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Better disease control before allogeneic stem cell transplantation is crucial to improve the outcomes of transplantation for acute myeloid leukemia patients with extramedullary disease

De novo acute myeloid leukemia (AML) with extramedullary disease (EMD) is defined as de novo-occurring sarcoma associated with the onset of AML. EMD presenting concurrently with marrow involvement requires systemic treatment directed at the underlying AML, including allogeneic hematopoietic cell transplantation (HCT) [1, 2]. Although AML patients with EMD undergo allogeneic HCT because of poor outcomes, AML with EMD has a similar post-transplant outcome compared with AML without EMD [3, 4]. Similar findings have been reported for AML patients with a history of central nervous system involvement, in which transplant outcomes were only related to the status of systemic disease at the time of HCT [5, 6]. The objective of this study was to analyze factors associated with the outcomes of allogeneic HCT, as well as cytogenetic and disease risks at HCT in AML patients with EMD to identify the potential clinical efficacy of allogeneic HCT and/or novel therapies.

A total of 9218 patients aged ≥20 years, who received a first allogeneic HCT for de novo AML from related or unrelated donors between January 2006 and December 2016, which had sufficient follow-up data, were eligible for the retrospective registry study in the Transplant Registry Unified Management Program [7]: 841 with EMD (EMD group) and 8377 without EMD (non-EMD group). The EMD site was determined by reporting in 10 categories. Pathological confirmation, including histology and immunohistochemistry or immunophenotype, or radiographic confirmation of EMD were included. Cytogenetics were classified according to the National Comprehensive Cancer Network guidelines for AML [8]. Because of the lack of data, FLT3-ITD/NPM1 were unavailable in this study. The primary outcome was overall survival (OS) after allogeneic HCT (defined as the time from HCT to death). Secondary endpoints included disease-free survival (DFS), incidence of relapse, and transplantation-related mortality (TRM; defined as any death in the first 35 days after HCT or any death after day 35 while in continuous remission). The percentages of patients who relapsed or were refractory to allogeneic HCT were determined (relapse). All data were censored at the date of the last reported follow-up. To accommodate competing risks, cumulative incidence curves for TRM and relapse of the two groups (EMD vs. non-EMD) were estimated, and their differences were compared using Gray’s test. Competing risk events for TRM and relapse were relapse and death, respectively. For each group, the Fine and Gray model was employed to evaluate the effects of patient-related and transplantation-related variables before HCT on TRM and relapse. To evaluate survival, Kaplan–Meier curves of the two groups were compared based on the log-rank test, and multivariate Cox regression analysis was performed for all and EMD groups. The Cox proportional hazard model included patient-related and transplantation-related variables before HCT. Covariates found to be significant in univariate analysis (p < 0.05) were included in the model. A two-sided p-value of <0.05 was considered to be statistically significant. All statistical analyses were performed using the Stata Version 14 statistical package (Stata Corporation, College Station, TX, USA) or EZR (Saitama Medical Center, http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0) [9].

Of the 9218 patients with de novo AML, 841 patients with EMD (9.1%) included nervous system (n = 288, 3.1%), skin and breast (n = 199, 2.1%), lymph nodes and spleen (n = 165, 1.7%), cardiopulmonary and mediastinum (n = 105, 1.1%), digestive system (n = 76, 0.8%), head and neck (n = 72, 0.7%), connective and soft tissue (n = 27, 0.2%), reproductive organs (n = 25, 0.2%), bones and joints (n = 22, 0.2%), and kidney, bladder, adrenal glands, and retroperitoneum (n = 9, 0.09%), and 8377 patients without EMD (90.8%) were identified (Supplemental Tables 1 and 2). The percentages of patients who had relapsed or refractory AML with EMD and died because of AML were higher in the EMD group compared with the non-EMD group (p < 0.001, Supplemental Tables 3 and 4). Normal and constitutional cytogenetics were the highest in the eight groups with and without EMD (Supplemental Table 5). According to EMD and disease risks at HCT, we divided the patients into four groups: EMD and complete remission (CR) [n = 393; first CR (CR1) n = 257, second CR (CR2) n = 136] or non-CR (n = 448), and non-EMD and CR (n = 4654; CR1 n = 3259, CR2 n = 1395) or non-CR (n = 3723) (Table 1). There was no significant difference in the cumulative incidence of TRM between EMD and non-EMD groups for patients with CR (p = 0.874; Supplemental Figure 1A). The cumulative incidence of TRM in patients with non-CR at HCT tended to be significantly higher in the non-EMD group (especially without nervous system involvement; p = 0.015, Supplemental Figure 6A) compared with the EMD group (p = 0.076, Supplemental Figure 2A). The Fine and Gray model showed that >60 years of age at HCT and Eastern Cooperative Oncology Group performance status (PS) PS ≥ 2 at HCT were significantly associated with TRM of AML patients with EMD (Supplemental Table 7). The cumulative incidence of relapse in patients with non-CR at HCT was significantly higher in the EMD group (especially without nervous system involvement, Supplemental Figure 6B) compared with the non-EMD group (p < 0.001, Supplemental Figure 2B). The Fine and Gray model showed that cytogenetic poor risk, CR at HCT, and ≥6 months from diagnosis to HCT were significantly associated with relapse of AML patients with EMD. Multivariate Cox regression analysis of AML patients with EMD showed that >60 years of age at HCT, PS ≥2 at HCT, and cytogenetic poor risk were independent predictors of poorer DFS and OS, and that CR at HCT was an independent predictor of better DFS and OS. The DFS and OS of patients with CR were similar between the two groups (log-rank, p = 0.934 and p = 0.586; Supplemental Figure 1C and D). DFS and OS of patients with non-CR were higher in the non-EMD group than in the EMD group (log-rank, p = 0.012 and p = 0.0068; Supplemental Figure 2C and D). OS of patients with non-CR were higher in the non-nervous group than in the nervous group (log-rank, p = 0.0098; Supplemental Figure 6D).

Bakst et al. recommend that AML patients with EMD undergo allogeneic HCT at the CR status because of poor outcomes [2]. The development of novel agents has allowed an increased rate of allogeneic HCT in the CR status pre-HCT without increasing relapse, but it might be controversial to use novel agents post-HCT because of their unknown effect on chronic GVHD and the protective effect of chronic GVHD on EMD relapse [10]. The median age of patients who undergo HCT has increased, and we have already reported that disease control at HCT and lower PS at HCT for older patients are important for de novo AML patients to improve outcomes after allogeneic HCT [11, 12].

In conclusion, our data suggest that allogeneic HCT can be considered for AML patients with EMD (Table 1). A cytogenetic poor risk may be an indicator of allogeneic HCT for these patients, especially in the non-CR status pre-HCT. Prospective trials of allogeneic HCT and new therapies with targeted agents, such as FLT3-ITD, are needed to improve the safety and efficacy of allografting, especially for the non-CR status of AML patients with EMD.

Table 1 Univariate outcome probabilities of patients with de novo AML with or without EMD according to the disease status at HCT

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Acknowledgements

We appreciate the patients and clinical staff for their participation in the study. We are very grateful to the Japanese Data Center for Hematopoietic Cell Transplantation for data management and the Clinical Research Institute of Kyushu Medical Hospital for their editorial support. This study was supported by The Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) of the Japan Agency for Medical Research and Development (AMED). We thank Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.

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Correspondence to Satoshi Yamasaki.

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This study was approved by the Data Management Committee of the Japanese Society for Hematopoietic Cell Transplantation and the Institutional Review Board of Kyushu Medical Center. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Yamasaki, S., Aoki, J., Mori, J. et al. Better disease control before allogeneic stem cell transplantation is crucial to improve the outcomes of transplantation for acute myeloid leukemia patients with extramedullary disease. Bone Marrow Transplant 55, 249–252 (2020). https://doi.org/10.1038/s41409-019-0527-z

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