Listen to the podcast by Dr Schiffer at J Clin Oncol 30: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 30 NUMBER 7 MARCH JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Impact of FLT3 Internal Tandem Duplication on the Outcome of Related and Unrelated Hematopoietic Transplantation for Adult Acute Myeloid Leukemia in First Remission: A Retrospective Analysis Salut Brunet, Myriam Labopin, Jordi Esteve, Jan Cornelissen, Gerard Socié, Anna P. Iori, Leo F. Verdonck, Liisa Volin, Alois Gratwohl, Jorge Sierra, Mohamad Mohty, and Vanderson Rocha Salut Brunet and Jorge Sierra, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Jordi Esteve, Institut d investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain; Myriam Labopin, Université Pierre et Marie Curie Paris 6, Hôpital Saint Antoine; Gerard Socié and Vanderson Rocha, Hôpital Saint-Louis, Paris; Mohamad Mohty, Centre Hospitalier et Universitaire de Nantes, Université de Nantes, and Institut National de la Santé et de la Recherche Médicale, Nantes, France; Jan Cornelissen, Erasmus Medical Center Daniel den Hoed Cancer Center, Rotterdam; Leo F. Verdonck, Isala Kliniecken Zwolle, Zwolle, the Netherlands; Anna P. Iori, Sapienza Università di Roma, Rome, Italy; Liisa Volin, Helsinki University Central Hospital, Helsinki, Finland; Alois Gratwohl, University Hospital, Basel, Switzerland; and Vanderson Rocha, Sirio-Libanes Hospital and Children s Cancer Hospital, University of Sao Paulo, Sao Paulo, Brazil. Submitted May 31, 2011; accepted December 5, 2011; published online ahead of print at on January 30, Written on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Supported in part by Grants No. EC07/ 90065, PI080672, PI080413, RD06/0020/ 0101, and RD06/0020/0004 from Instituto de Salud Carlos III, Madrid, and No SGR-1246 from the Agency for Administration of University and Research Grants, Barcelona, Spain. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Salut Brunet, MD, Hematology Service, Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, Barcelona, Spain; sbrunet@ santpau.cat by American Society of Clinical Oncology X/12/ /$20.00 DOI: /JCO Listen to the podcast by Dr Schiffer at A B S T R A C T Purpose Patients with acute myeloid leukemia (AML) and FLT3/internal tandem duplication (FLT3/ITD) have poor prognosis if treated with chemotherapy only. Whether this alteration also affects outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) remains uncertain. Patients and Methods We analyzed 206 patients who underwent HLA-identical sibling and matched unrelated HSCTs reported to the European Group for Blood and Marrow Transplantation with a diagnosis of AML with normal cytogenetics and data on FLT3/ITD (present: n 120, 58%; absent: n 86, 42%). Transplantations were performed in first complete remission (CR) after myeloablative conditioning. Results Compared with FLT3/ITD-negative patients, FLT3/ITD-positive patients had higher median leukocyte count at diagnosis (59 v /L; P.001) and shorter interval from CR to transplantation (87 v 99 days; P.04). Other characteristics were similar in the two groups. At 2 years, relapse incidence (RI; standard deviation) was higher (30% 5% v 16% 5%; P.006) and leukemia-free survival (LFS) lower (58% 5% v 71% 6%; P.04) in FLT3/ITD-positive compared with FLT3/ITD-negative patients. In multivariate analyses, FLT3/ITD led to increased RI (hazard ratio [HR], 3.4; 95% CI, 1.46 to 7.94; P.005), as did older age, female sex, shorter interval between CR and transplantation, and higher number of chemotherapy courses before achieving CR. FLT3/ITD positivity was associated with decreased LFS (HR, 0.37; 95% CI, 0.19 to 0.73; P.002), along with older age and higher number of chemotherapy courses before achieving CR. Conclusion FLT3/ITD adversely affected the outcome of HSCT in the same direction it does after chemotherapy; despite this, more than half of the patients harboring this mutation who received transplants were alive and leukemia free at 2 years. To further improve the results, use of FLT3 inhibitors before or after HSCT deserves investigation. J Clin Oncol 30: by American Society of Clinical Oncology INTRODUCTION Acute myeloid leukemia (AML) is clinically and biologically heterogeneous. 1 This reflects the diversity of pathophysiologic events in this disease, including acquired gene mutations and/or deregulation of gene expression. 2-6 It is well recognized that cytogenetic abnormalities of leukemic cells at diagnosis are the most important biologic prognostic factors in AML. In practice, patients with AML are allocated to prognostic categories to adapt postremission therapy according to cytogenetic risk. 7-9 Nonetheless, 45% of patients with AML have normal cytogenetics (NC-AML). In this latter group, molecular techniques are useful to detect somatic mutations of several genes such as internal tandem duplication of FLT3 (FLT3/ITD), NPM1, CEBPA, or MLL with marked prognostic relevance. 1-3,5,10,11 Among them, the presence of FLT3/ITD is the most powerful indicator of adverse prognosis in NC-AML. This mutation, detected in approximately one third of patients with NC-AML, 2012 by American Society of Clinical Oncology 735

2 Brunet et al increases the risk of relapse and has a negative impact on survival. 10,12-15 The role of autologous and allogeneic hematopoietic stem-cell transplantation (allohsct) for patients with FLT3/ITD AML remains controversial Many groups recommend allogeneic transplantation in first complete remission (CR) in the presence of this molecular abnormality, 2,18,19,21 because this treatment has the most powerful antileukemic effect. In contrast, other investigators argue that evidence supporting this approach is still limited, and a neat benefit after allohsct for this group of patients is not obtained. 17 Importantly, it is unknown whether FLT3/ITD also affects the outcome of allogeneic transplantation itself. This uncertainty is a result of the relatively reduced number of allografted patients with known FLT3 mutational status included in reported series. For this reason, analyses of large databases including molecular information are of particular interest. Herein, we report the first international transplantation registry study, to our knowledge, on the impact of FLT3/ITD on the outcome of patients with NC-AML. All patients received myeloablative conditioning in the first CR of their disease and received transplants between 2000 and 2008 from either HLA-identical siblings or matched unrelated donors (MUDs). Characteristics and outcomes were reported to the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS AND METHODS Data Collection EBMT is a voluntary organization including more than 500 transplantation centers. They are required to file annual reports of all consecutive SCTs with follow-up performed by EBMT physicians. All centers reporting specific disease questionnaires (Med-B forms) for patients with AML who underwent alloscts and fulfilled the inclusion criteria were asked to contribute additional data. Inclusion Criteria Adult patients age 18 years or older were included in the study if all of the following criteria were met: de novo AML, normal cytogenetics at diagnosis on chromosome-banding analysis, myeloablative allohsct, either from peripheral or bone marrow; non ex vivo T-cell depletion, HLA-identical sibling or MUD (MUDs were defined as 8/8, with high-resolution typing for HLA-A, -B, -C, -DRB1, and -DRB), transplantation performed from 2000 to 2008, and analysis of FLT3/ITD at diagnosis available. Ultimately, we were able to analyze 206 patients with available molecular information on FLT3/ITD (FLT3/ITD negative, 86; FLT3/ITD positive, 120) of 1,467 adult patients reported to EBMT fulfilling the aforementioned criteria. Cytogenetics and FLT3/ITD Molecular Studies Cytogenetics and molecular FLT3/ITD analyses were performed by referring institutions at diagnosis. FLT3/ITD was studied according to local standardized protocols. All participating transplantation centers had access to experienced laboratories in molecular techniques. End Points and Statistical Analysis Descriptive statistics included the main characteristics at diagnosis and transplantation, whereas end points considered were relapse incidence (RI), nonrelapse mortality (NRM), and leukemia-free survival (LFS). Cumulative incidences of relapse and NRM were calculated from the date of transplantation to date of relapse or death in remission, respectively, with competing risk as the other event. 22 LFS was defined as the interval from SCT to either relapse or death in remission. These end points were calculated at 2 years. Follow-up values reported correspond to patients alive when the analysis was performed. Proportions were compared by means of the 2 method, whereas the Mann-Whitney test was applied to detect differences between continuous parameters. Univariate comparisons of time-dependent end points were performed by means of the log-rank test in the case of Kaplan-Meier LFS curves and the Gray s test for RI and NRM cumulative incidences. Multivariable analyses were performed using the Cox proportional hazards model for LFS and Fine-Gray model for RI. 23 Factors differing in terms of distribution between the two groups and factors associated with a P value less than.15 by univariate analysis were included in the model. Then, a stepwise backward procedure was used with a cutoff significance level of.05 for deleting factors in the model. For all prognostic analyses, continuous variables were categorized, and the median was used as a cutoff point. All tests are two sided. The type I error rate was fixed at 0.05 for determination of factors associated with time-to-event outcomes. Statistical analyses were performed with SPSS (SPSS, Chicago, IL) and Splus (MathSoft, Seattle, WA) software packages. RESULTS Patients and Disease Characteristics Of 1,467 patients who met the eligibility criteria, we were able to analyze 206 patients (14%) with FLT/ITD data. Table 1 lists the main characteristics of patients according to FLT3/ITD status. Briefly, presence of FLT3/ITD was detected in 120 (58%) of 206 patients. FLT3/ ITD-positive patients presented with higher WBC counts at diagnosis (59 v /L; P.001) and underwent allohsct after having achieved CR (84 v 99 days; P.04). No statistical differences in age, sex, French-American-British classification, number of chemotherapy cycles before achieving CR, or interval from diagnosis to HSCT were found between the two groups. Median follow-up of survivors was 19 months (range, 2 to 96 months) for FLT3/ITD-positive patients and 12 months (range, 1 to 92 months) in the FLT3/ITDnegative group. Donor and Transplantation Characteristics All grafts were T-cell replete, from HLA-identical siblings or MUDs. Myeloablative conditioning regimen was based on total body irradiation or busulfan combined with other drugs, mainly cyclophosphamide (Table 1). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (CSA) combined with methotrexate in most cases, whereas a minority received CSA plus mycophenolate mofetil or CSA alone. No significant differences were observed between FLT3/ITDpositive and -negative groups in year of transplantation, donor type, donor sex, female-to-male recipient, serologic cytomegalovirus status, conditioning regimen, graft source, or GVHD prophylaxis. Neutrophil Recovery Most patients (99%) surviving at least 50 days after transplantation had a neutrophil count greater than /L; only two FLT3/ ITD-positive patients experienced primary engraftment failure, and another patient who was FLT3/ITD negative experienced secondary graft failure after an initial engraftment. Acute and Chronic GVHD The cumulative incidence of acute GVHD at 100 days ( standard deviation) was 43% 4% (FLT3/ITD positive, 36% 5%; FLT3/ITD negative, 53% 5%; P.04). In a multivariate analysis, FLT3/ITD positivity was not associated with higher incidence of acute GVHD (P.42). Data on chronic GVHD were available for 152 patients at risk, without significant difference in incidence according to FLT3/ITD mutational status. Cumulative incidence at 2 years was 49% 4% by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 Impact of FLT3/ITD in Allogeneic Transplantation Table 1. Patient, Disease, and Transplantation Characteristics According to FLT3/ITD Status Characteristic FLT3/ITD Negative (n 86) FLT3/ITD Positive (n 120) No. % No. % Patient Age, years.31 Median Range Sex.06 Male Female Disease FAB type.07 M M M M M WBC, 10 9 /L Median Range No. of courses to CR Interval from CR1 to transplantation, days Median Range Transplant Year of SCT Donor relation.5 HLA identical sibling MUD Donor sex.17 Male Female Female donor to male recipient.31 No Yes CMV donor-recipient serologic status.47 Negative-negative Positive-negative Negative-positive Positive-positive Conditioning regimen based on TBI.37 No Yes Source of stem cells.14 Bone marrow Peripheral blood Use of ATG/ALG.73 No Yes GVHD prophylaxis.67 CSA and MTX Other Abbreviations: ATG/ALG, antithymocyte or antilymhoglobulin; CMV, cytomegalovirus; CR1, first complete remission; CSA, cyclosporine; FAB, French- American-British; FLT3/ITD, internal tandem duplication of FLT3 gene; GVHD, graft-versus-host disease; MTX, methotrexate; MUD, matched unrelated donor; SCT, stem-cell transplantation; TBI, total body irradiation. P (FLT3/ITD positive, 47% 6%; FLT3/ITD negative, 52% 6%; P.72). NRM Two-year cumulative incidence of NRM ( standard deviation) was 13% 2%. Presence of FLT3/ITD was not associated with cumulative incidence of NRM (Table 2). Additionally, none of the other factors analyzed were associated with NRM. RI At 2 years, cumulative incidence of relapse for the whole population ( standard deviation) was 24% 5%, with a significant increased RI in the FLT3/ITD-positive group (30% 5% v 16% 5%; P.006; Fig 1A). This higher risk of relapse associated with FLT3/ITD mutation was also confirmed in the multivariable analysis (HR, 3.4; 95% CI, 1.46 to 7.94; P.005; Table 3). In addition, other factors such as older age ( 42 years), more than one course of chemotherapy before achieving CR, shorter interval from CR to transplantation, and female sex were associated with a higher RI (Table 3; Fig 1A). LFS Two-year LFS for the whole population ( standard deviation) was 64% 3% (Table 2). When comparing unadjusted probabilities of LFS between FLT3/ITD-positive and -negative patients, outcome was worse in the former group (58% 5% v 71% 6%; P.04; Table 2; Fig 1B). In the multivariable analysis, after adjustment for patient-, disease-, and transplantation-related variables, difference in LFS according to FLT3/ITD status was confirmed (HR, 0.37; 95% CI, 0.19 to 0.73; Table 3). Other variables influencing LFS in the univariate analysis were patient age and number of chemotherapy courses before achieving CR, a finding that was confirmed in the multivariable analysis after adjustment for other variables (Tables 2 and 3). Thus, younger patients (age 42 years), with a borderline significance level (74% 5% v 54% 5%; HR, 0.54; 95% CI, 0.3 to 0.99; P.05) and patients requiring only one course of chemotherapy before achieving CR (71% 5% v 30% 11%; HR, 0.26; 95% CI, 0.14 to 0.48; P.05) showed a more favorable outcome. On the contrary, other variables such as leukocyte count at diagnosis, time from CR to transplantation, donor source, and donor-recipient relation did not have an impact on LFS, either in the univariate or multivariable analysis. DISCUSSION This study is the largest analysis of the impact of FLT3/ITD mutation on the results of allohsct as treatment for patients with AML with normal karyotype in first CR. The presence of FLT3/ITD led to higher relapse risk and inferior LFS. Nonetheless, the observed 2-year LFS of 58% in patients with FLT3/ITD and the relapse risk of 30% favorably compares with the outcomes reported after postremission chemotherapy only. This suggests that allohsct has a relevant role in the management of AML involving this genetic lesion, although we acknowledge that some degree of selection bias in the series reported here cannot be ruled out. As an example, those patients who relapsed before transplantation could not be included in the series herein analyzed. Definition of risk in AML has been historically based on age, leukocyte count, and cytogenetics. Regarding the latter, treatment by American Society of Clinical Oncology 737

4 Brunet et al Two-Year Outcome Table 2. Main Results of Univariate Analysis of Prognostic Factors for LFS, RI, and NRM LFS RI NRM % SD P % SD P % SD P Overall FLT3/ITD Negative Positive Patient age, years Donor sex Male Female WBC, 10 9 /L No. of courses to CR Interval from diagnosis to SCT (median, 140 days) Median Median Interval from CR1 to SCT (median, 93 days) Median Median Year of SCT Donor-recipient relation HLA identical sibling MUD Total body irradiation No Yes Source of progenitor cells Bone marrow Peripheral cells T-cell depleted in vivo No Yes Abbreviations: CR1, first complete remission; FLT3/ITD, internal tandem duplication of FLT3 gene; LFS, leukemia-free survival; MUD, matched unrelated donor; NRM, nonrelapse mortality; RI, relapse incidence; SCT, stem-cell transplantation; SD, standard deviation. results in the large subgroup of patients with intermediate-risk karyotype have been diverse, reflecting the heterogeneous nature of this cytogenetic category. In recent years, it has become evident that the identification of mutations or overexpression of several genes allows for segregation of prognostic categories in the heterogeneous intermediate-risk cytogenetic group. Among them, FLT3 mutations resulting in an ITD of the juxtamembrane domain of this tyrosine kinase receptor consistently confer an adverse prognosis. 5,12-14 In the last few years, the impact of FLT3/ITD according to postremission strategy has been analyzed in some studies. Two reports showed that autologous transplantation improved outcome compared with chemotherapy. 19,24 Regarding allohsct, two consecutive trials conducted by the Medical Research Council cooperative group did not show a clear benefit from HLA-identical sibling transplantation in AML with FLT3/ITD, although the relapse rate was markedly reduced compared with that in other treatments. 17 In contrast, recently reported data indicate that allogeneic transplantation improves the outcome of these patients, as it does in other high-risk AML groups. 4,19,21 It may be argued that a caveat of this and other prognostic factor analyses could be not taking into account certain important variables with potential influence on transplantation outcome. Some of these relevant variables are included in the EBMT score, 25 which should be considered in future prognostic factor studies in the transplantation setting. This weakness of the present report is counterbalanced in part by the fact that we analyzed a rather homogeneous population (ie, early disease stage, only myeloablative conditioning, no ex vivo T-cell depletion, HLA-matched donors, and treatment during recent years). The key finding of this study was that patients with NC-AML in first CR harboring FLT3/ITD had increased RI and consequently decreased LFS compared with patients with FLT3/ITD-negative NC-AML. This increase in relapse incidence was observed in FLT3/ITD-positive patients by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 Impact of FLT3/ITD in Allogeneic Transplantation A Cumulative Incidence of Relapse (proportion) Table 3. Results of Multivariable Analyses for LFS and RI (n 158) Outcome HR 95% CI P LFS FLT3/ITD, positive v negative to Age 42 years to One course to CR to RI FLT3/ITD, positive v negative to Age 42 years to Patient sex, female v male to Interval from CR to transplantation 93 days to One course to CR to Abbreviations: CR, complete remission; FLT3/ITD, internal tandem duplication of FLT3 gene; HR, hazard ratio; LFS, leukemia-free survival; RI, relapse incidence. B Leukemia-Free Survival (proportion) Time (years) Time (years) Fig 1. Outcome after allogeneic transplantation performed in first complete remission for patients with acute myeloid leukemia and normal cytogenetics according to the presence (dashed line) or absence (solid line) of internal tandem duplication of FLT3 gene. (A) Estimated probability of 2 years of cumulative incidence of relapse; (B) leukemia-free survival after transplantation at 2 years. independently of other variables such as stem-cell source, donor type, and the combination of female donor to male recipient. Moreover, this effect does not seem to be related to a lower GVHD incidence or higher use of in vivo T-cell depletion in the FLT3/ITD-positive group, thus confirming the negative influence of this mutation in the allohsct setting as well Despite these findings, the adverse impact of FLT3/ITD on transplantation outcome does not preclude indication of this procedure in these patients if they have an HLA-identical sibling or MUD, because we observed a remarkable 2-year LFS of 58% and relapse incidence of 30%. These results seem by far better than those obtained with chemotherapy, which has been followed by a median survival of only 2.5 months. 3,5,10,11,14,17,29 Whether the recent introduction of FLT3 kinase inhibitors will significantly improve outcome after chemotherapy remains to be answered by ongoing clinical trials. These FLT3 inhibitors may in the future make unnecessary allogeneic transplantation in first CR in a substantial fraction of patients with this molecular alteration. On the other hand, these inhibitors, if effective, may increase the proportion of patients with FLT3/ ITD who achieve CR and reach allografting in the best condition. Therefore, the administration of FLT3 inhibitors before and/or after allogeneic transplantation may be a strategy to be explored with the aims of increasing transplantation feasibility and reducing relapse incidence after the procedure. The data herein reported suggest the existence of a strong antileukemic effect from myeloablative conditioning and graft versus FLT3/ITD-positive AML reaction. Therefore, only prospective randomized studies may definitively establish the best treatment option for this molecular group of AML. However, this type of study is unlikely to be performed, because it has now been established that the prognosis of patients with NC-AML harboring FLT3/ITD and treated with chemotherapy only is poor. We used the EBMT registry database with the acknowledgment that this type of study may have the selection bias of excluding patients who experience relapse before the procedure. This may particularly be the case in AML with FLT3/ITD, because early relapse is frequent. Despite this, investigating the outcome of patients with FLT3/ITD AML who reach allogeneic transplantation remains of interest; it is also worth knowing whether their results are worse than those achieved in the absence of this molecular feature. Despite this selection effect inherent to all studies based on transplantation registries, 30 the population of patients with FLT3/ITD AML included in this study had typical features characteristic of this AML subtype, such as high median WBC count at diagnosis. 5,10,12 As we have mentioned before, prospective randomized studies are needed to establish definitively the best treatment option for this molecular group of AML, although it may be difficult to launch in this setting given the poor outcome observed after chemotherapy-based postremission strategies. The 58% proportion of FLT3/ITD AML observed in this series of NC- AML is much higher than that observed in the overall population of patients with NC-AML. This finding likely reflects that FLT3/ITD is in practice a criterion indicating allohsct in first remission, whereas in the absence of this adverse molecular feature, patients with NC- AML are frequently treated with postremission chemotherapy only by American Society of Clinical Oncology 739

6 Brunet et al Because the majority of patients with AML who are candidates for allogeneic transplantation lack an HLA-identical sibling, the use of MUDs is increasing As recently reported by the EBMT group, 34 the current indications of allogeneic transplantation for AML do not differ according to type of donor, provided that an HLA match exists. This recommendation is also supported by our study, which showed a similar outcome in patients receiving transplants from HLA-identical siblings and those receiving transplants from MUDs. Another aspect that deserves attention is the fact that a substantial number of patients in this series received transplants from MUDs for AML in first remission, despite normal karyotype and absence of FLT3/ITD. Some groups claim that allohsct involving a matched donor is the best option for all patients with NC-AML in first remission, regardless of donor-recipient relation, unless a favorable molecular profile is present, such as NPM1 or CEBPA mutation. Furthermore, patients without FLT3/ITD could be also candidates for allogeneic transplantation based on other high-risk criteria, such as hyperleucocytosis at diagnosis or need of more than one chemotherapy course to achieve CR. 34 This latter variable also adversely influences the outcome of FLT3/ITD-positive patients, and in this circumstance, intensified conditioning regimens, preemptive strategies based on close monitoring of minimal residual disease after transplantation, and prophylactic use of donor lymphocyte infusions are potential strategies. Other aspects not analyzed in the present report that deserve investigation are the possible influence on transplantation results of FLT3/ITD allelic burden, duplication length, and location as well as the possible impact of the coexistence of other gene mutations with prognostic value, such as NPM1, WT1, IDH1 and IDH2, or DNMT3A. In summary, the presence of FLT3/ITD correlated with a higher risk of relapse and lower LFS after allohsct performed in first CR, and our study confirms that this mutation defines a high-risk entity even in the context of allogeneic transplantation. Nonetheless, the relative favorably outcome observed after transplantation, with a relapse incidence and LFS of 30% and 58% at 2 years, respectively, suggests that this procedure might have a relevant role for the management of this molecular entity. Tyrosine kinase inhibitors with activity on FLT3 receptor have been developed and are currently under clinical investigation. 35,36 These agents may improve the outcome of patients with FLT3 mutations treated with chemotherapy and make hematopoietic transplantation unnecessary in the future. Also, these inhibitors, used properly, may also significantly improve the results of allografts, contributing to sustaining this indication. Welldesigned large prospective trials including international collaborations are mandatory to define what these promising drugs offer in association with more conventional treatments. Fortunately, several of these collaborative efforts are now under way. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Jorge Sierra, Celgene (C), Genzyme (C) Stock Ownership: None Honoraria: Jorge Sierra, Celgene, Genzyme Research Funding: Jorge Sierra, Celgene, Novartis, Amgen Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Salut Brunet, Jordi Esteve, Jorge Sierra, Mohamad Mohty, Vanderson Rocha Financial support: Vanderson Rocha Administrative support: Myriam Labopin, Mohamad Mohty, Vanderson Rocha Provision of study materials or patients: Salut Brunet, Jordi Esteve, Jan Cornelissen, Gerard Socié, Anna P. Iori, Leo F. Verdonck, Liisa Volin, Alois Gratwohl, Vanderson Rocha Collection and assembly of data: Salut Brunet, Myriam Labopin, Jordi Esteve, Jorge Sierra, Vanderson Rocha Data analysis and interpretation: Salut Brunet, Myriam Labopin, Jordi Esteve, Jorge Sierra, Mohamad Mohty, Vanderson Rocha Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. 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