Using a genetic randomization through a ‘donor’ vs ‘no donor’ comparison, the aim of this analysis was to assess the real benefit of reduced intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) among 95 adult high-risk acute myeloid leukemia (AML) patients. In an ‘intention-to-treat’ analysis, leukemia-free survival (LFS) was significantly higher in the ‘donor’ group as compared to the ‘no donor’ group (P=0.01; 54 vs 30% at 4 years). The latter held true when restricting the analysis to the 25 patients who could actually receive the RIC-allo-SCT (P=0.001). Overall transplant-related mortality in the ‘transplant’ group was 12%, with overall survival (OS) being significantly higher in the ‘transplant’ group as compared to the ‘no transplant’ group (P=0.01). Also, in the ‘intention-to-treat’ analysis, OS was significantly higher in the ‘donor’ group as compared to the ‘no donor’ group (P=0.04). In the multivariate analysis, actual performance of RIC-allo-SCT (P=0.001; RR=4.0; 95% CI, 1.7–9.6) was the strongest factor significantly predictive of an improved LFS. We conclude that if a matched related donor is identified, RIC-allo-SCT should be proposed for AML patients not eligible for standard myeloablative allo-SCT.
Standard myeloablative allogeneic stem cell transplantation (allo-SCT) is a well-established therapy for adult patients with acute myeloid leukemia (AML).1, 2, 3, 4, 5, 6 However, because of the high incidence of procedure-related toxicity, this procedure is often limited to younger patients in good medical condition.7, 8 In an attempt to reduce procedure-related toxicity in elderly or heavily pretreated patients, or in patients with medical comorbidities precluding the use of myeloablative preparative regimens, reduced intensity conditioning regimens (RIC) have been investigated, with promising results in regards to feasibility, low early toxicity and induction of a potent graft-versus-tumor effect.9, 10, 11 However, only a few studies have specifically assessed the exact benefit of RIC-allo-SCT in a specific disease setting, such as AML.12, 13, 14 Of note, no randomized studies between RIC-allo-SCT for AML and chemotherapy alone are yet available. This report describes the results of 95 AML patients who were considered as potential candidates for RIC-allo-SCT. Using a genetic randomization through a ‘donor’ vs ‘no donor’ comparison, the aim of this analysis was to assess the real benefit of RIC-allo-SCT for adult AML and its impact on clinical outcome.
Patients and methods
In total, 95 consecutive newly diagnosed adult patients with AML treated between November 1999 and December 2003 at the Institut Paoli-Calmettes (IPC, Marseille, France), and having an identified sibling, were included in this retrospective analysis. Patients who did not achieve first complete remission (CR) or died within 40 days after diagnosis were excluded. Patients from the good cytogenetics risk group [t(15;17), t(8;21), and inv(16)] were also excluded.15 All 95 patients were considered as potential candidates for RIC-allo-SCT, because they had high-risk leukemic features, and/or high-risk clinical features that made them ineligible for our standard transplant program. High-risk leukemic features included at least one of the following criteria: high-risk cytogenetics (complex karyotype (ie ⩾3 unrelated aberrations), del(5q)/−5, −7, 3q rearrangements, t(9;22), t(6;9) or 11q23 rearrangements except t(9;11)), initial white blood cell count superior to 30 × 109/l, failure to reach first CR after one course of induction chemotherapy or secondary leukemia. High-risk clinical features were defined by the presence of at least one feature precluding the use of standard myeloablative allo-SCT: patient age older than 50 years, poor performance status, or significant medical comorbidities affecting heart, lungs, kidneys, or liver making patients at high risk of conditioning regimen-related toxicities.11, 16 None of the patients from this study was referred with already an identified donor. Also, patients included in this study were managed in a similar centralized manner by the same group from diagnosis until performance of allo-SCT and further follow-up. Moreover, no patients relapsing soon after HLA-typing were excluded from this study. HLA typing of patients was performed at a median of 42 days after diagnosis using standard techniques. Written informed consent was obtained from each patient and donor, and the study was approved by the IPC institutional review board.
After diagnosis, patients were included in different institutional protocols and received standard induction chemotherapy with daunorubicin and cytarabine. After achieving CR, a first course of consolidation therapy with cytarabine and daunorubicin was administered (details in Table 1). Subsequent chemotherapy consisted usually in intensive high-dose cytarabine followed or not with autologous stem cell transplantation conditioned with high-dose melphalan with or without busulfan (details in Table 1).17 The RIC regimen administered before allo-SCT included fludarabine, busulfan and antithymocyte globulin. Detailed transplant procedures were described elsewhere.16, 18 None of the patients included in this study received a standard myeloablative allograft.
All data was computed using s.e.m. for Windows (SILEX, Mirefleurs, France) and SPSS for Windows (SPSS Inc., Chicago, IL, USA). Detailed statistical methods were described elsewhere.16 Cumulative incidence estimates were used to measure the probability of relapse. Probability of leukemia-free survival (LFS) and overall survival (OS) were estimated from the time of diagnosis using the Kaplan–Meier product-limit estimates. Differences between groups were tested using the log-rank test. The association of time to leukemia relapse with other relevant variables was evaluated in a multivariate analysis, with the use of a time-dependent Cox proportional hazards regression model.19
Study population characteristics are summarized in Table 1. In total, 35 patients (37%; ‘donor’ group) had an HLA-identical sibling donor, while the remaining 60 patients had no related donor (‘no donor’ group) and were subsequently treated according to standard institutional procedures. No significant differences in patients or AML features were found between the two groups (Table 1). In the ‘donor’ group, 25 patients (71%) could actually proceed to the RIC-allo-SCT. The 10 remaining patients with an identified donor did not receive allo-SCT because of early relapse after CR (n=2), patient or donor refusal (n=6), and psychiatric disorders appearing before allo-SCT (n=2). With a median overall follow-up of 31 months, the median LFS in the whole study population was 21 months. In an ‘intention-to-treat’ analysis, the Kaplan–Meier estimate of LFS was significantly higher in the ‘donor’ group as compared to the ‘no donor’ group (P=0.01; 54 vs 30% at 4 years; Figure 1a). When restricting the analysis to patients who could actually receive the RIC-allo-SCT (median follow-up, 14 months from time of transplantation), the difference in LFS was also significant between this group of 25 patients (‘transplant’ group) and the remaining 70 patients (‘no transplant’ group) who did not receive allo-SCT (P=0.001; 62 vs 31% at 4 years; Figure 1b). Of note, before proceeding to RIC allo-SCT, and in comparison to patients from the ‘no transplant’ group, patients from the ‘transplant’ group did not receive more treatment during a longer duration of time. In the ‘transplant’ group, RIC-allo-SCT was performed at a median of 209 (range, 119–413) days after diagnosis. No grade 3 or 4 toxicities were encountered during RIC administration, and only three patients died from transplant-related toxicity, for an overall cumulative incidence of transplant-related mortality (TRM) of 12% (95% CI, 3–32%). This relatively low TRM translated towards a significantly higher OS in the ‘transplant’ group as compared to the ‘no transplant’ group (P=0.01; Figure 1c). In the ‘intention-to-treat’ analysis, OS was still significantly higher in the ‘donor’ group as compared to the ‘no donor’ group (P=0.04; Figure 1d).
Overall, 41 patients (43%; 95% CI, 33–53%) had relapsed at a median of 295 (range, 116–823) days after diagnosis, with the 4-year cumulative incidence of relapse being significantly higher in the ‘no transplant’ group as compared to the ‘transplant’ group (P=0.0002; 54 vs 12%; Figure 1e). After controlling for all relevant factors (demographic characteristics, leukemia features (FAB subtype, leukemia origin (secondary vs de novo), cytogenetics risk group, history of prior high-dose cytarabine or autologous transplantation, and number of chemotherapy induction courses to achieve first CR), identification of an HLA-identical sibling donor, and actual performance of RIC-allo-SCT), in the multivariate analysis, only an intermediate cytogenetic risk group (P=0.01; RR=1.2; 95% CI, 1.2–4.7) as previously described,20 and performance of RIC-allo-SCT (P=0.001; RR=4.0; 95% CI, 1.7–9.6), were significantly predictive of an improved LFS, further confirming the overall benefit of RIC-allo-SCT for adult AML patients.
Results from this study suggest that a potent graft-versus-leukemia effect can be induced in adult AML patients after RIC-allo-SCT, with a significant benefit in term of LFS. At our institution, it is the treatment policy since 1999 to offer allo-SCT with a RIC regimen to all AML patients aged between 50 and 65 years or to patients aged under 50 years, but with a comorbidity precluding the use of standard myeloablative allo-SCT, if a sibling related donor is available. The main objective of this analysis was to evaluate the outcome of such patients based on this treatment strategy, and to determine whether or not all such patients should receive a RIC-allo-SCT. To our knowledge, there have been no randomized trials in which patients with a matched sibling donor have been randomized between allo-SCT (whatever the type of conditioning) vs chemotherapy. In this context, in comparison to matched pair analysis or comparative studies, ‘genetic’ randomization can be a suitable way of comparing RIC-allo-SCT with other treatment modalities, while eliminating potentially unknown selection biases.21 As we did in this analysis, one important aspect is to analyze the results according to the ‘intention-to-treat’ principle in order to avoid misleading interpretations and biased treatment effects.22 Indeed, lack of compliance with the assigned treatment reflects one of the obstacles intrinsic to this type of analysis. In our study, only 71% of patients with a matched sibling donor actually received the RIC-allo-SCT, in accordance with previous data from the myeloablative allo-SCT setting.23, 24 However, it should be noted that only two patients (6%) could not proceed for RIC-allo-SCT because of early relapse. The latter might reflect the fact that >85% of the patients from this series received some form of high-dose chemotherapy (high-dose cytarabine and/or autologous transplantation) prior to allo-SCT. However, one must admit that the definitive benefit of the introduction of intensive chemotherapy such as autologous transplantation prior to RIC-allo-SCT is still yet to be assessed. Preliminary results from our ongoing prospective study suggest that leukemic control in the setting of RIC-allo-SCT may depend upon the intensity of chemotherapy given prior to allo-SCT (Blaise et al, Blood, 2004; 104: 101; abstract). The latter might imply that the assessment of the overall benefit of RIC-allo-SCT for AML must rather take into account the ‘global’ treatment strategy combining intensive sequential chemotherapy followed by ‘less toxic’ allogeneic immunotherapy. As for the problematic group of patients with a poor cytogenetics risk, and although not statistically significant because of the relatively limited number of patients, on an intention to treat basis, OS was higher in the six patients with a poor cytogenetics risk and a donor (median OS not reached), as compared to the 12 patients with a poor cytogenetics risk and without a donor (median OS, 10 months; data not shown).
This study did not address issues related to the optimal chemotherapy to be applied prior to RIC-allo-SCT, the type of RIC regimen to be used,25 quality of life after RIC-allo-SCT, or the role of matched unrelated RIC-allo-SCT for AML that have been reported with promising results.26 However, despite these obvious limitations, based on the current results, and given the low overall TRM rate observed in this high-risk population, we can reasonably envision that if a matched related donor is identified, RIC-allo-SCT should be proposed since it represents a valid option for AML patients not eligible for standard myeloablative allo-SCT.
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We thank FB Petersen, MD (University of Utah Health Sciences Center, Salt Lake City, Utah) for critical reading of the manuscript. We thank D Maraninchi (Institut Paoli-Calmettes) for helpful discussions and his continuous support. We thank the nursing staff for providing excellent care for our patients. We also thank the following physicians at the Institut Paoli-Calmettes for their important study contributions and dedicated patient care: R Benramdane, JM Schiano de Collela, J El-Cheikh, A Charbonnier, E Dinca, MF Doglio, R Bouabdallah, J Rey, and T Aurran.
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Mohty, M., de Lavallade, H., Ladaique, P. et al. The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia 19, 916–920 (2005). https://doi.org/10.1038/sj.leu.2403770
- acute myeloid leukemia
- allogeneic stem cell transplantation
- reduced intensity conditioning
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