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1 Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo-hsct) by analyzing survival end points in defined groups of acute myeloid leukemia patients: A retrospective, multicenter Polish Adult Leukemia Group study AJH Sebastian Grosicki, 1 Jerzy Holowiecki, 2 Kazimierz Kuliczkowski, 3 Aleksander Skotnicki, 4 Andrzej Hellmann, 5 Slawomira Kyrcz-Krzemien, 6 Anna Dmoszynska, 7 Kazimierz Sułek, 8 Janusz Kloczko, 9 Wieslaw W. Jedrzejczak, 10 Krzysztof Warzocha, 11 Barbara Zdziarska, 12 Agnieszka Wierzbowska, 13 Agnieszka Pluta, 13 Mieczyslaw Komarnicki, 14 and Sebastian Giebel 2 * The importance of allogeneic hematopoietic stem cell transplantation (allo-hsct) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-hsct. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during The Mantel Byar approach was used to assess allo-hsct on survival endpoints, accounting for a changing transplant status. Undergoing allo-hsct significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged The CIR demonstrated that allo-hsct reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-hsct significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged The allo-hsct treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis. Am. J. Hematol. 90: , VC 2015 Wiley Periodicals, Inc. Introduction Acute myeloid leukemia (AML) intrigues with its diverse biology, genetic aberrations, and clinical picture, however it is also life-threatening, due to hematopoiesis being almost immediately eliminated by leukemia cells that accumulate and replace those of the healthy bone marrow. Cytogenetic analysis of the leukemia cell has in particular been confirmed as important to making a prognosis. To date, major studies have indicated improvements in defining cytogenetic risk groups that currently play a dominant role in predicting treatment outcomes [1 9]. However, in 10 40% of patients with AML, it is not possible to determine the cytogenetic characteristics of leukemic clones [1 9]. For such patients, investigating the blastic cell with biomolecular techniques is thereby vital as well as determining other, non-cytogenetic prognostic factors. For the latter, the following are still stressed: age, leukocytosis before treatment, and the presence of organ infiltrations or myelodysplasia (MDS) preceding AML [1]. Despite improvements in post-remission practices and the increasingly widespread use of allo-hsct, the long-term results of treatment remain unsatisfactory [1 3,5,7,10 13]. The purpose of this study was to assess the importance of undertaking allo-hsct determined by leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM) for patients with AML in first complete remission (CR1). 1 Department of Cancer Prevention, School of Public Health, Medical University of Silesia, Katowice, Poland; 2 Department of Bone Marrow Transplantation, Branch Gliwice, Comprehensive Cancer Center M. Sklodowska-Curie Memorial Institute, Gliwice, Poland; 3 Department of Haematology, Hematopoietic Malignancies and BMT, Medical University, Wroclaw, Poland; 4 Department of Haematology, Collegium Medicum, Jagiellonian University, Cracow, Poland; 5 Department of Haematology and Transplantology, Medical University, Gdansk, Poland; 6 Department of Haematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland; 7 Samodzielna Pracownia Transplantologii Klinicznej, Uniwersytet Medyczny, Lublin, Poland; 8 Military Medical Institute, Warsaw, Poland; 9 Department of Hematology, Medical University, Bialystok, Poland; 10 Department of Hematology, Oncology and Internal Medicine, Medical University, Warsaw, Poland; 11 Department of Haematology, Institute of Haematology and Transfusion Medicine, Warsaw, Poland; 12 Department of Internal Medicine and Haematology, SPSK Nr 1, Szczecin, Poland; 13 Department of Haematology, Copernicus Memorial Hospital, Medical University, Lodz, Poland; 14 Department of Hematology and Proliferative Diseases of The Hematopoietic Systems, Poznan University of Medical Sciences, Poznan, Poland Conflict of interest: Authors have nothing to declare. *Correspondence to: Sebastian Grosicki, Oddział Hematologiczny SPZOZ Zespoł Szpitali Miejskich w Chorzowie, ul. Karola Miarki 40, Chorzow, Poland. sgrosicki@wp.pl Received for publication: 27 February 2015; Revised: 5 May 2015; Accepted: 2 July 2015 Am. J. Hematol. 90: , Published online: 6 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh VC 2015 Wiley Periodicals, Inc. 904 American Journal of Hematology, Vol. 90, No. 10, October 2015 doi: /ajh.24113

2 AlloHSCT Importance for the Survival of Patients with AML TABLE I. Descriptive Statistics of Covariates for Survival Analysis Without allo-hsct Allo-HSCT All N P 622 Induction regimen DA N (%) 189 (39.79) 51 (34.69) (38.59) DAC N (%) 212 (44.63) 60 (40.82) (43.73) DAF N (%) 74 (15.58) 36 (24.49) (17.68) Age (years) Mean 6 standard deviation < Range [16;60] [18;59] [16;60] Median % CI [43.43;45.54] [32.77;36.17] [41.16;43.08] Age groups (years) < N (%) 149 (31.43) 103 (70.07) < (40.58) N (%) 133 (28.06) 34 (23.13) (26.89) N (%) 192 (40.51) 10 (6.8) < (32.53) Cytogenetic risk group (according to SWOG) N (%) 55 (15.94) 16 (13.68) 71 (15.37) 1 N (%) 238 (68.99) 81 (69.23) 319 (69.05) 2 N (%) 52 (15.07) 20 (17.09) 72 (15.58) MDS No N (%) 369 (87.44) 113 (91.13) 482 (88.28) Yes N (%) 53 (12.56) 11 (8.87) 64 (11.72) WBC_DGN (G/l) Mean 6 standard deviation Range [0.5;346] [0.7;374.5] [0.5;374.5] Median % CI [34.36;45.29] [25.95;46.01] [34.1;43.68] Number of cycles N (%) 403 (84.84) 130 (88.44) 533 (85.69) 2 N (%) 70 (14.74) 17 (11.56) 87 (13.99) 3 N (%) 2 (0.42) 0 (0) 2 (0.32) Allo-HSCT: allogeneic hematopoietic stem cells transplantation; DA: daunorubicin/cytarabine; DAC: daunorubicin/cytarabine/cladribine; DAF: daunorubicin/ cytarabine/fludarabine; N: number, 95% CI: the confidence interval; SWOG: South West Oncology Group; SWOG 0: favorable cytogenetic risk group according to SWOG; SWOG 1: intermediate cytogenetic risk group according to SWOG; SWOG 2: unfavorable risk cytogenetic group according to SWOG; MDS: AML secondary to myelodysplastic syndrome; WBC_DGN: white blood cells at diagnosis; Number of cycles: number of induction cycles to achieve first complete remission. Materials and Methods Subjects consisted 622 (58%) of 1,074 patients with AML with a median age of 44 (16 60) years who were treated through two prospective, randomized, multicenter clinical trials: PALG AML DAC vs. DA ( ) (Study 1) [13] and PALG AML 1/2004 DAC vs. DAF vs. DA ( ) (Study 2) [12], and who had achieved CR1. In both studies, treatments were compared between the standard induction chemotherapy program DA (DNR 60 mg/m 2 /day iv on Days 1 3, Ara-C 200 mg/m 2 /day ci on Days 1 7) with the DAC program where additionally, cladribine 5 mg/m 2 /day on Days 1 5 iv in Study 1 had been administered [13], as well as comparing the DAC with DAF programs, where in place of cladribine, 25 mg/m 2 fludarabine iv in Study 2 had been given [12]. Consolidation chemotherapy was similar in both programs. Patients received HAM as the first course (Ara-C 1.5 g/m 2 /day on Days 1 3, Mitoxantrone 10 mg/m 2 /day on Days 3 5), and HD AraC as the second course (2 g/m 2 iv every 12 hr on Days 1, 3, 5). In Study 1, patients who received cladribine in the induction, also received it for consolidation in the same daily dose on Days 1, 3, 5. Maintenance therapy was recommended for patients who were not transplanted. As alternative reinduction chemotherapy, CLAG [14,15] and CLAG-M [16] were respectively used in Studies 1 and 2. In the former, patients with intermediate or high cytogenetic risk and those patients requiring two induction treatments to achieve CR were qualified for allo-hsct. In Study 2, for the group having an unfavorable cytogenetic risk, allo-hsct was recommended as soon as possible after CR1. The study qualified for each patient, who was treated in these studies who received CR1. The endpoint of this study was to assess the importance of undertaking allo-hsct determined by LFS, OS, CIR, and NRM for patients with AML in CR1. Patients were classified into two groups: allo-hsct if after CR1 allo-hsct was performed (N 5 147) and non-allo-hsct (N 5 475). In the former group, matched sibling donor transplantations (MSD-HSCT) (N 5 103, 70%) and matched unrelated donor transplantations (MUD-HSCT) (N 5 44, 30%) were distinguished. The median follow-up amounted to 3.1 years. The median time from CR1 to allo-hsct was days (25 1,064) and for MSD-HSCT and MUD-HSCT this was respectively (25 936) and 257 (122 1,054) days. Statistical analyses.. In both studies, early results of treatment were defined in accordance with the International Working Group criteria [17]. Patients with acute promyelocytic leukemia were excluded from the study. In Studies 1 and 2, cytogenetic risk groups were defined in accordance with SWOG (Southwest Oncology Group) criteria [5]. Survival was assessed by analyzing OS, LFS, CIR, and NRM end points for patients with AML in CR1. OS and LFS analyses were based on the Cox proportional hazards model while CIR and NRM were estimated by the cumulative incidence method, where recurrence and death in remission were treated as representing competing risks. The effect of allo-hsct on these survival outcome models so obtained was assessed using the Mantel Byar approach. The OS and LFS probabilities were estimated adequately on obtaining CR1. CIR and NRM analyses were also performed based on the proportional risk, and were interpreted with the aid of charts, the relevance of particular independent variables, and by verifying the time dependence of allo-hsct. All models included the following factors: allo-hsct (time-dependent co-variable), cytogenetic risk group according SWOG criteria, number of induction courses, preceding MDS, age (continuous variable), and WBC at diagnosis of AML (continuous variable). The results of MSD-HSCT were compared with MUD-HSCT using the Cox proportional hazards model; because no differences were observed, these groups were then treated collectively as the allo-hsct group in all subsequent analyses. The comparison group included patients in whom allo-hsct was not used. All statistical calculations were carried out using the StatSoft, Inc. (2011) statistical package, STATISTICA (data analysis software system; version R version and Excel spreadsheets. Significance was taken as being P 0.05 Both studies were approved by the Bioethics Commitees of the participating institutions and performed in accordance with the Declaration of Helsinki. All patients signed their informed consent. Results Patients The results of two prospective, randomized, multi-center clinical trials: PALG AML DAC vs. DA ( ) study and PALG AML 1/2004 DAC vs. DAF vs. DA ( ) study were previously doi: /ajh American Journal of Hematology, Vol. 90, No. 10, October

3 Grosicki et al. TABLE II. Analysis Using allo-hsct as a Single Time-Dependent Covariate for OS and LFS (N 5 622) for the Whole AML Patient Group in CR1 LFS OS Variable Relative risk 95% CI P Relative risk 95% CI P Allo-HSCT 0.50 [0.35;0.71] [0.45;0.84] LFS: leukemia free survival; OS: overall survival; N: number, allo-hsct: allogeneic hematopoietic stem cells transplantation; 95% CI: the confidence interval. published [12,13]. Descriptive statistics of the independent variables for the survival analysis are presented in Table I. Comparing MSD-HSCT with MUD-HSCT There was no significant effect of donor type on OS (hazard ratio (HR) 0.85, P ) or LFS (HR 1.3, P 5 0,58) for patients with AML in CR1 following univariate analyses. Probability of LFS after 5 years follow-up in MSD-HSCT was 65%, and in MUD-HSCT was 57%. Probability of OS after 5 years follow-up in MSD-HSCT was 60%, and in MUD-HSCT was 58%. Effect of allo-hsct on the survival A significant improvement in LFS (HR 0.5, P ) and OS (HR 0.62, P ) was seen following univariate analysis for the allo-hsct group (Table II, Fig. 1). However, using the multivariate model, only allo-hsct proved beneficial to LFS, whereas only MDS preceding AML (HR 1.58, P ) adversely impacted the OS (Table III). Effect of allo-hsct on the survival of patients treated with DAC induction Significant improvements in LFS (HR 0.47, P ) and OS (HR 0.5, P ) were shown according to univariate analysis in the allo-hsct group. Factors benefitting LFS, as determined from multivariate analysis, were allo-hsct (HR 0.38, P ) and a younger age (HR 0.98, P ), whilst an adverse one proved to be higher numbers of induction courses for achieving CR1 (HR , P ). Effect of allo-hsct on the survival of patients aged For this group, a significant improvement of LFS were also observed (HR 0.54, P ), by univariate analysis but there was no improvement of OS (HR 0.78, P ) in the allo-hsct group. The multivariate analysis showed that the only factor benefitting the LFS to be allo-hsct (HR 0.54, P ), whereas none of the independent factors affected OS. Effect of allo-hsct on the survival of patients aged Univariate analysis demonstrated significant improvements of LFS (HR 0.29, P ) and OS (HR 0.39, P ) in the allo- HSCT group. Factors found to be beneficial to LFS from the multivariate analysis proved to be only allo-hsct (HR 0.25, P ), whilst one that proved adverse was having more than one course of induction chemotherapy for achieving CR1. For OS, allo-hsct was also beneficial (HR 0.37, P ), whereas those with adverse effects were MDS preceding AML (HR 1.94, P ) and WBC at diagnosis (HR 1.1, P ). Effect of allo-hsct on the survival of patients with favorable cytogenetics With the exception of the MDS preceding AML being identified as an adverse factor on LFS from multivariate analysis, no other factors showed significant effects by either of the two analyses. Figure 1. Kaplan Meier curves with time-dependent covariate allo-hsct (Mantel Byar estimation) for the whole AML patient group in CR1. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Effect of allo-hsct on the survival of patients for the intermediate cytogenetic risk group No significant effect of allo-hsct on OS was shown by univariate analysis, nevertheless this treatment was found beneficial to LFS (HR , P ). The allo-hsct also improved LFS as determined by multivariate analysis (HR 0.49, P ) and the only factor affecting OS by this analysis was MDS preceding AML (HR , P ). 906 American Journal of Hematology, Vol. 90, No. 10, October 2015 doi: /ajh.24113

4 AlloHSCT Importance for the Survival of Patients with AML TABLE III. Multivariate Analysis With Allogeneic Hematopoietic Stem Cell Transplantation (allo-hsct) and Other Covariables for Overall Survival (OS) and Relapse-Free Survival (LFS) Using Mantel Byar Method in Whole Group of Acute Myeloid Leukemia Patients in First Complete Remission (CR1) (N 5 558) LFS OS Covariate Hazart ratio 95% CI P Hazard ratio 95% CI P Allo-HSCT 0.47 [0.31;0.73] [0.49;.02] Age (years) 1.00 [0.98;1.00] [1.00;1.02] Cytogenetic risk according to SWOG a 1.35 [0.93;1.94] [0.71;1.43] WBC [G/l] 1.00 [1.00;1.003] [1.00;1.004] Number of cycles 1.26 [0.86;1.84] [0.78;1.59] MDS 1.27 [0.85;1.91] [1.08;2.31] LFS: leukemia free survival; OS: overall survival; CI: confidence interval; SWOG: Southwest Oncology Group; WBC: white blood cells at diagnosis; MDS: acute myeloid leukemia secondary to myelodysplastic syndrome; Number of cycles: number of induction chemotherapy cycles before CR1. a Covariate SWOG treated as a continuous, assigning categories HR (high risk), IR (intermediate risk), LR (low risk) values 0, 1, 2 TABLE IV. Analysis Using Allo-HSCT as a Single Time-Dependent Covariate for OS and LFS (N 5 72) by the Mantel Byar Method for the AML Patient Group in CR1 for the Unfavorable Risk Group According to SWOG (SWOG 2) LFS OS Variable Relative incidence 95% CI P Relative incidence 95% CI P Allo-HSCT 0.37 [0.13;1.04] [0.16;0.93] LFS: leukemia free survival; OS: overall survival; N: number; allo-hsct: allogeneic hematopoietic stem cells transplantation; 95% CI: the confidence interval. Effect of allo-hsct on the survival of patients in the unfavorable cytogenetic risk group In this group, a significant improvement of LFS (HR 0.37, P ) and OS (HR 0.38, P ) was observed in those patients undergoing allo-hsct as determined by univariate analysis (Table IV, Fig. 2). Likewise, allo-hsct proved by multivariate analysis to be the only factor improving LFS and OS, respectively, HR 0.24, P and HR , P CIR in the competing risks category Undergoing allo-hsct was found, by univariate analysis, to decrease CIR risk in the above category as well as the patient group with unfavorable cytogenetic risk; P values being respectively and When using the multivariate analysis for competing risks, it was found that allo-hsct significantly decreased CIR risk for all patients with AML in CR1, those patients treated with DAC, in the 16 40, age groups, and in the intermediate cytogenetic risk group; P values being respectively , , , , This analysis also found that patient age at diagnosis and the number of induction courses required for achieving CR were additional factors increasing CIR risk, in linear fashion, for all patients with AML in CR1; P values, respectively, were and NRM in the competing risks category of all patients The allo-hsct was demonstrated by univariate analysis to significantly reduce NRM risk in the above category as well as in the subgroup of those aged years; P values being respectively , Multivariate analysis did not confirm the effect of allo-hsct, as well as other factors on NRM. Discussion The key importance of allo-hsct for AML treatment outcomes had already been demonstrated back in 1977 by Thomas et al., who reported a 20% survival rate after 4 years in 54 patients with AML subjected to transplantation during active relapse [18]. At present, AML is the most common indication for allo-hsct. Indeed, the decision of whether or not to perform allo-hsct in patients attaining Figure 2. Kaplan Meier curves with time-dependent covariate allo-hsct (Mantel Byar estimation) for the whole AML patient group in CR1 in the unfavorable risk group according to SWOG (SWOG 2). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] CR is crucial to their survival but is particularly hampered by the lack of objective randomized studies concerning its use. Previous studies regarding the effect of allo-hsct on OS for patients with AML in CR1 have demonstrated benefits to the unfavorable cytogenetic risk group [19], intermediate cytogenetic risk group [20], or for both such groups [21]. These had been undertaken by comparing the treatment efficacy with or without allo-hsct, taking into account donor availability or lack off for transplantation [19 21]. These studies are nowadays questionable because of the dated treatments used on patients years ago, which are now significantly divergent from current standards of therapeutic procedure [22 24]. Furthermore, the availability of MUD has now become widespread and the number of MUD-HSCT in individual centers exceeds the number of MSD-HSCT [13]. It should also be borne in mind doi: /ajh American Journal of Hematology, Vol. 90, No. 10, October

5 Grosicki et al. TABLE V. The Significance of Effects in Undergoing Allo-HSCT and Other Chosen Factors on the LFS and OS for the Whole AML Patient Group in CR1 and Subgroups as Determined by Univariate and Multivariate Analyses Group of patients Analysis LFS OS AML in CR1 The effect of allo-hsct by univariate analysis Favorable Favorable Factor (s) in the multivariate analysis Allo-HSCT (1) MDS (2) AML in CR1 after The effect of allo-hsct by univariate analysis Favorable Favorable induction DAC Factor (s) in the multivariate analysis Allo-HSCT(1), age (1), number of cycles (2) AML in CR1 age The effect of allo-hsct by univariate analysis Favorable Lack of benefits Factor (s) in the multivariate analysis Allo-HSCT (1) AML in CR1 age The effect of allo-hsct by univariate analysis Favorable Favorable Factor (s) in the multivariate analysis Allo-HSCT (1), MDS (2), number of cycles (2) Allo-HSCT (1), WBC (2), MDS (2) AML in CR1 SWOG 0 The effect of allo-hsct by univariate analysis Lack of benefits Lack of benefits Factor (s) in the multivariate analysis MDS (2) AML in CR1 SWOG 1 The effect of allo-hsct by univariate analysis favorable Lack of benefits Factor (s) in the multivariate analysis Allo-HSCT (1) MDS (2) AML in CR1 SWOG 2 The effect of allo-hsct by univariate analysis Favorable Favorable Factor (s) in the multivariate analysis Allo-HSCT (1) Allo-HSCT (1) AML: acute myeloid leukemia; CR1: first complete remission; LFS: leukemia free survival; OS: overall survival; allo-hsct: allogeneic hematopoietic stem cells transplantation; MDS: AML secondary to myelodysplastic syndrome; age: age at diagnosis; number of cycles: number of cycles of induction to achieve CR1; DAC: induction chemothepary regimen daunorubicin/cytarabine/cladribine; SWOG 0: favorable risk group according to SWOG; SWOG 1: intermediate risk group according to SWOG; SWOG 2: unfavorable risk group according to SWOG; (1) beneficial effect; (2) unfavorable effect. that the issue of choosing the most appropriate/unbiased methodology for evaluating the merits of treating patients, with or without transplantation, is still being hotly debated. This is related to the inherent ethical dilemma of randomizing individual AML patients to undergo or not undergo allo-hsct [25]. Until recently, the evaluation method most commonly proposed was to compare the divided groups on the grounds of donor availability (i.e., donor vs. no donor), as in the above-cited studies. This may to some extent counterbalance the lack of randomization in the patients therapeutic plan. It is however not possible to apply this method when dealing with the large number of patients present in the high risk group with early relapse, and performing allotransplantation in CR1, which often in the later stage of therapy is not possible. In such a patient group, the fact of finding an allogeneic donor may not be relevant for their prognosis. Another drawback of the allocation into donor versus no donor has become the more frequent use of a MUD, who most often cannot be identified at the time the allocation is made, which is ideal at the time of CR1. There are several methods proposed for taking into account the so-called guaranteed time until the moment of allo-hsct [26]. It seems that the most appropriate is in treating allo-hsct as a time-dependent variable developed by Mantel and Byar [27], which was used in this work for analyzing the comparison between allo-hsct vs. no allo-hsct. Previous studies comparing analyses of donor vs. no donor and allo-hsct vs. no allo- HSCT showed differences between the same groups of patients with AML, particularly in the high cytogenetic risk patient group [28,29]. The BMRC AML12 study results were analyzed by the donor vs. no donor and Mantel Byar methods [30]. No benefits of allo-hsct had been shown, both in the risk of relapse, LFS, and OS for patients with unfavorable karyotype using the donor vs. no donor analysis. However, with the Mantel Byar analysis, a significant improvement of LFS and OS was demonstrated after allo-hsct in the group of patients with AML with unfavorable karyotype aged below 45 years [30]. The presented study did not show any differences between OS after MSD-HSCT and MUD-HSCT for patients with AML in CR1, which is consistent with the findings of others [31 35]. Using the Mantel Byar approach, a significantly favorable effect of allo-hsct (following univariate analysis) on LFS and OS was demonstrated for the entire group of patients with AML in CR1 as well as in the subgroup of patients treated with DAC induction, thus confirming that the addition of cladribine to a standard chemotherapeutic treatment does not remove the benefits of allo-hsct (Table V). It is also worth noting that, from multivariate analysis, the case of MDS preceding AML turned out to be the only independent factor that adversely affected OS for the entire group of patients, while undergoing allo-hsct turned out to be the only factor that benefitted the LFS (Table III). There was no effect allo-hsct the OS for this analysis may be cause by the limitation of the work which is relatively low proportion of transplant patients (Tables I and III). The univariate analysis of those aged demonstrated that undergoing allo-hsct was only beneficial for LFS, as well as OS for the patient group aged (Table V). A similar observation of allo-hsct benefitting OS in patients aged was reported by Sakamaki et al. [36], but from a donor vs. no donor analysis. When multivariate analysis of factors influencing treatment results was performed on the group, only allo-hsct independently showed LFS and OS benefit. In the age group 41 60, allo-hsct and preceding MDS independently gave LFS benefit, while the number of inductions needed to obtain CR1 gave an adverse LFS (Table V). Within this group, undergoing allo-hsct gave OS benefit but a preceding MDS was adverse along with, in linear fashion, WBC at diagnosis. No benefits were demonstrated in LFS and OS for allo-hsct patients in the favorable cytogenetic risk group, which is consistent with other findings [31 34,37,38]. Also in these patients, multivariate analysis showed that only the preceding MDS independently had an adverse effect on LFS. In the AML group of intermediate cytogenetic risk, allo-hsct bore a significant LFS benefit. Undergoing allo-hsct was found by multivariate analysis to independently show LFS benefit, whereas a preceding MDS independently had an adverse effect on OS (Table V). Performing the allo-hsct in patients from the intermediate cytogenetic risk group requires that MDS preceding AML be taken into account. By far, patients presenting with adverse prognostic cytogenetic risk (Table I) [5] benefited most from allo-hsct. Performing allo-hsct significantly improved LFS and OS, and allo-hsct was the only independent factor demonstrating LFS and OS benefit in the multivariate analysis (Table V). Furthermore, undertaking allo-hsct decreased the risk of relapse and death by almost three times. The beneficial role of allo-hsct in the unfavorable cytogenetic risk group of patients is probably due to the AML in these patients having already developed from the lowest differentiated cells in normal hematopoiesis, which explains the inefficacy of standard chemotherapy in such cases [39]. 908 American Journal of Hematology, Vol. 90, No. 10, October 2015 doi: /ajh.24113

6 In the univariate analysis of CIR, performing allo-hsct in patients with AML turned out to significantly reduce the risk of relapse for the group of all patients with AML in CR1 and an unfavorable cytogenetic prognosis. CIR was also independently influenced by allo-hsct, patient age, and the number of courses of induction until CR1 following multidimensional analysis for the whole group of AML patients in CR1. AlloHSCT Importance for the Survival of Patients with AML For the NRM analysis, in univariate analysis undertaking allo- HSCT for treating patients with AML in CR1 reduced the risk of death in the entire group but, interestingly, also in patients aged 41 60, where our concerns about the safety of performing allo-hsct are greater. These findings are consistent with other studies [40]. Multivariate analysis did not confirm the impact of allo-hsct for NRM. References 1. Byrd JC, Mrozek K, Dodge RK, et al. 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