Development and validation of a comorbidity index for predicting survival outcomes after allogeneic stem cell transplantation in adult patients with acute leukemia: a Korean nationwide cohort study

Sung-Soo Park; Hee-Je Kim; Tong Yoon Kim; Joon yeop Lee; Jong Hyuk Lee; Gi June Min; Silvia Park; Jae-Ho Yoon; Sung-Eun Lee; Byung-Sik Cho; Ki-Seong Eom; Yoo-Jin Kim; Seok Lee; Dong-Wook Kim

doi:10.5045/br.2021.2021107

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Blood Res 2021; 56(3):

Published online September 30, 2021

https://doi.org/10.5045/br.2021.2021107

Development and validation of a comorbidity index for predicting survival outcomes after allogeneic stem cell transplantation in adult patients with acute leukemia: a Korean nationwide cohort study

Sung-Soo Park¹, Hee-Je Kim^1,2, Tong Yoon Kim¹, Joon yeop Lee¹, Jong Hyuk Lee¹, Gi June Min¹, Silvia Park¹, Jae-Ho Yoon^1,2, Sung-Eun Lee^1,2, Byung-Sik Cho^1,2, Ki-Seong Eom^1,2, Yoo-Jin Kim^1,2, Seok Lee^1,2, Dong-Wook Kim^1,2

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¹Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, ²Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to : Hee-Je Kim, M.D., Ph.D.
Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: cumckim@catholic.ac.kr

Received: May 29, 2021; Revised: July 14, 2021; Accepted: August 4, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background
Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment option for acute leukemia. We aimed to identify the comorbidity factors affecting survival outcomes after alloSCT and develop a new comorbidity index tool for predicting overall survival (OS).
Methods
A Korean nationwide cohort of 3,809 adults with acute leukemia treated with alloSCT between January 2002 and December 2018 was analyzed as the development cohort. A retrospective cohort comprising 313 consecutive adults with acute leukemia who underwent alloSCT between January 2019 and April 2020 was analyzed as the validation cohort.
Results
In the development cohort, advanced age, male sex, and comorbidities such as previous non-hematologic malignancy, hypertension, and coronary or cerebral vascular disease were significantly related to poor OS. Subsequently, a new comorbidity scoring system was developed, and risk groups were created, which included the low-risk (score ≤0.17), intermediate-risk (0.17< score ≤0.4), high-risk (0.4< score ≤0.55), and very high-risk (score ＞0.55) groups. The 1-year OS rates were discriminatively estimated at 73.5%, 66.2%, 61.9%, and 50.9% in the low-risk, intermediate-risk, high-risk, and very high-risk groups in the development cohort, respectively (P <0.001). The developed scoring system yielded discriminatively different 1-year OS rates and 1-year incidence of non-relapse mortality according to the risk group (P =0.085 and P=0.018, respectively). Furthermore, the developed model showed an acceptable performance for predicting 1-year non-relapse mortality with an area under the curve of 0.715.
Conclusion
The newly developed predictive scoring system could be a simple and reliable tool helping clinicians to assess risk of alloSCT in adults with acute leukemia.

Keywords Comorbidity, Allogeneic, Transplantation, Stem cell, Acute leukemia, Score

Article

Original Article

Blood Res 2021; 56(3): 184-196

Published online September 30, 2021 https://doi.org/10.5045/br.2021.2021107

Development and validation of a comorbidity index for predicting survival outcomes after allogeneic stem cell transplantation in adult patients with acute leukemia: a Korean nationwide cohort study

Correspondence to:Hee-Je Kim, M.D., Ph.D.
Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: cumckim@catholic.ac.kr

Received: May 29, 2021; Revised: July 14, 2021; Accepted: August 4, 2021

Abstract

Keywords: Comorbidity, Allogeneic, Transplantation, Stem cell, Acute leukemia, Score

Abstract

Fig 1.

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Figure 1.Flow diagram of the con-struction of the development and validation cohorts.
Abbreviation: KNHIS, Korean National Health Insurance Service.

Blood Research 2021; 56: 184-196https://doi.org/10.5045/br.2021.2021107

Fig 2.

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Figure 2.Kaplan-Meier analysis to calculate the overall survival rate in the development cohort.

Blood Research 2021; 56: 184-196https://doi.org/10.5045/br.2021.2021107

Fig 3.

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Figure 3.Probability of overall survival (OS) according to (A) decile risk scores and (B) the final risk groups in the development cohort. Using decile risk scores, we classified the patients into 10 groups: rank 1 (score ≤0.17), rank 2 (score, >0.17 and ≤0.26), rank 3 (score, >0.26 and ≤0.4), rank 4 (score, >0.4 and ≤0.55), rank 5 (score, >0.55 and ≤0.68), rank 6 (score, >0.68 and ≤0.81), rank 7 (score, >0.81 and ≤0.91), rank 8 (score, >0.91 and ≤1.08), rank 9 (score, >1.08 and ≤1.21), and rank 10 (>1.21). Based on the 5-year OS rates in each rank group, we then stratified the patients into 4 risk groups. The low-risk group included patients with rank 1; the intermediate-risk group included patients with ranks 2 and 3; the high-risk group included patients with rank 4; and the very high-risk group included patients with ranks 5, 6, 7, 8, 9, and 10. The log-rank test showed significant differences in the OS among the risk groups (P<0.001).

Blood Research 2021; 56: 184-196https://doi.org/10.5045/br.2021.2021107

Fig 4.

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Figure 4.Validation of the developed scoring system in the validation cohort. (A) The 1-year overall survival (OS) rate was divided according to the risk groups (P=0.085). The post-hoc analysis illustrated a better 1-year OS rate in the low- or intermediate-risk groups than that in the high- or very high-risk groups (P=0.018, * is indicated in the Fig. 1A for the pos-hoc analysis). (B) The cumulative incidence of non-relapse mortality (NRM) was significantly divided according to the risk groups (P=0.035), (C) whereas the cumulative incidence of relapse was not significantly different between the 4 risk groups (P=0.349). (D) A receiver operating characteristic curve analysis achieved an area under the curve (AUC) of 0.715 (95% CI, 0.658–0.772) for predicting NRM events 1-year post-allogeneic hematopoietic stem cell transplantation.

Blood Research 2021; 56: 184-196https://doi.org/10.5045/br.2021.2021107

Table 1 . Demographics of the cohorts..

Variables	Development cohort (N=3,809)	Validation cohort (N=313)
Age at alloSCT, median, years (range)	47 (18–74)	48 (18–74)
<30 years, no (%)	608 (16.0)	57 (18.2)
30–39 years, no (%)	614 (16.1)	60 (19.2)
40–49 years, no (%)	1,023 (26.9)	61 (19.5)
50–59 years, no (%)	1,072 (28.1)	78 (24.9)
60–69 years, no (%)	475 (12.5)	51 (16.3)
≥70 years, no (%)	17 (0.4)	6 (19.2)
Male, N (%)	2,055 (54.0)	152 (48.6)
Stem cell source
Bone marrow stem cell, N (%)	469 (12.3)	3 (1.0)
Mobilized peripheral blood stem cell, N (%)	3,246 (85.2)	310 (99.0)
Cord blood, N (%)	94 (2.5)	12 (3.8)
HCT-CI, median, points (range)	NA	2 (0–8)
0 (low-risk)	NA	89 (28.4)
1–2 (intermediate-risk)	NA	126 (40.3)
≥3 (high-risk)	NA	98 (31.3)
Previous non-hematologic malignancy (%)
Yes	387 (10.2)	20 (6.3)
No	3,422 (89.8)	293 (93.6)
Hypertension (%)
Yes	1,224 (32.1)	74 (23.6)
No	2,585 (67.9)	239 (76.4)
Diabetes (%)
Yes	1,125 (29.5)	43 (13.7)
No	2,684 (70.5)	270 (86.3)
Dyslipidemia (%)
Yes	2,135 (56.1)	43 (13.7)
No	1,674 (43.9)	270 (86.3)
Chronic obstructive pulmonary disease (%)
Yes	191 (5.0)	7 (2.2)
No	3,618 (95.0)	306 (97.8)
Cerebrovascular or cardiovascular disease (%)
Yes	166 (4.4)	25 (8.0)
No	3,643 (95.6)	288 (92.0)
Anxiety disorder (%)
Yes	900 (23.6)	46 (14.7)
No	2,909 (76.4)	267 (85.3)
Depression (%)
Yes	613 (16.1)	35 (11.2)
No	3,196 (83.9)	278 (88.8)

Abbreviations: alloSCT, allogeneic stem cell transplantation; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; NA, not available..

Table 2 . Univariable and multivariable analysis for comorbidities associated with overall survival in the development cohort..

Variables	N	Univariable analysis	P	Multivariable analysis	P
Variables	N	1-year OS rate (95% CI)	P	Hazard ratio (95% CI)	P
Age			<0.001
<50 years	2,245	71.8 (69.9–73.8)		1
50–64 years	1,438	64.1 (61.5–66.7)		1.228 (1.107–1.362)	<0.001
≥65 years	126	48.1 (39.6–58.4)		1.733 (1.340–2.232)	<0.001
Sex			<0.001
Female	1,754	69.1 (66.9–71.3)		1
Male	2,055	67.4 (65.3–69.6)		1.142 (1.038–1.255)	<0.001
Previous non-hematologic malignancy			0.002
No	3,422	69.1 (67.5–70.7)		1
Yes	387	60.3 (55.4–65.6)		1.182 (1.015–1.376)	0.031
Hypertension			<0.001
No	2,585	70.8 (69.0–72.6)		1
Yes	1,224	62.6 (59.8–65.5)		1.141 (1.026–1.268)	0.015
Diabetes			0.005
No	2,684	69.2 (67.4–71.0)		1
Yes	1,125	65.7 (62.9–68.7)		1.002 (0.899–1.117)	0.965
Dyslipidemia			0.007
No	1,674	70.1 (67.9–72.4)		1
Yes	2,135	66.6 (64.5–68.7)		1.036 (0.937–1.144)	0.486
Chronic obstructive pulmonary disease			0.21
No	3,618	68.4 (66.8–70.0)		NA
Yes	191	64.3 (57.4–71.9)		NA
Cerebrovascularor cardiovascular disease			<0.001
No	3,643	68.8 (67.2–70.4)		1
Yes	166	54.1 (46.6–62.9)		1.498 (1.212–1.848)	<0.001
Anxiety disorder and/or depression			0.006
No	3,501	68.8 (67.2–70.4)		1
Yes	308	60.8 (55.4–66.8)		1.176 (0.996–1.386)	0.055

Abbreviations: CI, confidence interval; NA, not available; OS, overall survival..

Table 3 . The final scoring model in the development cohort..

	Hazard ratio (95% CI)	Log_e value of hazard ratio
Age
<50 years	1 (reference)	0
50–64 years	1.228 (1.107–1.362)	0.21
≥65 years	1.733 (1.340–2.232)	0.55
Sex
Female	1 (reference)	0
Male	1.142 (1.038–1.255)	0.13
Previous non-hematologic malignancy
No	1 (reference)	0
Yes	1.182 (1.015–1.376)	0.17
Hypertension
No	1 (reference)	0
Yes	1.141 (1.026–1.268)	0.13
Cerebrovascular or cardiovascular disease		-
No	1 (reference)	0
Yes	1.498 (1.212–1.848)	0.4