
==== Front
Blood Adv
Blood Adv
Blood Advances
2473-9529
2473-9537
The American Society of Hematology

S2473-9529(24)00415-4
10.1182/bloodadvances.2024013442
Transplantation
Associations between acute and chronic graft-versus-host disease∗
Tamaki Masaharu m.tamaki.221@gmail.com
12∗
Akahoshi Yu akahoshiu@gmail.com
13∗∗
Inamoto Yoshihiro 4
Morita Kaoru 5
Uchida Naoyuki 6
Doki Noriko 7
Tanaka Masatsugu 8
Nishida Tetsuya 9
Ohigashi Hiroyuki 10
Nakamae Hirohisa 11
Onizuka Makoto 12
Katayama Yuta 13
Matsuoka Ken-ichi 14
Sawa Masashi 15
Ishimaru Fumihiko 16
Kanda Yoshinobu 15
Fukuda Takahiro 17
Atsuta Yoshiko 1819
Terakura Seitaro 20
Kanda Junya 21
1 Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
2 Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University Shimotsuke, Japan
3 Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
4 Department of Bone and Marrow Transplantation & Cellular Therapy, Fujita Health University School of Medicine, Toyoake, Japan
5 Division of Hematology, Jichi Medical University, Shimotsuke, Japan
6 Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan
7 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
8 Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
9 Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
10 Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
11 Department of Hematology, Osaka Metropolitan University Hospital, Osaka, Japan
12 Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
13 Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
14 Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
15 Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
16 Technical Department, Japanese Red Cross Society Blood Service Headquarters, Tokyo, Japan
17 Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
18 Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
19 Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
20 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
21 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
∗ Correspondence: Masaharu Tamaki, Division of Hematology, Jichi Medical University Saitama Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan; m.tamaki.221@gmail.com
∗∗ Yu Akahoshi, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place/Box 1128, New York, NY 10029; akahoshiu@gmail.com
14 7 2024
27 8 2024
14 7 2024
8 16 42504261
22 4 2024
25 6 2024
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
2024
The American Society of Hematology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Key Points

• The risk for chronic GVHD increased with each increment in the grade of acute GVHD.

• The preceding profiles of acute GVHD have the potential to help in predicting the future occurrence of chronic GVHD and its severity.

Visual Abstract

Abstract

Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD.
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pmcIntroduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is an intensive and curative treatment for various hematologic malignancies and hematopoietic dysfunctions. Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allo-HCT. In previous studies,1, 2, 3 the incidence of chronic GVHD has been reported to be 15% to 50%, and chronic GVHD has been shown to have a detrimental effect on the quality of life, functional status, and survival outcomes.4, 5, 6, 7, 8, 9, 10, 11, 12, 13

Previous studies have reported that recipient age,14, 15, 16, 17, 18, 19, 20 donor age,15,16,19 peripheral blood grafts,14, 15, 16,18,20, 21, 22, 23, 24 unrelated donor,15,16 female donor–male recipient combination,14, 15, 16,25, 26, 27 HLA disparity,14,23 in vivo T-cell depletion,14,17,28 and posttransplantation cyclophosphamide (PTCy)29, 30, 31 were associated with the risk for chronic GVHD. Several studies have also reported that antecedent acute GVHD was an independent risk factor for chronic GVHD.14,16,17,20,22,23,32 For example, 1 of the largest studies conducted by the Seattle group that analyzed only patients who underwent myeloablative conditioning regimens showed that only grade 3 to 4 acute GVHD, but not mild acute GVHD, increased the subsequent risk for chronic GVHD. However, several characteristics of acute GVHD, including the severity and involvement of specific organs, could potentially affect the subsequent risk for chronic GVHD differently in modern GVHD prophylaxis.

In this nationwide, retrospective study, we examined the influence of acute GVHD on chronic GVHD according to the acute GVHD profile. An increased understanding of the association between clinical acute and chronic GVHD would contribute to elucidating the underlying pathophysiology of chronic GVHD and help to identify potential candidates for early intervention for chronic GVHD.

Patients and methods

Donor source and patient selection

Clinical data were provided by the Transplantation Registry Unified Management Program of the Japanese Society for Transplantation and Cellular Therapy (JSTCT) and the Japanese Data Center for Hematopoietic Cell Transplantation.33,34

This study included adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, myeloproliferative neoplasm, malignant lymphoma, or multiple myeloma who underwent their first allo-HCT between 2010 and 2021.

This retrospective study was approved by the data management committee of the Transplantation Registry Unified Management Program and by the institutional review board of the Jichi Medical University Saitama Medical Center and was performed in accordance with the Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants.

Definitions

Acute GVHD and chronic GVHD were diagnosed and graded according to standard criteria.35,36 The severity of chronic GVHD was also evaluated based on the National Institutes of Health (NIH) criteria.37 The disease risk index and the hematopoietic cell transplantation–specific comorbidity index were classified according to previous reports.38,39 In terms of donor type, a related donor with 6 of 6 antigen matches for HLA-A, -B, and -DR was considered to be an HLA-matched related donor. A related donor with 1 antigen mismatch of HLA was considered to be a mismatched related donor, and a related donor with ≥2 antigen mismatches of HLA was a haploidentical donor. An unrelated donor with 8 of 8 allelic matches of HLA-A, -B, -C, and -DRB1 was classified as an HLA-matched unrelated donor, whereas all other voluntary donors were classified as an HLA-mismatched unrelated donor. Conditioning regimens were distinguished according to the criteria of the Center for International Blood and Marrow Transplant Research.40 In vivo T-cell depletion included the use of antithymocyte globulin and alemtuzumab.

Statistical analysis

The patients with complete information on all covariates were classified into the bone marrow and peripheral blood stem cell transplantation (BM/PB) cohort and the umbilical cord blood transplantation (UCB) cohort. Because UCB is not a common donor source outside of Japan,41 the UCB cohort was analyzed separately in the same manner as the BM/PB cohort as follows. The cumulative incidence of chronic GVHD that required systemic steroids was set as the primary end point to exclude mild cases that have minimal impact on survival and quality of life.5,7,42 Outcomes were assessed using a landmark point at day 100 after allo-HCT. Among the eligible patients (n = 27 610), 6857 cases with either mortality or disease progression before day 100 were excluded from the analysis. The previous occurrences of acute GVHD were classified based on the maximum GVHD grades and organ involvement by day 100. In all multivariate analyses, the cause-specific Cox proportional hazard regression model was used to evaluate the subsequent risk for chronic GVHD. In addition to acute GVHD profiles, the following covariates were adjusted for in the multivariate analyses: recipient’s age, sex mismatch, disease risk index, hematopoietic cell transplantation–specific comorbidity index, donor type, donor source, conditioning regimen, GVHD prophylaxis, and in vivo T-cell depletion. P values for each acute GVHD grade (grade 1 vs 2 and grade 2 vs 3-4) were adjusted using the Bonferroni method.

A 2-tailed P value <.05 was considered to be statistically significant. All analyses were performed using R, version 4.2.3 (The Foundation for Statistical Computing, Vienna, Austria) and EZR, which is a graphical user interface for R (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html, Jichi Medical University Saitama Medical Center, Saitama, Japan).43

Results

Patient characteristics

This study included 14 618 cases in the BM/PB cohort and 6135 cases in the UCB cohort (Table 1). The median age was 50 years (range, 16-80) in the BM/PB cohort and 55 years (range, 16-79) in the UCB cohort. A total of 1969 patients (13.5%) in the BM/PB cohort and 213 (3.5%) in the UCB cohort underwent in vivo T-cell depletion. Among the patients who underwent allo-HCT from haplo-identical donors (n = 1715), 1165 patients (67.9%) were treated with PTCy. The BM/PB cohort included 5750 cases (39.3%) of no acute GVHD, 3403 (23.3%) of grade 1, 3884 (24.6%) of grade 2, and 1581 (10.8%) of grade 3 to 4 acute GVHD, whereas the UCB cohort included 2229 (36.3%) cases of no acute GVHD, 1199 (19.5%) of grade 1, 1941 (31.6%) of grade 2, and 766 (12.5%) of grade 3 to 4 acute GVHD. The median duration of follow-up for survivors was 52.3 months (range, 3.4-152.8) in the BM/PB cohort and 46.0 months (range, 3.4-153.5) in the UCB cohort.Table 1. Patient characteristics

	BM/PB (n = 14 618)	UCB (n = 6135)			BM/PB (n = 14 618)	UCB (n = 6135)	
Age							
 >55 y	5 221 (35.7)	2956 (48.2)	Donor type	MRD	4 176 (28.6)	0 (0.0)	
 36-55 y	6 336 (43.3)	2235 (36.4)		MUD	5 214 (35.7)	0 (0.0)	
 16-35 y	3 061 (20.9)	944 (15.4)		MMUD	3 046 (20.8)	0 (0.0)	
Sex mismatch							
 FtoM	2 994 (20.5)	1749 (28.5)		1 locus MMRD	467 (3.2)	0 (0.0)	
 Others	11 624 (79.5)	4386 (71.5)		Haploidentical	1 715 (11.7)	0 (0.0)	
Disease							
 AML	6 041 (41.3)	3036 (49.5)		UCB	0 (0.0)	6135 (100.0)	
 ALL	2 949 (20.2)	1033 (16.8)	Donor source	BM	8 818 (60.3)	0 (0.0)	
 MDS	2 284 (15.6)	830 (13.5)		PB	5 800 (39.7)	0 (0.0)	
 MPN	871 (6.0)	231 (3.8)		UCB	0 (0.0)	6135 (100.0)	
 ML	2 372 (16.2)	975 (15.9)	Conditioning	MAC	9 592 (65.6)	3776 (61.5)	
 MM	101 (0.7)	30 (0.5)		RIC	5 026 (34.4)	2359 (38.5)	
Disease risk index							
 Low	1 104 (7.6)	345 (5.6)	GVHD prophylaxis	CsA based	4 000 (27.4)	1192 (19.4)	
 Intermediate	88 00 (60.2)	3030 (49.4)		TAC based	10 618 (72.6)	4943 (80.6)	
 High	3 789 (25.9)	2190 (35.7)	In vivo T-cell depletion		1 969 (13.5)	213 (3.5)	
 Very high	761 (5.2)	526 (8.6)	SCT year	2010-2015	7 056 (48.3)	2261 (36.9)	
HCT-CI							
 0-1	11 235 (76.9)	4430 (72.2)		2016-2021	7 562 (51.7)	3874 (63.1)	
 ≥2	3 312 (22.7)	1659 (27.0)					
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CsA, cyclosporin; FtoM, female-to-male; HCT-CI, hematopoietic cell transplantation–specific comorbidity index; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; ML, malignant lymphoma; MM, multiple myeloma; MMRD, mismatched related donor; MMUD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor; 1-locus MMRD, 1-locus mismatched related donor; RIC, reduced intensity conditioning; SCT, stem cell transplantation; TAC, tacrolimus.

Risk factors for chronic GVHD that require systemic steroids

The 4-year cumulative incidence of chronic GVHD that requires systemic steroids in the BM/PB cohort was 18.4% for grade 0, 23.1% for grade 1, 30.7% for grade 2, and 28.0% for grade 3 to 4 acute GVHD (Figure 1A), whereas the 4-year cumulative incidence in the UCB cohort was 8.0% for grade 0, 10.6% for grade 1, 17.9% for grade 2, and 18.3% for grade 3 to 4 acute GVHD (Figure 1B).Figure 1. Cumulative incidence of chronic GVHD requiring systemic steroids. (A) BM/PB cohort. (B) UCB cohort. The plots show the results using Gray’s test.

In the multivariate analyses that did not include acute GVHD as a covariate in the BM/PB cohort, younger age, female-to-male sex mismatch, donor type, PB, and the use of in vivo T-cell depletion were associated with the risk for chronic GVHD (Table 2). After adjusting for the baseline characteristics, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between grade 2 and grade 3 to 4 acute GVHD (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0; Table 2; Figure 2A). The interaction between acute GVHD and donor source (BM vs PB) was not statistically significant (interaction P value = .054).Table 2. Multivariate analysis of chronic GVHD with systemic steroid therapy in the BM/PB cohort

Risk factors	Adjustment for acute GVHD	
No	Yes	
HR (95% CI)	P value	HR (95% CI)	P value	
Acute GVHD					
 None	NA	NA	Reference	1.0	
 Grade 1	NA	NA	1.32 (1.19-1.46)	<.001	
 Grade 2	NA	NA	1.86 (1.70-2.04)	<.001	
 Grade 3-4	NA	NA	1.90 (1.69-2.14)	<.001	
Age					
 ≤56 y	1.06 (0.97-1.15)	.19	1.08 (0.99-1.18)	.074	
 36-55 y	Reference	1.0	Reference	1.0	
 16-35 y	0.78 (0.71-0.86)	<.001	0.78 (0.71-0.86)	<.001	
Sex mismatch					
 Match or male-to-female	Reference	1.0	Reference	1.0	
 Female-to-male	1.49 (1.37-1.61)	<.001	1.49 (1.38-1.62)	<.001	
Disease risk index					
 Low	Reference	1.0	Reference	1.0	
 Intermediate	0.94 (0.82-1.08)	.37	0.95 (0.83-1.09)	.46	
 High	1.03 (0.89-1.19)	.72	1.01 (0.88-1.17)	.89	
 Very high	0.95 (0.77-1.17)	.62	0.91 (0.74-1.12)	.39	
HCT-CI					
 0-1	Reference	1.0	Reference	1.0	
 ≥2	1.00 (0.92-1.09)	.92	1.01 (0.93-1.1)	.81	
Donor type					
 Matched related	Reference	1.0	Reference	1.0	
 Matched unrelated	0.96 (0.85-1.09)	.53	0.9 (0.79-1.02)	.10	
 Mismatched unrelated	1.12 (0.98-1.29)	.097	1.01 (0.87-1.16)	.95	
 1-locus MMRD	1.04 (0.84-1.28)	.73	0.95 (0.76-1.17)	.61	
 Haploidentical	0.63 (0.54-0.73)	<.001	0.61 (0.52-0.71)	<.001	
Donor source					
 BM	Reference	1.0	Reference	1.0	
 PB	1.26 (1.14-1.39)	<.001	1.25 (1.13-1.38)	<.001	
Conditioning regimen					
 MAC	Reference	1.0	Reference	1.0	
 RIC	0.89 (0.82-0.97)	.0080	0.89 (0.82-0.97)	.0095	
GVHD prophylaxis					
 CsA based	Reference	1.0	Reference	1.0	
 TAC based	1.01 (0.91-1.12)	.82	1.06 (0.95-1.17)	.29	
In vivo T-cell depletion					
 No	Reference	1.0	Reference	1.0	
 Yes	0.71 (0.63-0.80)	<.001	0.72 (0.64-0.81)	<.001	
Abbreviations are explained in Table 1.

NA, Not available.

Figure 2. Associations between acute and each subtype of chronic GVHD. (A) Chronic GVHD requiring systemic steroids in the BM/PB cohort. (B) Chronic GVHD requiring systemic steroids in the UCB cohort. (C) Lung chronic GVHD. (D) Extensive skin chronic GVHD. (E) NIH criteria–based moderate or severe chronic GVHD in the BM/PB cohort. (F) NIH criteria–based severe chronic GVHD in the BM/PB cohort. Ref, reference.

Similarly, in the UCB cohort, the subsequent risk for chronic GVHD that requires systemic steroids significantly increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [HR, 1.38; 95% CI, 1.08-1.76; P = .0092]; grade 1 vs 2 [HR, 1.73; 95% CI, 1.39-2.15; P < .001]), but this trend was not observed when grade 2 acute GVHD was compared with grade 3 to 4 acute GVHD (HR, 1.14; 95% CI, 0.92-1.40; P = .460; Table 3; Figure 2B).Table 3. Multivariate analysis of chronic GVHD with systemic steroid therapy in the UCB cohort

Risk factors	Adjustment for acute GVHD	
No	Yes	
HR (95% CI)	P value	HR (95% CI)	P value	
Acute GVHD					
 None	NA	NA	Reference	1.0	
 Grade 1	NA	NA	1.38 (1.08-1.76)	.0092	
 Grade 2	NA	NA	2.38 (1.97-2.88)	<.001	
 Grade 3-4	NA	NA	2.71 (2.14-3.41)	<.001	
Age					
 ≤56 y	1.09 (0.91-1.29)	.35	1.06 (0.90-1.27)	.48	
 36-55 y	Reference	1.0	Reference	1.0	
 16-35 y	0.89 (0.71-1.12)	.32	0.88 (0.70-1.11)	.29	
Sex mismatch					
 Match or male-to-female	Reference	1.0	Reference	1.0	
 Female-to-male	1.08 (0.92-1.27)	.36	1.12 (0.95-1.31)	.17	
Disease risk index					
 Low	Reference	1.0	Reference	1.0	
 Intermediate	0.88 (0.64-1.19)	.40	0.91 (0.67-1.24)	.56	
 High	0.81 (0.59-1.11)	.19	0.81 (0.59-1.11)	.19	
 Very high	0.91 (0.62-1.33)	.62	0.93 (0.63-1.36)	.70	
HCT-CI					
 0-1	Reference	1.0	Reference	1.0	
 ≥2	1.00 (0.85-1.19)	.97	0.98 (0.82-1.16)	.78	
Conditioning regimen					
 MAC	Reference	1.0	Reference	1.0	
 RIC	0.76 (0.65-0.90)	.0018	0.81 (0.69-0.96)	.016	
GVHD prophylaxis					
 CsA based	Reference	1.0	Reference	1.0	
 TAC based	1.21 (0.99-1.48)	.065	1.25 (1.02-1.53)	.029	
In vivo T-cell depletion					
 No	Reference	1.0	Reference	1.0	
 Yes	0.74 (0.47-1.18)	.21	0.74 (0.47-1.18)	.20	
Abbreviations are explained in Table 1.

We also evaluated the how organ involvement during acute GVHD affected the risk for chronic GVHD that requires systemic steroids. Involvement of the skin, gastrointestinal system, and liver carried a similar risk for chronic GVHD in the BM/PB cohort (skin [HR, 1.28; 95% CI, 1.11-1.47; P < .001]; gut [HR, 1.24; 95% CI, 1.13-1.37; P <.001]; liver [HR, 1.24; 95% CI, 1.06-1.46; P = .0094]; supplemental Table 1). Moreover, the skin (HR, 1.61; 95% CI, 1.25-2.07; P < .001) and gut (HR, 1.26; 95% CI, 1.08-1.47; P = .003), but not the liver (HR, 0.93; 95% CI, 0.40-2.12; P = .863) during acute GVHD were associated with an increased risk for lung chronic GVHD. Involvement of any of these 3 organs during acute GVHD, particularly skin involvement, were also associated with the risk for extensive skin chronic GVHD44 (skin [HR, 1.90; 95% CI, 1.51-2.39; P < .001]; gut [HR, 1.18; 95% CI, 1.03-1.34; P = .017]; liver [HR, 1.43; 95% CI, 1.14-1.78; P = .0017]).

Association of the severity between acute and chronic GVHD

Associations between the severity of acute and chronic GVHD were examined only in the BM/PB cohort because of a limited number of events in the UCB cohort. Lung chronic GVHD, manifesting as bronchiolitis obliterans syndrome, is considered a high-risk manifestation that is associated with poor outcomes. We first evaluated the impact of the grade of acute GVHD on the risk for lung chronic GVHD. The 4-year cumulative incidence of lung chronic GVHD was 6.7% in grade 0, 8.8% in grade 1, 9.6% in grade 2, and 10.1% in grade 3 to 4 acute GVHD (Figure 3A). In a multivariate analysis, the eventual HR for the risk for lung chronic GVHD increased with each increase in the grade of acute GVHD (grade 1: HR, 1.34; grade 2: HR, 1.48; grade 3-4: HR, 1.72), but the differences among grade 1 to 4 were not statistically significant (grade 1 vs 2 [HR, 1.10; 95% CI, 0.94-1.29; P = .468]; grade 2 vs 3-4 [HR, 1.16; 95% CI, 0.96-1.41; P = .252]; Figure 2C; supplemental Table 2).Figure 3. Cumulative incidence of each subtype of chronic GVHD in the BM/PB cohort. (A) Lung chronic GVHD. (B) Extensive skin chronic GVHD. (C) NIH criteria–based moderate or severe chronic GVHD. (D) NIH criteria–based severe chronic GVHD. The plots show the results using Gray’s test.

Similarly, we evaluated the impact of acute GVHD on the risk for extensive skin chronic GVHD,44 because this is another phenotype that increases the risk for nonrelapse mortality (NRM).7,8 The 4-year cumulative incidence of extensive skin chronic GVHD is 7.5% in grade 0, 10.0% in grade 1, 15.0% in grade 2, and 14.3% in grade 3 to 4 acute GVHD (Figure 3B). The risk for extensive skin chronic GVHD was increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [HR, 1.34; 95% CI, 1.16-1.55; P < .001]; grade 1 vs 2 [HR, 1.57; 95% CI, 1.37-1.81; P < .001]), but the risk was equivalent between grade 2 and grade 3 to 4 acute GVHD (HR, 1.07; 95% CI, 0.91-1.25; P = 1.0; Figure 2D; supplemental Table 2).

We also evaluated the impact of the grade of acute GVHD on the severity of chronic GVHD assessed using the NIH criteria for the recent BM/PB cohort, included between 2019 and 2021, for which information on severity was available in our database. The 2-year cumulative incidence of moderate or severe chronic GVHD was 14.0% in grade 0, 13.5% in grade 1, 21.0% in grade 2, and 23.3% in grade 3 to 4 acute GVHD (Figure 3C). In a multivariate analysis, the risk for moderate or severe chronic GVHD significantly increased in patients with grade 2 (HR, 1.53; 95% CI, 1.25-1.88; P < .001) and those with grade 3 to 4 acute GVHD (HR, 1.94; 95% CI, 1.49-2.52; P < .001), but the difference between grade 2 and grade 3 to 4 was not statistically significant (HR, 1.26; 95% CI, 0.96-1.66; P = .179; Table 4; Figure 2E).Table 4. Multivariate analysis of chronic GVHD according to NIH criteria in the BM/PB cohort

Risk factors	Moderate/Severe	Severe	
HR (95% CI)	P value	HR (95% CI)	P value	
Acute GVHD					
 None	Reference	1.0	Reference	1.0	
 Grade 1	0.93 (0.74-1.18)	.57	1.18 (0.80-1.72)	.41	
 Grade 2	1.53 (1.25-1.88)	<.001	1.55 (1.09-2.21)	.014	
 Grade 3-4	1.94 (1.49-2.53)	<.001	2.65 (1.76-3.98)	<.001	
Age					
 ≤56 y	1.16 (0.95-1.42)	.14	1.25 (0.90-1.73)	.18	
 36-55 y	Reference	1.0	Reference	1.0	
 16-35 y	0.90 (0.70-1.15)	.40	1.06 (0.71-1.58)	.76	
Sex mismatch					
 Match or male-to-female	Reference	1.0	Reference	1.0	
 Female-to-male	1.14 (0.93-1.40)	.21	1.04 (0.73-1.47)	.83	
Disease risk index					
 Low	Reference	1.0	Reference	1.0	
 Intermediate	0.87 (0.63-1.20)	.39	0.93 (0.54-1.58)	.78	
 High	0.84 (0.59-1.18)	.31	0.93 (0.52-1.66)	.81	
 Very high	0.68 (0.37-1.22)	.19	1.39 (0.62-3.11)	.43	
HCT-CI					
 0-1	Reference	1.0	Reference	1.0	
 ≥2	1.03 (0.85-1.25)	.77	1.06 (0.78-1.46)	.70	
Donor type					
 Matched related	Reference	1.0	Reference	1.0	
 Matched unrelated	1.16 (0.87-1.55)	.31	1.77 (1.10-2.86)	.020	
 Mismatched unrelated	1.19 (0.86-1.65)	.29	1.82 (1.06-3.13)	.031	
 1-locus MMRD	0.74 (0.34-1.59)	.44	1.11 (0.34-3.66)	.86	
 Haploidentical	0.63 (0.47-0.86)	.0038	0.75 (0.44-1.25)	.27	
Donor source					
 BM	Reference	1.0	Reference	1.0	
 PB	1.33 (1.07-1.64)	.010	1.76 (1.24-2.50)	.0016	
Conditioning regimen					
 MAC	Reference	1.0	Reference	1.0	
 RIC	0.91 (0.75-1.11)	.36	0.88 (0.64-1.22)	.45	
GVHD prophylaxis					
 CsA based	Reference	1.0	Reference	1.0	
 TAC based	1.00 (0.77-1.29)	.97	0.99 (0.64-1.54)	.97	
In vivo T-cell depletion					
 No	Reference	1.0	Reference	1.0	
 Yes	0.77 (0.6-0.99)	.039	0.41 (0.25-0.67)	<.001	
Abbreviations are explained in Table 1.

The 2-year cumulative incidence of severe chronic GVHD was 4.7% in grade 0, 5.5% in grade 1, 7.1% in grade 2, and 10.3% in grade 3 to 4 acute GVHD (Figure 3D). A multivariate analysis showed that grade 2 to 4 acute GVHD was significantly associated with a higher risk for severe chronic GVHD (grade 2: HR, 1.55; 95% CI, 1.09-2.21; P = .014; grade 3-4: HR, 2.64; 95% CI, 1.76-3.98; P < .001; Table 4; Figure 2F). Remarkably, we detected a significant difference between grade 2 and grade 3 to 4 acute GVHD in terms of the risk for severe chronic GVHD (HR, 1.70; 95% CI, 1.12-2.58; P = .025).

Survival outcomes from the treatment initiation of chronic GVHD

We evaluated the impact of acute GVHD on NRM and overall survival (OS) only among patients in the BM/PB cohort with chronic GVHD that required systemic steroids. The cumulative incidence of NRM within 4 years was 22.8% in grade 0, 21.9% in grade 1, 24.1% in grade 2. and 41.1% in grade 3 to 4 acute GVHD (supplemental Figure A), whereas 4-year OS was 65.8% in grade 0, 67.0% in grade 1, 65.6% in grade 2, and 51.2% in grade 3 to 4 acute GVHD (supplemental Figure B). In the multivariate analysis, only grade 3 to 4 had an adverse impact on NRM (HR, 2.28; 95% CI, 1.86-2.79; P < .001) and OS (HR, 1.80; 95% CI, 1.51-2.16; P < .001; supplemental Table 3).

Discussion

This study elucidated the close association between acute and chronic GVHD. In this large Japanese cohort, baseline characteristics, including recipient's age, donor type, sex mismatch, PB, and the use of in vivo T-cell depletion, were associated with the risk for chronic GVHD that requires systemic steroids, which is consistent with previous studies.14, 15, 16,28 The risk for chronic GVHD that requires systemic steroids increased with each increase in GVHD grade among grade 0, 1, and 2 to 4 in the BM/PB cohort, and these findings were also confirmed in the UCB cohort. Moreover, we found that the risk for severe chronic GVHD, as assessed by the NIH criteria, was significantly higher among those with grade 3 to 4 acute GVHD, indicating a strong association between the severity of acute and chronic GVHD.

Severe chronic GVHD remains one of the most morbid complications after allo-HCT.1,8 Specifically, lung chronic GVHD, often referred to as bronchiolitis obliterans syndrome, is 1 of the most devastating subtypes of chronic GVHD.37 Although several treatment options have become available for chronic GVHD, long-term survival remains unsatisfactory.6, 7, 8,45,46 In particular, it is challenging to ameliorate organ dysfunction after the involved organs of chronic GVHD progress to fibrosis. Therefore, early interventions before progression to fibrosis are potential treatment strategies for chronic GVHD. Notably, the subsequent risk for severe chronic GVHD increased commensurately with the severity of acute GVHD, whereas the adjustment for the grade of acute GVHD showed no remarkable influence on other risk factors of chronic GVHD. Furthermore, we found that previous severe acute GVHD exhibited a notable adverse impact on survival outcomes among patients who developed chronic GVHD that required systemic steroids. This was not shown in the previous studies, which did not account for the severity of previous acute GVHD.47,48 Although a history of acute GVHD alone is not a sufficient trigger to initiate early interventions, the inclusion of a history of acute GVHD could enhance the predictive accuracy of models for chronic GVHD that include baseline characteristics (eg, PB or sex mismatch) and potential biomarkers.49 Therefore, these findings might help to identify potential candidates who could benefit from early treatment interventions.

Although the pathophysiological mechanism between acute and chronic GVHD has not been fully elucidated, thymus damage caused by acute GVHD might contribute to the development of chronic GVHD. Various studies using mouse models have suggested that damaged thymus caused by acute GVHD impairs negative selection, thereby inducing chronic GVHD.50, 51, 52, 53, 54 Although the thymus in human adults is gradually replaced by fat, rebound thymic hyperplasia is observed after chemotherapy until the patient is ∼35 years old.55 Furthermore, a recent retrospective study suggested that there is residual thymic function after thymus atrophy in older adults.56 Our study demonstrated a reduced risk for chronic GVHD in younger patients (<36 years) before complete thymus atrophy, indicating that the reserved functionality of the thymus in this population might help to avoid the development of chronic GVHD. These findings partially support the notion that impaired thymus function caused by acute GVHD may underlie the mechanism of chronic GVHD. One of the other potential explanations is the involvement of dysbiosis. One study suggested that dysbiosis is associated with the incidence of chronic GVHD.57 Dysbiosis caused by previous acute GVHD might induce subsequent chronic GVHD.58 Prolonged use of calcineurin inhibitors for acute GVHD might also inhibit immune tolerance and induce chronic GVHD.59,60 Although further investigations are required, our findings might serve as a basis for exploring the underlying pathophysiological mechanisms in acute and chronic GVHD.

This study had several limitations. First, some subgroup analyses, including the association between the severity of acute and chronic GVHD assessed by the NIH criteria in the UCB cohort, could not be performed because of the small sample size. Second, although several biomarkers have the potential to predict the future occurrence of chronic GVHD and its outcomes,61, 62, 63, 64, 65, 66, 67, 68 serum samples were not available in our database. Third, our registry lacked data on late acute GVHD, which is increasing according to the recent changes in practice.69 For instance, late acute GVHD can sometimes develop into chronic GVHD overlapped by acute GVHD (progressive onset). Our study could not include such scenarios in the analysis. Fourth, the study included a limited number of patients who received PTCy as GVHD prophylaxis, all of whom underwent allo-HCT from haplo-identical donors because the use of PTCy in nonhaplo-identical settings was not permitted in Japan during the study period.

In conclusion, grade 2 to 4 acute GVHD was significantly associated with an increased risk for chronic GVHD. In addition, our study suggested that the risk for severe chronic GVHD correlated with the severity of acute GVHD. Although our findings should be validated in other retrospective and prospective cohorts, the preceding profiles of acute GVHD have the potential to help in predicting the future occurrence of chronic GVHD and its severity, which could facilitate the development of treatment strategies for chronic GVHD.

Conflict-of-interest disclosure: M. Tamaki reports receiving honoraria from Astellas Pharma and Kyowa Kirin. Y. Kanda reports receiving honoraria from Pfizer, Sumitomo Pharma, Novartis Pharma, Sanofi K.K., Chugai Pharmaceutical, SymBio Pharmaceuticals, Bristol Myers Squibb, Janssen Pharmaceutical K.K., Asahi Kasei Pharma, MSD, Astellas Pharma, Kyowa Kirin; and subsidies from Sumitomo Pharma, Chugai Pharmaceutical, Kyowa Kirin, and Eisai. The remaining authors declare no competing financial interests.

Supplementary Material

Supplemental Tables and Figure

Acknowledgments

The authors are grateful for the work of all of the physicians and data managers at the centers that contributed valuable data on transplantation to the JSTCT. The authors thank all of the members of the Transplant Registry Unified Management committees at JSTCT for their dedicated data management.

Authorship

Contribution: M. Tamaki and Y. Akahoshi contributed equally as primary investigators, and conceived the original idea, analyzed the data, and wrote the manuscript; K.M., Y.I., S.T., and J.K. advised on methods and wrote the manuscript; N.U., N.D., M. Tanaka, T.N., H.O., H.N., M.O., Y. Katayama, K.-i. M., and M.S. collected the data and revised the manuscript; F.I., Y. Kanda, and T.F. collected data, revised the manuscript, and were responsible for data management at JSTCT; Y. Atsuta managed the unified registry database and revised the manuscript; J.K. was responsible for this project of the JSTCT/GVHD Working Group; and all authors approved the final version of the manuscript.

∗ M.T. and Y.A. contributed equally to this study.

The data of this study are not publicly available because of ethical restrictions that exceed the scope of the recipient/donor’s consent for research used in the registry.

The full-text version of this article contains a data supplement.
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References

1 Arai S Arora M Wang T Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research Biol Blood Marrow Transplant 21 2 2015 266 274 25445023
2 Boyiadzis M Arora M Klein JP Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia Clin Cancer Res 21 9 2015 2020 2028 25348512
3 Inamoto Y Valdés-Sanz N Ogawa Y Ocular graft-versus-host disease after hematopoietic cell transplantation: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT Bone Marrow Transplant 54 5 2019 662 673 30531954
4 Yu J Hamilton BK Turnbull J Patient-reported symptom burden and impact on daily activities in chronic graft-versus-host disease Cancer Med 12 3 2023 3623 3633 36394207
5 Pidala J Kurland B Chai X Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium Blood 117 17 2011 4651 4657 21355084
6 Flowers ME Martin PJ How we treat chronic graft-versus-host disease Blood 125 4 2015 606 615 25398933
7 Inamoto Y Martin PJ Storer BE Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease Haematologica 99 10 2014 1618 1623 24997150
8 DeFilipp Z Alousi AM Pidala JA Nonrelapse mortality among patients diagnosed with chronic GVHD: an updated analysis from the Chronic GVHD Consortium Blood Adv 5 20 2021 4278 4284 34521116
9 Baumrin E Baker LX Byrne M Prognostic value of cutaneous disease severity estimates on survival outcomes in patients with chronic graft-vs-host disease JAMA Dermatol 159 4 2023 393 402 36884224
10 Lee SJ Onstad L Chow EJ Patient-reported outcomes and health status associated with chronic graft-versus-host disease Haematologica 103 9 2018 1535 1541 29858386
11 Kurosawa S Yamaguchi T Oshima K Resolved versus active chronic graft-versus-host disease: impact on post-transplantation quality of life Biol Blood Marrow Transplant 25 9 2019 1851 1858 31129353
12 Lee CJ Wang T Chen K Severity of chronic graft-versus-host disease and late effects following allogeneic hematopoietic cell transplantation for adults with hematologic malignancy Transplant Cell Ther 30 1 2024 97.e1 97.e14
13 Lee CJ Wang T Chen K Association of chronic graft-versus-host disease with late effects following allogeneic hematopoietic cell transplantation for children with hematologic malignancy Transplant Cell Ther 28 10 2022 712.e1 712.e8
14 Kanda J Nakasone H Atsuta Y Risk factors and organ involvement of chronic GVHD in Japan Bone Marrow Transplant 49 2 2014 228 235 24076549
15 Watkins BK Horan J Storer B Martin PJ Carpenter PA Flowers ME Recipient and donor age impact the risk of developing chronic GvHD in children after allogeneic hematopoietic transplant Bone Marrow Transplant 52 4 2017 625 626 27991888
16 Flowers ME Inamoto Y Carpenter PA Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria Blood 117 11 2011 3214 3219 21263156
17 Afram G Simón JAP Remberger M Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting Med Oncol 35 6 2018 79 29696461
18 Lazaryan A Weisdorf DJ DeFor T Risk factors for acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched sibling donors Biol Blood Marrow Transplant 22 1 2016 134 140 26365153
19 Qayed M Wang T Hemmer MT Influence of age on acute and chronic GVHD in children undergoing HLA-identical sibling bone marrow transplantation for acute leukemia: implications for prophylaxis Biol Blood Marrow Transplant 24 3 2018 521 528 29155316
20 Cuvelier GDE Li A Drissler S "Age related differences in the biology of chronic graft-versus-host disease after hematopoietic stem cell transplantation" Front Immunol 11 2020 571884
21 Kollman C Spellman SR Zhang MJ The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy Blood 127 2 2016 260 267 26527675
22 Cuvelier GDE Nemecek ER Wahlstrom JT Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria Blood 134 3 2019 304 316 31043425
23 Grube M Holler E Weber D Holler B Herr W Wolff D Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation-results from a single-center observational study Biol Blood Marrow Transplant 22 10 2016 1781 1791 27343720
24 Im A Rashidi A Wang T Risk factors for graft-versus-host disease in haploidentical hematopoietic cell transplantation using post-transplant cyclophosphamide Biol Blood Marrow Transplant 26 8 2020 1459 1468 32434056
25 Bazarbachi A Boumendil A Finel H Influence of donor type, stem cell source and conditioning on outcomes after haploidentical transplant for lymphoma - a LWP-EBMT study Br J Haematol 188 5 2020 745 756 31498883
26 Carlens S Ringdén O Remberger M Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis Bone Marrow Transplant 22 8 1998 755 761 9827972
27 Nakasone H Tian L Sahaf B Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans Blood 125 20 2015 3193 3201 25766725
28 Chang YJ Wu DP Lai YR Antithymocyte globulin for matched sibling donor transplantation in patients with hematologic malignancies: a multicenter, open-label, randomized controlled study J Clin Oncol 38 29 2020 3367 3376 32650683
29 Saliba RM Alousi AM Pidala J Characteristics of graft-versus-host disease (GvHD) after post-transplantation cyclophosphamide versus conventional GvHD prophylaxis Transplant Cell Ther 28 10 2022 681 693 35853610
30 Bolaños-Meade J Hamadani M Wu J Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis N Engl J Med 388 25 2023 2338 2348 37342922
31 Mehta RS Saliba RM Rondon G Post-transplantation cyclophosphamide versus tacrolimus and methotrexate graft-versus-host disease prophylaxis for HLA-matched donor transplantation Transplant Cell Ther 28 10 2022 695.e1 695.e10
32 Chen YB Wang T Hemmer MT GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes Bone Marrow Transplant 52 3 2017 400 408 27941764
33 Atsuta Y Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data) Int J Hematol 103 1 2016 3 10 26547570
34 Kanda J Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation Int J Hematol 103 1 2016 11 19 26588927
35 Przepiorka D Weisdorf D Martin P 1994 consensus conference on acute GVHD grading Bone Marrow Transplant 15 6 1995 825 828 7581076
36 Filipovich AH Weisdorf D Pavletic S National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report Biol Blood Marrow Transplant 11 12 2005 945 956 16338616
37 Jagasia MH Greinix HT Arora M National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report Biol Blood Marrow Transplant 21 3 2015 389 401.e1 25529383
38 Armand P Kim HT Logan BR Validation and refinement of the disease risk index for allogeneic stem cell transplantation Blood 123 23 2014 3664 3671 24744269
39 Sorror ML Maris MB Storb R Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT Blood 106 8 2005 2912 2919 15994282
40 Giralt S Ballen K Rizzo D Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant Research Biol Blood Marrow Transplant 15 3 2009 367 369 19203728
41 D'Souza A Fretham C Lee SJ Current use of and trends in hematopoietic cell transplantation in the United States Biol Blood Marrow Transplant 26 8 2020 e177 e182 32438042
42 Im A Pusic I Onstad L Patient-reported treatment response in chronic graft-versus-host disease Haematologica 109 1 2024 143 150 37226713
43 Kanda Y Investigation of the freely available easy-to-use software 'EZR' for medical statistics Bone Marrow Transplant 48 3 2013 452 458 23208313
44 Shulman HM Sullivan KM Weiden PL Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients Am J Med 69 2 1980 204 217 6996481
45 Palmer J Williams K Inamoto Y Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease Biol Blood Marrow Transplant 20 3 2014 337 344 24315845
46 Miklos DB Abu Zaid M Cooney JP Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study J Clin Oncol 41 10 2023 1876 1887 36608310
47 Arora M Klein JP Weisdorf DJ Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis Blood 117 24 2011 6714 6720 21493797
48 Arora M Pidala J Cutler CS Impact of prior acute GVHD on chronic GVHD outcomes: a chronic graft versus host disease consortium study Leukemia 27 5 2013 1196 1201 23047477
49 Martens MJ Kou J Logan BR Paczesny S Machine learning validates risk biomarkers of chronic graft-versus-host disease in 936 patients from BMT CTN 0201 & 1202 cohorts Blood 142 suppl 1 2023 479
50 Zeiser R Teshima T Nonclassical manifestations of acute GVHD Blood 138 22 2021 2165 2172 34482399
51 Hauri-Hohl MM Keller MP Gill J Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation Blood 109 9 2007 4080 4088 17213290
52 Krenger W Rossi S Piali L Holländer GA Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells Blood 96 1 2000 347 354 10891472
53 Dertschnig S Hauri-Hohl MM Vollmer M Holländer GA Krenger W Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD Blood 125 17 2015 2720 2723 25691159
54 Sakoda Y Hashimoto D Asakura S Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease Blood 109 4 2007 1756 1764 17032915
55 Choyke PL Zeman RK Gootenberg JE Greenberg JN Hoffer F Frank JA Thymic atrophy and regrowth in response to chemotherapy: CT evaluation AJR Am J Roentgenol 149 2 1987 269 272 3496749
56 Kooshesh KA Foy BH Sykes DB Gustafsson K Scadden DT Health consequences of thymus removal in adults N Engl J Med 389 5 2023 406 417 37530823
57 Markey KA Schluter J Gomes ALC The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD Blood 136 1 2020 130 136 32430495
58 Rafei H Jenq RR Microbiome-intestine cross talk during acute graft-versus-host disease Blood 136 4 2020 401 409 32526029
59 Senjo H Harada S Kubota SI Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT Blood 142 5 2023 477 492 37216687
60 Wang Y Ullah MA Waltner OG Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD J Clin Invest 134 11 2024 e170125
61 Subburaj D Ng B Kariminia A Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease Blood 139 2 2022 287 299 34534280
62 Inamoto Y Martin PJ Onstad LE Relevance of plasma matrix metalloproteinase-9 for bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation Transplant Cell Ther 27 9 2021 759.e1 759.e8
63 Reikvam H Vo AK Johansen S MicroRNA serum profiles and chronic graft-versus-host disease Blood Adv 6 18 2022 5295 5306 35443023
64 Inamoto Y Martin PJ Lee SJ Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation Blood Adv 4 11 2020 2409 2417 32492155
65 Yu J Storer BE Kushekhar K Biomarker panel for chronic graft-versus-host disease J Clin Oncol 34 22 2016 2583 2590 27217465
66 Inamoto Y Martin PJ Paczesny S Association of plasma CD163 concentration with de novo-onset chronic graft-versus-host disease Biol Blood Marrow Transplant 23 8 2017 1250 1256 28455006
67 Akahoshi Y Nakasone H Kawamura K Increased Mac-2 binding protein glycan isomer in patients at risk for late nonrelapse mortality after HSCT Blood Adv 3 21 2019 3287 3296 31698460
68 Paczesny S Hakim FT Pidala J National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. The 2014 Biomarker Working Group Report Biol Blood Marrow Transplant 21 5 2015 780 792 25644957
69 Akahoshi Y Spyrou N Hogan WJ Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD Blood Adv 7 16 2023 4479 4491 37315175
