remission: comparison of two regimens. Bone Marrow Transplant 42, 689–691 (2008). https://doi.org/10.1038/bmt.2008.231
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