Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Poor-Prognosis Cytogenetics in First Complete Remission

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Conditioning intensity for allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with poor-prognosis cytogenetics in first complete remission Takaaki Konuma , Tadakazu Kondo , Shohei Mizuno , Noriko Doki , Jun Aoki , Takahiro Fukuda , Masatsugu Tanaka , Masashi Sawa , Yuta Katayama , Naoyuki Uchida , Yukiyasu Ozawa , Satoshi Morishige , Ken-ichi Matsuoka , Tatsuo Ichinohe , Makoto Onizuka , Junya Kanda , Yoshiko Atsuta , Masamitsu Yanada , Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation PII: DOI: Reference:

S1083-8791(19)30636-6 https://doi.org/10.1016/j.bbmt.2019.09.025 YBBMT 55736

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Biology of Blood and Marrow Transplantation

Received date: Accepted date:

7 August 2019 18 September 2019

Please cite this article as: Takaaki Konuma , Tadakazu Kondo , Shohei Mizuno , Noriko Doki , Jun Aoki , Takahiro Fukuda , Masatsugu Tanaka , Masashi Sawa , Yuta Katayama , Naoyuki Uchida , Yukiyasu Ozawa , Satoshi Morishige , Ken-ichi Matsuoka , Tatsuo Ichinohe , Makoto Onizuka , Junya Kanda , Yoshiko Atsuta , Masamitsu Yanada , Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation, Conditioning intensity for allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with poor-prognosis cytogenetics in first complete remission, Biology of Blood and Marrow Transplantation (2019), doi: https://doi.org/10.1016/j.bbmt.2019.09.025

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Highlights 

In comparison with reduced-intensity conditioning (RIC), myeloablative conditioning (MAC) reduced leukemia-related mortality and improved overall survival for patients with cytogenetically poor-risk AML undergoing allogeneic HCT during CR1.



In the subgroup analysis, these results applied to patients aged 16–59 years, with HCT-CI scores ≥3, and with cytogenetic remission.



Among MAC regimens, there was a trend for worse survival and non-relapse mortality with the busulfan/fludarabine-based regimen compared to the total body irradiation-based regimen.

Full Length Article

Conditioning intensity for allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with poor-prognosis cytogenetics in first complete remission

Running title: Conditioning intensity for HCT with poor-risk AML in CR1

Takaaki Konuma1, Tadakazu Kondo2, Shohei Mizuno3, Noriko Doki4, Jun Aoki5, Takahiro Fukuda5, Masatsugu Tanaka6, Masashi Sawa7, Yuta Katayama8, Naoyuki Uchida9, Yukiyasu Ozawa10, Satoshi Morishige11, Ken-ichi Matsuoka12, Tatsuo Ichinohe13, Makoto Onizuka14, Junya Kanda2, Yoshiko Atsuta15,16, Masamitsu Yanada17: Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation

1

Department of Hematology/Oncology, The Institute of Medical Science, The

University of Tokyo, Tokyo, Japan. 2

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto

University, Kyoto, Japan. 3

Division of Hematology, Department of Internal Medicine, Aichi Medical

University, Nagakute, Japan. 4

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases

Center, Komagome Hospital, Tokyo, Japan.

5

Department of Hematopoietic Stem Cell Transplantation, National Cancer

Center Hospital, Tokyo, Japan. 6

Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.

7

Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan.

8

Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb

Survivors Hospital, Hiroshima, Japan. 9

Department of Hematology, Toranomon Hospital, Tokyo, Japan.

10

Department of Hematology, Japanese Red Cross Nagoya First Hospital,

Nagoya, Aichi, Japan. 11

Division of Hematology and Oncology, Kurume University School of Medicine,

Kurume, Japan. 12

Department of Hematology and Oncology, Okayama University Graduate

School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. 13

Department of Hematology and Oncology, Research Institute for Radiation

Biology and Medicine, Hiroshima University, Hiroshima, Japan. 14

Department of Hematology and Oncology, Tokai University School of

Medicine, Isehara, Japan. 15

Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya,

Japan. 16

Department of Healthcare Administration, Nagoya University Graduate School

of Medicine, Nagoya, Japan. 17

Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya,

Japan.

Corresponding author: Takaaki Konuma, M.D., Ph.D., Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tel: +81-3-3443-8111, Fax: +81-3-5449-5429, E-mail: [email protected]

Abstract

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n=652) or reduced-intensity conditioning (RIC; n=188) between 2006 and 2017. The median age at HCT was 50.5 years (range: 16–77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P=0.011 and P=0.025, respectively). In the subgroup analysis, these results applied to

patients aged 16–59 years, with HCT-CI scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and non-relapse mortality with the busulfan/fludarabine-based regimen compared to the total body irradiation (TBI) ≥8 Gy-based regimen (P=0.082 and P=0.062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.

Keywords; allogeneic hematopoietic cell transplantation, poor-risk cytogenetics, acute myeloid leukemia, first complete remission, myeloablative conditioning, reduced-intensity conditioning.

Introduction

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative postremission therapy for patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) [1,2]. Allogeneic HCT, traditionally using myeloablative conditioning (MAC), has been restricted to younger patients due to concerns about the higher risk of non-relapse mortality (NRM). The introduction of reduced-intensity conditioning (RIC) has expanded the applicability of allogeneic HCT to older patients or those with comorbidities [3,4]. There have been several retrospective and a few prospective studies

comparing MAC with RIC allogeneic HCT [5–10]. Most of these studies have shown that RIC is associated with lower NRM but higher relapse, resulting in comparable survival in patients with AML [5–7], making it difficult to conclude which conditioning regimen should be the treatment choice. Meanwhile, it is well known that the risk of post-transplant relapse varies according to the cytogenetics at the time of diagnosis [11–13] and disease status at the time of HCT [14,15]. Therefore, the optimal intensity of conditioning regimen needs to be addressed based on not only age and comorbidities but also disease characteristics and risk for post-transplant relapse. However, comparative data of MAC and RIC in patients with poor-risk AML in CR1 is limited [16]. Here, we evaluate the effects of conditioning intensity on post-transplant outcomes by focusing on adult patients with AML harboring poor-risk cytogenetics in CR1. With this aim, we retrospectively analyzed the Japanese registry data of 840 such patients who underwent allogeneic HCT following MAC (n=652) and RIC (n=188) between 2006 and 2017.

Patients and methods

Data collection

This retrospective study was performed by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Data were obtained from the Transplant Registry Unified Management Program (TRUMP) of the Japanese Data Center for Hematopoietic Cell

Transplantation (JDCHCT) [17–19]. This study population consisted of patients aged 16 years or older with AML in CR1 who had poor-risk cytogenetics and received the first allogeneic HCT between 2006 and 2017 in Japan. This retrospective study was approved by the institutional review board at the Institute of Medical Science, The University of Tokyo (2019-23-0722).

Objectives and Definitions

The primary objective of this retrospective study was to assess the impact of conditioning intensity on overall survival (OS) among adult AML patients with poor-risk cytogenetics who received allogeneic HCT between 2006 and 2017. Poor-risk cytogenetics was defined according to the National Comprehensive Cancer Network (NCCN) Guidelines for AML [13,20]. The MAC regimen was defined according to the criteria proposed by the Center for International Blood and Marrow Transplant Research (CIBMTR), which included a regimen containing either total body irradiation (TBI) fractionated doses totaling ≥8 Gy, oral busulfan (BU) doses of ≥9 mg/kg, intravenous BU doses of ≥7.2 mg/kg, or melphalan (MEL) doses of ≥140 mg/m2. Other regimens were classified as reduced-intensity conditioning (RIC) [21]. OS was defined as the time from the date of HCT until death or last observation alive. Leukemia-related mortality was defined as death without remission or after hematological relapse. Non-relapse mortality (NRM) was defined as death without relapse after HCT. The degree of HLA matching was based on the antigenic levels for HLA-A, HLA-B, and HLA-DR loci for related donors, or the allele levels for HLA-A, HLA-B, and

HLA-DRB1 loci for unrelated adult donors. Pre‐existing comorbidities were assessed according to the HCT‐specific comorbidity index (HCT‐CI) [22]. Cytogenetic remission at the time of HCT was determined at each institution by karyotype analysis and/or fluorescence in situ hybridization (FISH) analysis.

Statistical analysis

Patients, disease, and transplant characteristics between groups were compared by using a chi-square test or Fisher's exact test for categorical variables and the Kruskal–Wallis test for continuous variables. The probability of OS was estimated according to the Kaplan–Meier method, and the log-rank test was used for comparison. The probability of leukemia-related mortality and NRM were estimated according to cumulative incidence curves, taking into account competing risks, and Gray’s test was used for comparison. For leukemia-related mortality, NRM was the competing risk, whereas for NRM, leukemia-related mortality was the competing risk. The Cox proportional hazards regression model for overall mortality (inverse of OS) or a Fine and Gray proportional hazards model for leukemia-related mortality and NRM was used to estimate hazard ratios (HRs) with a 95% confidence interval in the multivariate analysis. The following factors were included in the multivariate model: age (16–59 vs. ≥60 years), sex (male vs. female), HCT-CI score (0–2 vs. ≥3), prior history of myelodysplastic syndrome (MDS) (absence vs. presence), year of HCT (2006– 2011 vs. 2012–2017), donor (related vs. unrelated), and conditioning regimen (MAC vs. RIC). All P-values were two-sided. Data were analyzed by EZR

(Saitama Medical Center, Jichi Medical University, Saitama, Japan) [23], a graphical user interface for the R 3.5.3 software program (R Foundation for Statistical Computing, Vienna, Austria).

Results

Characteristics of patients, disease, and transplantation

A total of 840 patients met the study eligibility criteria. The median age at HCT was 50.5 years (range: 16–77 years), and 96 (12%) patients had an HCT-CI score ≥3. Among the entire cohort, 652 (78%) patients were treated with MAC and 188 (22%) patients with RIC. Characteristics of the patients are shown in Table 1. Compared to patients in the MAC group, patients in the RIC group were older and had a higher proportion of HCT-CI scores ≥3. Secondary AML, a history of MDS, and lower white blood cell (WBC) counts at diagnosis (<10000/μL) were more frequently present in the RIC group. Patients in the MAC group were more likely to have received calcineurin inhibitors and methotrexate for GVHD prophylaxis.

Survival, leukemia-related mortality, and NRM according to the conditioning intensity

With a median follow-up of 38 months (range, 1–151 months) for survivors in the entire cohort, the probability of OS at 3 years was 51% (95% confidence interval

[CI], 47–55%), and the cumulative incidences of leukemia-related mortality and NRM at 3 years were 24% (95% CI, 21–27%) and 26% (95% CI, 22–29%), respectively (Figure S1). According to the intensity of conditioning regimen, the probability of OS at 3 years was 54% (95% CI, 50–58%) for the MAC group and 40% (95% CI, 32– 47%) for the RIC group (P<0.001, Figure 1a). The cumulative incidence of leukemia-related mortality at 3 years was 21% (95% CI, 18–25%) for the MAC group and 31% (95% CI, 24–39%) for the RIC group (P=0.007, Figure 1b). The cumulative incidence of NRM at 3 years was 25% (95% CI, 21–28%) for the MAC group and 29% (95% CI, 22–36%) for the RIC group (P=0.170, Figure 1c). In the multivariate analysis, age older than 60 years (HR, 1.37; 95% CI, 1.07– 1.77; P=0.011), female sex (HR, 1.35; 95% CI, 1.05–1.74; P=0.019), HCT-CI scores ≥3 (HR, 0.67; 95% CI, 0.54–0.83; P<0.001), a history of MDS (HR, 1.54; 95% CI, 1.12–2.11; P=0.007), and RIC (HR, 1.37; 95% CI, 1.07–1.77; P=0.011) were significantly associated with overall mortality. A history of MDS (HR, 1.60; 95% CI, 1.02–2.52; P=0.039) and RIC (HR, 1.51; 95% CI, 1.05–2.17; P=0.025) were significantly associated with leukemia-related mortality. Age older than 60 years (HR, 1.44; 95% CI, 1.00–2.07; P=0.048) and female sex (HR, 0.57; 95% CI, 0.42–0.78; P<0.001) were significantly associated with NRM, but not conditioning regimen (HR, 1.08; 95% CI, 0.75–1.55; P=0.670) (Table S1). Donor source did not affect OS, leukemia-related mortality, or NRM in the univariate (Figure S2, Table 2) and multivariate analyses (Table S1).

Subgroup analyses for transplant outcomes

The intensity of conditioning regimen is usually determined by the institution’s policy based on age and/or comorbidities. Therefore, we performed subgroup analyses defined by age (16–59 and ≥60 years) and comorbidities (HCT-CI scores 0–2 and ≥3). Among patients aged 16–59 years, the probability of OS was higher in the MAC group compared with the RIC group (P=0.030, Figure S3a). The cumulative incidence of leukemia-related mortality, but not NRM, was lower in the MAC group compared with the RIC group (P=0.040, Figure S3b and S3c). However, these differences were not observed in patients older than 60 years (Figure S3d–f). Meanwhile, according to the HCT-CI score, the probability of OS was significantly higher in the MAC group compared with the RIC group in patients with both an HCT-CI score of 0–2 (P=0.001, Figure S4a) and ≥3 (P=0.014, Figure S4d). The cumulative incidence of leukemia-related mortality, but not NRM, was lower in the MAC group compared with the RIC group only among patients with HCT-CI scores ≥3 (P=0.008, Figure S4e). In the multivariate analysis, the intensity of conditioning regimen also significantly affected overall mortality and leukemia-related mortality only in patients aged 16–59 years and with HCT-CI scores ≥3 (Figure 2). Next, we evaluated whether the cytogenetic remission status at HCT was associated with outcomes among 757 patients with an evaluable cytogenetic status. In the univariate analysis, compared with the RIC group, the probability of OS was higher and the cumulative incidence of leukemia-related mortality was lower in the MAC group among patients with cytogenetic remission (Figure S5).

However, these differences were not observed in patients without cytogenetic remission (Figure S5). In the multivariate analysis, the intensity of conditioning regimen significantly affected overall mortality and leukemia-related mortality only in patients with cytogenetic remission (Figure 2).

Transplant outcomes according to type of MAC or RIC regimen

Finally, we evaluated differences in the outcomes according to the type of MAC regimen. For this purpose, the MAC regimen was categorized into TBI≥8Gy/cyclophosphamide (CY)+others (n=91), TBI≥8Gy/CY (n=181), TBI≥8Gy+others (n=27), BU3or4/CY±others (n=115), BU3or4/fludarabine (FLU)±others (n=168), and FLU/MEL≥140mg/m2±others (n=70). Given that there were no significant differences in transplant outcomes among TBI≥8Gy/CY+others, TBI≥8Gy/CY, and TBI≥8Gy+others (Figure 3a–c), these three groups were combined to form the group TBI≥8Gy-based regimen. In the univariate analysis, the probability of OS significantly differed among the four MAC groups (P=0.002, Figure 3d). Although there was no significant difference of leukemia-related mortality between the four MAC groups (P=0.801, Figure 3e), the cumulative incidence of NRM significantly differed among the four groups in the univariate analysis (P=0.013, Figure 3f). In the multivariate analysis, BU3or4/FLU±others showed a marginal significance for higher overall mortality (HR, 1.35; 95% CI, 0.96–1.91; P=0.082) and NRM (HR, 1.50; 95% CI, 0.97–2.31; P=0.062), when the TBI≥8Gy-based regimen was used as the reference group.

Compared with the MAC regimen, we also evaluated differences in the outcomes according to the type of RIC regimen. For this purpose, the RIC regimen was categorized into BU2/FLU±others (n=98), and FLU/MEL 80-120mg/m2±others (n=54). In the univariate analysis, the probability of OS significantly differed among the three groups (P<0.001, Figure 4a). The cumulative incidence of leukemia-related mortality (P=0.002, Figure 4b) and NRM (P=0.027, Figure 4c) also significantly differed among the three groups in the univariate analysis. When the MAC regimen was used as the reference group, BU2/FLU±others (HR, 1.40; 95% CI, 1.02–1.92; P=0.034) and FLU/MEL 80-120mg/m2±others (HR, 1.48; 95% CI, 1.01–2.19; P=0.044) were significantly associated with higher overall mortality in the multivariate analysis. BU2/FLU±others was significantly associated with higher leukemia-related mortality (HR, 1.73; 95% CI, 1.11–2.68; P=0.014), whereas FLU/MEL 80-120mg/m2±others showed a marginal significance for higher NRM (HR, 1.64; 95% CI, 0.97–2.79; P=0.062) in the multivariate analysis.

Discussion

Choosing the optimal conditioning regimen requires an appropriate balance between the risk of post-transplant relapse and that of NRM. We hypothesized that patients with poor-risk cytogenetics might benefit from a MAC regimen in terms of reducing the risk of relapse, whereas patients undergoing allogeneic HCT during CR1 might benefit from a RIC regimen in terms of reducing the risk

of NRM. Because of this contradictory situation, it has remained unclear whether patients with cytogenetically poor-risk AML in CR1 should be conditioned with MAC or RIC. Previous studies have failed to show any beneficial effects on survival of either type of conditioning regimen in patients with cytogenetically poor-risk AML undergoing allogeneic HCT during CR1 [8,16,24,25]. In contrast with these studies, our data, by focusing on this patient population, clearly demonstrated that MAC provides a lower leukemia-related mortality and better OS than RIC. AML is a disease that predominantly affects elderly individuals. Older patients with AML are more likely to have poor-risk cytogenetics, secondary AML, preceding MDS, and a high prevalence of comorbidity [26]. Indeed, our data showed that the ratio of patients aged 60 years or older was much higher in the RIC group than in the MAC group (54% vs 18%), and age older than 60 years was an independent factor for inferior OS and NRM. Moreover, an HCT-CI score of ≥3 was an independent factor associated with inferior OS and NRM among younger patients, but not older patients. Unexpectedly, donor source did not significantly affect the outcomes, which is not consistent with previous reports showing that MMUD, UCB, and haploidentical donors were significantly associated with higher NRM in patients with poor-risk AML in CR1 [24,25]. Taken together, our data suggest that patients with cytogenetically poor-risk AML in CR1 should preferentially be offered MAC if they are younger than 60 years, irrespective of donor source. Although a variety of MAC regimens were included in our study, the optimal intensity of conditioning regimen for cytogenetically poor-risk AML in CR1 needs

to be determined. Bredeson et al. prospectively compared the myeloablative intravenous BU vs. TBI in patients with myeloid malignancies undergoing allogeneic HCT and showed that an intravenous BU-based regimen was significantly associated with better survival than a TBI-based regimen in patients with AML [27]. In addition, Rambaldi et al. performed a prospective study comparing myeloablative BU/CY and BU/FLU in AML patients aged 40–65 years and showed that BU/FLU results in decreased NRM compared with BU/CY [28]. However, in our study, dealing with only patients with AML harboring poor-risk cytogenetics in CR1, compared with the TBI ≥8 Gy-based regimen, the myeloablative BU/CY-based regimen and myeloablative FLU/MEL-based regimen had a similar survival and NRM, but the myeloablative BU/FLU-based regimen had an inferior survival and NRM. Nevertheless, patients receiving the myeloablative BU/FLU-based regimen were older and had higher HCT-CI scores, which could have contributed to inferior survival and NRM in our study. Thus, it is difficult to draw definitive conclusions on the optimal MAC regimen for patients with cytogenetically poor-risk AML in CR1. Previous studies have shown that measurable residual disease (MRD) status is a significant risk factor for relapse after chemotherapy and allogeneic HCT in AML [29–31]. However, the impact of MRD status at the time of HCT on relapse according to intensity of conditioning regimen has not been fully investigated. Walter et al. reported that pre-HCT multiparameter flow cytometry-based MRD positivity is associated with higher relapse in AML after both MAC and RIC [30]. Recently, Gilleece et al. examined the association between MRD status, conditioning intensity, age, and outcomes after allogeneic HCT for AML in CR1

and found that MAC yields better survival and lower relapse than RIC only for patients younger than 50 years with detectable MRD at the time of HCT [31], while MRD was evaluated using a variety of molecular and/or immunophenotyping criteria. In contrast, while cytogenetic remission was determined at each institution by karyotype analysis and/or FISH analysis, our data demonstrated that the intensity of conditioning regimen significantly affected overall mortality and leukemia-related mortality only in patients with cytogenetic remission at the time of HCT, indicating that it is not advisable to choose RIC for these patients with a hope for decreased toxicity. On the other hand, for those with detectable MRD at the time of HCT, our data suggest that a higher intensity of conditioning regimen is not effective in preventing post-transplant relapse and underscore the need for the development of novel strategies to prevent post-transplant relapse. However, because the method of MRD measurement was not standardized in each study, further studies are required to clarify the association between method of MRD measurement and optimal intensity of conditioning regimen for patients with cytogenetically poor-risk AML in CR1. Our data had several limitations. First, this was a retrospective study based on registry data, and the selection of conditioning regimen was determined at the discretion of the treating physicians. This could have been a source of bias for our study. For example, better results with MAC than RIC for patients with HCT-CI scores ≥3 may reflect the selection bias. Nevertheless, our study provided the result of comparative data of MAC and RIC in a relatively large number of patients focusing on AML harboring poor-risk cytogenetics in CR1.

Second, the types of pre-transplant induction and consolidation chemotherapy could not be evaluated due to insufficient data. The intensity of pre-transplant chemotherapy may also affect the outcomes after allogeneic HCT for AML in CR1. Third, we were unable to evaluate the genetic mutation profiles, which could have affected the risk of post-transplant relapse. While acknowledging such limitations, the inclusion of a homogeneous patient population, i.e., adult patients with AML harboring poor-risk cytogenetics undergoing allogeneic HCT in CR1, represents a strength of this study and provides a good opportunity to evaluate the effects of conditioning intensity for this group of patients still having a poor prognosis after allogeneic HCT. In conclusion, our registry-based study showed that MAC, in comparison to RIC, reduced leukemia-related mortality and improved OS for patients with cytogenetically poor-risk AML undergoing allogeneic HCT during CR1. Prospective studies are needed to confirm this observation.

Acknowledgements

We thank all of the physicians and staff at the centers who provided the clinical data to the Transplant Registry Unified Management Program (TRUMP) of the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT). This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from Japan Agency for Medical Research and Development, AMED under Grant Number 18ek0510023h0002.

Conflict of Interest

The authors declare no competing financial interests.

Authorship Contributions

T Konuma designed the research, analyzed the data, performed the statistical analysis and wrote the first draft of the manuscript. T Kondo, SM, and MY contributed to the critical review of the manuscript. All the other authors contributed to data collection. All authors approved the final version.

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24. Gupta V, Tallman MS, He W, et al. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood. 2010;116:1839-1848. 25. Versluis J, Labopin M, Ruggeri A, et al. Alternative donors for allogeneic hematopoietic stem cell transplantation in poor-risk AML in CR1. Blood Adv. 2017;1:477-485. 26. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-3485. 27. Bredeson C, LeRademacher J, Kato K, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122:3871-3878. 28. Rambaldi A, Grassi A, Masciulli A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015;16:1525-1536. 29. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275-1291. 30. Walter RB, Gyurkocza B, Storer BE, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia. 2015;29:137-144.

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Figure legends

Figure 1. The probabilities of overall survival (OS) and the cumulative incidences of leukemia-related mortality and non-relapse mortality after allogeneic hematopoietic cell transplantation for cytogenetically poor-risk acute myeloid leukemia patients in first complete remission according to the intensity of conditioning regimen.

Figure 2. Forest plots for hazard ratios (HR) of overall mortality (a), leukemia-related mortality (b), and non-relapse mortality (c) in the overall cohort and subgroups according to age, HCT-CI score, and cytogenetic CR.

Figure 3. The probabilities of overall survival (OS) and the cumulative incidences of leukemia-related mortality and non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation for cytogenetically poor-risk acute myeloid leukemia patients in first complete remission according to the type of myeloablative conditioning regimen.

TBI, total body irradiation; CY, cyclophosphamide; BU, busulfan; FLU, fludarabine; MEL, melphalan.

Figure 4. The probabilities of overall survival (OS) and the cumulative incidences of leukemia-related mortality and non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation for cytogenetically poor-risk acute myeloid leukemia patients in first complete remission according to the type of myeloablative and individual reduced-intensity conditioning regimen. MAC, myeloablative conditioning; BU, busulfan; FLU, fludarabine; MEL, melphalan.

Table1. Characteristics of patients and transplantations.

Number of patients Age, years, median (range) * <60 years ≥60 years Gender Male Female PS 0,1 ≥2 Missing HCT-CI 0-2 ≥3 Missing CMV serostatus of recipients Positive Negative Missing

Entire cohort 840 50.5 (16-77) 619 (74%) 221 (26%)

MAC 652 47 (16-71) 532 (82%) 120 (18%)

RIC 188 60.5 (17-77) 87 (46%) 101 (54%)

P-value

500 (60%) 340 (40%)

382 (59%) 270 (41%)

118 (63%) 70 (37%)

0.313

797 (95%) 40 (5%) 3

622 (96%) 28 (4%) 2

175 (94%) 12 (6%) 1

0.244

683 (88%) 96 (12%) 61

544 (89%) 65 (11%) 43

139 (82%) 31 (18%) 18

0.012

666 (85%) 118 (15%) 56

522 (85%) 89 (15%) 41

144 (83%) 29 (17%) 15

0.472

<0.001 <0.001

Etiology of AML De novo Secondary Prior history of MDS MDS (-) MDS (+) WBC at diagnosis <100 ≥100 Missing Numbers of chemotherapy to enter CR1 1 cycle ≥2 cycles Missing Time from diagnosis to HCT <6 months ≥6 months Year of HCT 2006-2011 2012-2017 Donor source MRD MMRD MUD MMUD UCB Missing Use of ATG ATG (-) ATG (+) Conditioning TBI≥8Gy/CY+others TBI≥8Gy/CY TBI≥8Gy+others BU3or4/CY±others BU3or4/FLU±others FLU/MEL ≥140mg/m2±others BU2/FLU±others FLU/MEL 80-120 mg/m2±others Others GVHD Prophylaxis CI+MTX CI+MMF Others Cytogenetic status at the time of HCT Cytogenetic remission Cytogenetic nonremission

775 (92%) 65 (8%)

609 (93%) 43 (7%)

166 (88%) 22 (12%)

0.029

761 (91%) 79 (9%)

600 (92%) 52 (8%)

161 (86%) 27 (14%)

0.011

543 (66%) 285 (34%) 12

395 (61%) 248 (39%) 9

148 (80%) 37 (20%) 3

<0.001

523 (67%) 264 (33%) 53

418 (68%) 198 (32%) 36

105 (61%) 66 (39%) 17

0.120

496 (59%) 344 (41%)

389 (60%) 263 (40%)

107 (57%) 81 (43%)

0.502

324 (39%) 516 (61%)

244 (37%) 408 (63%)

80 (43%) 108 (57%)

0.204

185 (22%) 67 (8%) 203 (24%) 134 (16%) 247 (30%) 4

152 (24%) 49 (8%) 159 (25%) 105 (16%) 183 (28%) 4

33 (18%) 18 (10%) 44 (23%) 29 (15%) 64 (34%) 0

0.299

771 (92%) 69 (8%)

604 (93%) 48 (7%)

167 (89%) 21 (11%)

0.099

91 (11%) 181 (22%) 27 (3%) 115 (14%) 168 (20%) 70 (8%) 98 (12%) 54 (6%) 36 (4%)

91 (14%) 181 (28%) 27 (4%) 115 (18%) 168 (26%) 70 (11%) 0 0 0

0 0 0 0 0 0 98 (52%) 54 (29%) 36 (19%)

<0.001

684 (81%) 106 (13%) 50 (6%)

554 (85%) 69 (11%) 29 (4%)

130 (69%) 37 (20%) 21 (11%)

<0.001

640 117

497 (85%) 84 (15%)

143 (81%) 33 (19%)

0.190

83

Unknown

PS, performance status; HCT-CI, HCT-comorbidity index; CMV, cytomegalovirus; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; WBC, white blood cell; CR1, first complete remission; HCT, hematopoietic cell transplantation; MRD, matched related donor; MMRD, mismatched related donor; MUD, matched unrelated donor; MMUD, mismatched related donor; UCB, unrelated cord blood; ATG, antithymocyte globulin; TBI, total body irradiation; CY, cyclophosphamide; BU, busulfan; FLU, fludarabine; MEL, melphalan; GVHD, graft-versus-host disease; CI, calcineurin inhibitor; MTX, methotrexate; MMF, Mycophenolate mofetil; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning. The P values in bold are statistically significant (<0.05). *The 7 patients older than 70 years included MAC (n=1) and RIC (n=6) groups.

Table 2. Univariate analysis of overall survival (OS), leukemia-related mortality, and non-relapse mortality (NRM) at 3 years. OS Numbe r 840

% (95% CI) 51(47-55 )

<60 years

619

≥60 years

221

56(51-60 ) 37(30-44 )

Male

500

Female

340

0,1

797

≥2

40

0-2

683

≥3

96

Entire cohort Age

0.179 23(20-27)

0.182 23(19-26)

666

Negative

118

52(48-56 ) 52(42-61 )

0.884 23(19-26)

De novo

775

Secondary

65

52(48-56 ) 39(26-51 )

0.362 23(20-26)

0.266 25(22-28 ) 32(20-44 )

30(18-42) <0.001

0.665 26(22-29 ) 25(17-33 )

23(15-32) 0.060

Etiology of AML

0.006 24(21-28 ) 36(26-46 )

30(20-40) 0.582

Positive

0.237 25(22-28 ) 34(19-49 )

31(17-46) <0.001

CMV serostatus

<0.001 30(26-34 ) 19(15-23 )

23(18-27)

53(49-57 ) 35(25-45 )

0.001

0.374 24(20-29)

0.004

P-valu e

23(19-26 ) 34(27-40 )

29(23-36)

52(48-56 ) 35(20-50 )

% (95% CI) 26(22-29 )

0.033

<0.001

HCT-CI

P-valu e

22(18-25)

46(41-50 ) 59(53-64 )

PS

NRM

24(21-27) <0.001

Gender

Prior history

P-valu e

Leukemia-relate d mortality % (95% CI)

0.009

0.190

of MDS MDS (-)

761

MDS (+)

79

53(49-57 ) 32(21-43 )

22(19-25) 36(25-48) 0.193

WBC at diagnosis <100

543

≥100

285

50(45-54 ) 54(48-60 )

Numbers of chemotherap y to enter CR1

0.212 24(21-28)

523

≥2 cycles

264

57(53-62 ) 41(35-48 )

<6 months ≥6 months

496

20(16-23)

2006-201 1 2012-201 7

324

MRD

185

MMRD

67

MUD

203

MMUD

134

UCB

247

ATG (-)

771

ATG (+)

69

344

27(23-32)

516

0.385 22(18-27)

54(46-61 ) 49(35-61 ) 53(45-60 ) 53(43-61 ) 46(40-53 )

0.769 25(19-32)

21(15-27) 23(16-31) 25(20-31)

51(47-55 ) 54(40-65 )

Conditioning regimen

0.600 23(20-27)

652

RIC

188

54(50-58 ) 40(32-47 )

CI+MTX

684

CI+MMF

106

Others

50

52(48-56 ) 43(32-53 ) 51(35-64 )

0.170

0.007 21(18-25)

25(21-28 ) 29(22-36 )

31(24-39) 0.093

GVHD Prophylaxis

0.470 26(23-29 ) 20(11-31 )

26(16-38) <0.001

MAC

0.322 21(15-27 ) 29(18-40 ) 26(20-33 ) 24(17-33 ) 28(23-34 )

23(13-35)

0.863

Use of ATG

0.569 27(22-32 ) 25(21-29 )

24(20-29) 0.257

Donor source

23(19-27 ) 30(25-35 )

19(14-23)

51(46-57 ) 51(46-56 )

0.064

0.009

0.887

Year of HCT

23(20-27 ) 28(23-34 )

31(25-37)

50(45-55 ) 52(46-57 )

0.163

0.004

0.718

Time from diagnosis to HCT

0.864 26(22-30 ) 25(20-30 )

22(17-27) <0.001

1 cycle

25(22-28 ) 32(22-43 )

0.452 23(20-26) 30(20-40) 21(11-34)

0.511 25(22-28 ) 28(19-37 ) 28(16-42 )

PS, performance status; HCT-CI, HCT-comorbidity index; CMV, cytomegalovirus; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; WBC, white blood cell; CR1, first complete remission; HCT, hematopoietic cell transplantation; ATG, antithymocyte globulin; GVHD, graft-versus-host disease; MRD, matched related donor; MMRD, mismatched related donor; MUD, matched unrelated donor; MMUD, mismatched related donor; UCB, unrelated cord blood; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; CI, calcineurin inhibitor; MTX, methotrexate; MMF, Mycophenolate mofetil, CI, confidence interval. The P values in bold are statistically significant (<0.05).

Graphical Abstract