Blood Reviews (2008) 22, 293–302

www.elsevier.com/locate/blre

REVIEW

Allogeneic stem cell transplantation in acute myeloid leukemia: a risk-adapted approach Tom Lodewyck, Jan J. Cornelissen

*

Department of Hematology, Erasmus University Medical Center-Daniel Den Hoed, Rotterdam, the Netherlands

KEYWORDS

Summary Allogeneic hematopoietic stem cell transplantation (alloSCT) is nowadays most frequently applied in patients with acute myeloid leukemia (AML). It combines chemoradiotherapy with immunotherapy, also known as the graftversus-leukemia (GVL) effect. While it effectively reduces the relapse rate in patients, transplanted in remission, non-relapse mortality (NRM) may counterbalance that beneficial effect. As a result, alloSCT is generally associated with a modest gain in overall survival. Therefore, alloSCT may especially be applied in patients with a relatively high risk of relapse and a relatively low risk of NRM. Here, we discuss how recent findings that have identified and validated specific prognostic factors may affect our decision making for which category of AML-patients alloSCT may especially be indicated. c 2008 Elsevier Ltd. All rights reserved.

Allogeneic hematopoietic stem cell transplantation; Acute myeloid leukemia; Non-relapse mortality; Alternative donors

 Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease, in which a variety of cytogenetic and molecular alterations can be identified. Cytogentic abnormalities can be detected in approximately 50–60% of newly diagnosed AML patients. In addition, different gene mutations have been found in cytogenetically normal AML, but also in patients with specific cytogentic abnormalities, underscoring the multi-event pathogenenesis of AML. Spe* Corresponding author. Tel.: +31 10 7041367; fax: +31 10 7041004. E-mail address: [email protected] (J.J. Cornelisse).



cific chromosomal abnormalities have been established as particularly strong prognostic markers for survival following chemotherapy, but also following hematopoietic stem cell transplantation.1,2 Cytogenetic analysis has allowed for distinguishing three cytogenetic prognostic categories (favorable, intermediate, poor) with each having a significantly different prognosis. After achieving first complete remission, favorable, intermediate, and poor-risk AML have probabilities of relapse of approximately 30%, 50% and 80%, respectively, and probabilities of overall survival of 60%, 40%, and 10–20%. Several prospective studies have addressed the role of alloSCT in patients with AML in remission

0268-960X/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.blre.2008.03.008

294 in each of these 3 cytogenetic categories. Randomized controlled trials (RCT) are generally the gold standard for the evaluation of treatment efficacy, but a randomized comparison of alloSCT versus chemotherapy or autologous SCT has sofar not been performed in patients with AML in first remission. Alternatively, a genetic randomization has been proposed and has been applied by different cooperative groups. As the availability of a matched sibling donor is essentially a random process, the presence or absence of a donor can be used as a surrogate for randomization.3,4 While such an analysis has the advantage of avoiding selection bias, it may have the disadvantage of underestimating the effects of allo-SCT when low numbers of patients with a sibling donor actually receive the transplant planned. Furthermore, these studies obviously require considerable numbers of patients as well as mature follow-up in order to evaluate the net effect of (long-term) adverse and favorable effects with sufficient power. Furthermore, in order to study alloSCT in a sufficient number of patients, combining prospective studies of similar design in a meta-analysis may add to the conclusions and interpretation of each individual study.

AlloSCT using sibling donors for younger AML patients in first CR Although several individual studies had shown a significant reduction of relapse by alloSCT, the beneficial effect on overall survival proved less clear. However, the first meta-analysis of 5 earlier studies by Yanada et al clearly showed improved outcome for patients with poor-risk cytogenetics, but the role of alloSCT in intermediate risk AML still proved subject of debate.5 The MRC study6 had suggested improved survival in patients with an intermediate risk AML, but the EORTC/GIMEMA study7 rather suggested a beneficial effect restricted to AML with a poor risk profile. The more recent BGMT study, using an adapted risk-index, however, showed an advantage for intermediate risk patients.8 The recent study performed by the HOVON/SAKK consortium showed improved DFS in both intermediate and poor-risk patients.9 Given these not entirely concordant results, the absence of a significant overall benefit in survival in intermediate risk AML, and the availability of new data from studies of similar design, a new meta-analysis was performed using the combined dataset of the HOVON/SAKK, MRC, EORTC and BGMT studies.9 It offered the opportunity for a study in a large number of patients with enhanced statistical power.

T. Lodewyck, J.J. Cornelissen Relapse, NRM, DFS and OS results were analyzed by donor availability for all patients and then broken down for cytogenetic risk category. Tables 1 and 2 show the hazard ratios for relapse and OS of donor versus no donor, split by study and cytogenetic risk and the overall estimate together with 95% confidence intervals. The findings from all four studies proved fairly similar with a strong reduction of relapse of approximately 50% in each study and in each of the cytogentic subcategories. Furthermore, a statistically significant OS benefit of 12% (HR = 0.84, CI 0.74–0.95, p = 0.01) was demonstrated for all patients without favorable cytogenetics. While relapse was also strongly reduced in patients with a favorable risk profile, a counterbalancing NRM of approximately 20% prevented an improvement of alloSCT on survival to emerge. Collectively, these results demonstrate that in the context of a NRM of 20%, the beneficial effect of alloSCT becomes apparent as soon as the risk of relapse exceeds approximately 30–40%, irrespective of the specific type of underlying cytogenetic abnormality, that causes the higher relapse rate. Moreover, it indicates that the immunotherapeutic effect (graft versus leukemia) is similarly exerted in all those subcategories of AML. Although relapse is also significantly reduced in favorable risk patients with a risk of relapse below 35%, those patients do not profit from alloSCT in terms of overall survival as a NRM of approximately 20% attenuates the beneficial effect of alloSCT in those patients. Therefore, myeloablative alloSCT cannot generally be recommended for patients in first complete remission with cytogenetic favorable subtypes of AML where the relapse probability is 35% or less. In those conditions the risk of procedure-related death does not outweigh the potential benefit of the transplant and it seems reasonable to reserve the option of an alloSCT for relapsing patients. Most patients with AML in first CR are characterized by an intermediate risk profile. While most of these leukemias lack a specific karyotypic abnormality, molecular genetic markers such as gene mutations and deregulated gene expression can be identified in the majority and may be associated with a more specific prognosis. Approximately 50% of cytogenetically normal AML may carry a mutation in the nucleophosmin (NPM1) gene.10 The prognostic value of the presence of the NPM1 mutation depends on the additional presence of the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor (FLT3/ITD).11–14 Myeloid leukemia’s characterized by the NPM1 mutation without FLT3/ITD, appeared to exhibit a more favorable prognosis with relapse rates less than

Allogeneic stem cell transplantation in acute myeloid leukemia Table 1

295

Meta-analysis of reduction of relapse by donor availability9a.

Category

Number of patients Donor

Hazard ratio with 95% CI

p-value

0.64 0.56 0.53 0.89

(0.52–0.78) (0.44–0.73) (0.37–0.64) (0.44–0.65)