Clinical Manifestations and Risk Factors of Ocular Graft-versus-Host Disease (GVHD) after Hematopoietic Stem Cell Transplantation

Min Gyu Lee; Gi Hyun Bae; Dong Hui Lim; Eui Sang Chung; Tae Young Chung

doi:10.3341/jkos.2014.55.7.969

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Lee, Bae, Lim, Chung, and Chung: Clinical Manifestations and Risk Factors of Ocular Graft-versus-Host Disease (GVHD) after Hematopoietic Stem Cell Transplantation

Original Article

J Korean Ophthalmol Soc 2014;55(7):969-977.

Published online: 30 August 2014

DOI: https://doi.org/10.3341/jkos.2014.55.7.969

Clinical Manifestations and Risk Factors of Ocular Graft-versus-Host Disease (GVHD) after Hematopoietic Stem Cell Transplantation

Min Gyu Lee, MD¹, Gi Hyun Bae, MD^1,², Dong Hui Lim, MD¹, Eui Sang Chung, MD, PhD¹, Tae Young Chung, MD, PhD¹

¹Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Department of Ophthalmology, Sahmyook Medical Center, Seoul, Korea

Address reprint requests to Tae Young Chung, MD, PhD, Department of Ophthalmology, Samsung Medical Center, #81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea, Tel: 82-2-3410-3548, Fax: 82-2-3410-0029 E-mail: tychung@skku.edu

Received 8 July 2013 Revised 25 January 2014 Accepted 9 June 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

To investigate the incidence, clinical manifestations, and risk factors of ocular graft-versus-host disease (GVHD) as well as the survival of the patients after allogeneic hematopoietic stem cell transplantation (HSCT).

Methods

The medical records of 99 patients who visited our clinic and were screened for ocular GVHD after allogeneic HSCT were reviewed retrospectively. Subjects were divided into 2 groups depending on the occurrence of ocular GVHD on slit-lamp biomicroscopy. We compared clinical manifestations and survival between the 2 groups and analyzed the risk factors associated with the development of ocular GVHD.

Results

Ocular GVHD was diagnosed in 38 patients (38.38%) at a mean of 315 days after HSCT. Out of the 38 patients who developed ocular GVHD, 22 patients (57.89%) were diagnosed with dry eye only and 16 patients (42.11%) were diagnosed with conjunctival disease. The presence of extraocular GVHD (hazard ratio (HR) 35.76, p < 0.001), the number of extraocular GVHD (HR 3.07, p < 0.001), skin GVHD (HR 2.31, p = 0.029), oral GVHD (HR 8.16, p < 0.001), and gastrointestinal tract GVHD (HR 5.00, p = 0.002) were independent risk factors of ocular GVHD. Comparisons of the survival demonstrated decreased survival of patients with conjunctival disease compared to patients without ocular GVHD and patients with dry eye only, but there was no statistically significant differences (log rank test, p = 0.208).

Conclusions

Ocular GVHD is common after allogeneic HSCl. Ihe majority of ocular GVHD occurs in the chronic stage and is associated with decreased survival. Therefore, more intensive and long-term follow-up with ophthalmic and systemic monitoring is necessary, especially in patients who have extraocular GVHD, for early recognition and proper treatment of ocular GVHD.

Keywords: Allogeneic hematopoietic stem cell transplantation (HSCT), Incidence, Ocular graft-versus-host disease (GVHD), Risk factors, Survival

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Figure 1.

Cumulative incidence of ocular GVHD after allogeneic hematopoietic stem cell transplantation. Probability of developing ocular GVHD was 48.33% at 2 years. GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.

Figure 2.

Categorization of subjects who developed ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation by clinical courses. GVHD = graft-versus-host disease.

Figure 3.

Kaplan-Meier survival curves of 3 groups according to the manifestation of ocular GVHD in patients who underwent allogeneic hematopoietic stem cell transplantation. Survival rates of groups of patients without ocular GVHD, with dry eye only, and with conjunctival disease are 79.8%, 95.5%, and 72.7% at 1 year, 56.9%, 70.9%, and 46.5% at 2 years, and 52.2%, 60.8%, and 34.9% at 3 years after allogeneic hematopoietic stem cell transplantation, respectively (log rank test, p = 0.208). GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.

Table 1.

Characteristics of 99 subjects who underwent allogeneic hematopoietic stem cell transplantation

	Without ocular GVHD (n = 61)	With ocular GVHD (n = 38)	p-value
Sex (n) (M/F, % of male)	30/31 (49.18)	26/12 (68.42)	0.060^‡
Age (years) (range)	41.40 ± 12.83, 18-64	41.42 ± 13.36, 18-65	0.905^§
Diagnosis^* (n, %)
Myeloid hematologic malignancy	40 (65.57)	33 (86.85)	0.030^Π
Lymphoid hematologic malignancy	17 (27.87)	3 (7.89)
Others	4 (6.56)	2 (5.26)
Conditioning regimens (n, %)			0.144^‡
With TBI^†	30 (49.18)	13 (34.21)
Without TBI	31 (50.82)	25 (65.79)
Extraocular GVHD (n, %)	32 (52.46)	38 (100.00)	<0.001^‡
Onset of extraocular GVHD	17/15 (53.13)	12/26 (31.58)	0.068^‡
(acute/chronic, % of acute onset)
Number of involved organ (%)			0.016^‡
1	14 (43.75)	5 (13.16)
2	10 (31.25)	18 (47.37)
≥3	8 (25.00)	15 (39.47)
Site of involved organ (n, %)
Skin	19 (59.38)	26 (68.42)	0.431^‡
Mouth	12 (37.50)	24 (63.16)	0.032^‡
GI tract	6 (18.75)	8 (21.05)	0.810^‡
Liver	14 (43.75)	23 (60.53)	0.161^‡
Others	11 (34.38)	10 (26.32)	0.464^‡

Values are presented as mean ± SD.

TBI = total body irradiation; GVHD = graft-versus-host disease; GI = gastrointestinal.

^* The numbers of patients were 56 for acute myeloid leukemia, 2 for chronic myeloid leukemia, 12 for myelodysplastic syndrome, 3 for myelofibrosis, 16 for acute lymphoblastic leukemia, 4 for Non-Hodgikin's lymphoma, 1 for multiple myeloma, and 5 for aplastic anemia;

^† Total dose was 999cGy (333cGy for 3 days);

^‡ Chi-square test;

^§ Mann-Whitney U-test;

^Π Fisher's exact test.

Table 2.

Risk factors of ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Risk factors	Hazard ratio (95% confidence interval), p-value^*
Risk factors	Ocular GVHD	Dry eye only	Conjunctival disease
Female gender	0.40 (0.18-0.87)	0.26 (0.09-0.80)	0.67 (0.22-2.03)
Female gender	0.021	0.019	0.474
Age	1.00 (0.98-1.03)	1.01 (0.98-1.05)	1.00 (0.96-1.04)
Age	0.667	0.505	0.996
Conditioning regimens with TBI	0.29 (0.13-0.65)	0.34 (0.12-0.97)	0.22 (0.06-0.81)
Conditioning regimens with TBI	0.002	0.044	0.023
Site of involved organ with extraocular GVHD
Skin	2.31 (1.09-4.89)	2.58 (0.96-6.91)	2.21 (0.69-7.14)
Skin	0.029	0.060	0.184
Mouth	8.16 (3.20-20.82)	11.64 (3.10-43.74)	4.93 (1.35-18.07)
Mouth	<0.001	<0.001	0.016
GI tract	5.00 (1.79-13.92)	3.43 (0.64-18.48)	7.35 (1.94-27.79)
GI tract	0.002	0.151	0.003
Liver	1.58 (0.66-3.77)	1.30 (0.40-4.20)	1.84 (0.51-6.70)
Liver	0.304	0.663	0.356
Others	0.90 (0.40-2.02)	0.88 (0.30-2.60)	0.90 (0.26-3.09)
Others	0.799	0.820	0.861

TBI = total body irradiation; GVHD = graft-versus-host disease; GI = gastrointestinal.

^* Time-dependent Cox regression with multivariate analysis using gender, age, TBI, and site of involved organ with extraocular GVHD as covariates.

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