Incidence, risk factors, and clinical outcomes of cataracts following hematopoietic stem cell transplantation
Authors: Yuho Najima, Kazuhiko Kakihana, Kazuteru Ohashi, Narumichi Yamamoto, Takeshi Kobayashi, Takuya Yamashita, Hisashi Sakamaki, Hideki Akiyama
Journal: American Journal of Hematology (2011)

To evaluate the characteristics of cataracts following hematopoietic stem cell transplantation (HSCT), 561 patients without any ocular complications before HSCT were reviewed. Ocular complications occurred in 196 patients (34.9%). Cataract was diagnosed in 45 of 561 patients. The 10-year estimated cataract incidence was 14%. The median onset time was 498 days after transplant (range, 38–4,535 days). The onset of cataracts was later than that of other ocular complications. Phacoemulsification was performed in 13 patients (29%) at a median of 1,028 days after HSCT (range, 375–4,549 days). In 6 of 13 patients (46%) who underwent cataract surgery, visual acuities gradually deteriorated because of the development of posterior capsule opacification. YAG (yttrium-aluminum-garnet) laser posterior capsulotomy successfully recovered their sight without any sequelae. A multivariate analysis revealed that age, acute and chronic graft versus host disease (GVHD), and systemic infection were significant risk factors for cataract, whereas neither steroid nor total body irradiation (TBI)-containing regimens affected the development of cataract. Our results showed that the clinical outcomes of cataract after HSCT are favorable and comparable to those in the general population. Hyperfractionated TBI with eye shielding may be effective for the prevention of cataract. Numerous advances in allogeneic hematopoietic stem cell transplantation (HSCT) techniques have improved recipients' long-term survival. Currently, patients with acute leukemia or chronic myeloid leukemia who survive without recurrent malignancy for 2 years after allogeneic HSCT have an 89% probability of surviving for at least 5 years, and recently, the quality of life (QOL) of such long-term survivors has been investigated [1]. Several reports revealed that a significantly large population of patients developed ocular complications [2, 3], such as cataract, dry eye, retinal bleeding, or intraocular infection, and some of these complications affected patients' QOL. Although cataract formation is one of the major late complications following HSCT, its risk factors are still controversial. Previous reports showed that total body irradiation (TBI) increased the risk of cataract, and single dose TBI was more cataractogeneic than hyperfractionated TBI [4]. In the largest series evaluating a cohort of 1,064 patients, risk factors for the development of cataract were older age, higher dose rate (>0.04 Gy/min), allogeneic HSCT, and steroid administration [5]. Recently, hyperfractionated TBI has become one of the widespread standard precautions for HSCT-associated complications, and lens protection with custom-made shielding blocks for each patient is also expected to decrease the incidence of cataracts following HSCT [6, 7]. Furthermore, cataract surgery has recently become a low-risk procedure and improves visual acuity in more than 90% of eyes in normal healthy subjects [8-11] but the long-term outcome of surgical repair in patients who undergo HSCT remains to be clarified [3]. Thus, in this study, the characteristics, risk factors, and long-term outcomes of cataract following HSCT were retrospectively analyzed. The patients' characteristics are summarized in Table I. The median follow-up time was 836 days (range, 0–7,316 days). Of the 561 patients who had no preceding history of ocular complications, 520 (93%) underwent HSCT for hematological malignancies. HLA-matched and unrelated transplantation was performed in 435 (78%) and 276 (49%) patients, respectively. For conditioning regimens, 316 (56%) patients received radiation-containing regimens. Cataracts developed in 45 patients. The 10-year estimated cataract incidence was 14% (Fig. 1). Age (P value, 0.001), acute (0.027) and chronic (<0.001) GVHD, other ocular complications (0.007), and systemic infections (0.009) were significantly higher in patients with cataract. For systemic infections, total 340 episodes were documented in whole patient and 42 episodes were in patients with cataract, 11 bacterial, 9 mycoses, 13 viral, 2 pneumocystis, and 7 pathogen not identified. Chronic GVHD was apparent in 38 (84%) of 45 cataract patients, and 29 patients (64%) were classified as extensive type. The steroid dose and radiotherapy for the conditioning regimen were not different between the two groups (Table I). For ocular complications, 196 patients (34.9%) had a total of 253 ocular lesions during the study period. Ocular lesions other than cataract were dry eye (13.0%), keratoconjunctivitis (12.4%), ocular infection (6.2%), retinal bleeding (2.1%), and others (3.2%), including glaucoma, intraocular relapse, and uveitis. Cataract occurred at a median of 498 days (range, 38–4,535 days); most (91%) developed over 100 days after HSCT, whereas other ocular lesions occurred earlier (keratoconjunctivitis at 97 days, dry eye at 206 days, ocular infection at 139 days, and retinal bleeding at 116 days, respectively). Cumulative incidence of cataract. For clinical management and outcome of cataract, 13 of 45 (29%) patients with cataract underwent phacoemulsification and intraocular lens implantation at a mean of 1,028 days (range, 375–4,549 days) after HSCT. The median age at surgery was 42 (range, 17–52) years. The median follow-up period after cataract surgery was 1,415 (range, 252–2,277) days. During this period, six patients developed posterior capsule opacification (PCO). YAG (yttrium-aluminum-garnet) laser posterior capsulotomy was performed in five patients and successfully improved their visual acuity without any sequelae. The median period from cataract surgery to YAG laser therapy was 983 (range, 727–2,120) days. On univariate analysis, age, extensive chronic GVHD, use of steroids, acute GVHD (grade II to IV), other ocular complications, and systemic infection were significantly related to the incidence of cataract. TBI-containing regimen did not affect the development of cataract. On multivariate analysis, age, acute and extensive chronic GVHD, and systemic infection were identified as independent factors that significantly affected the development of cataract (Table II). In this study, the 10-year estimated cataract incidence was lower (14%, Fig. 1) than in previous reports [4-6, 12-17]. This might be due to several reasons. First, ocular screening tests were not performed until patients noticed ocular symptoms such as impaired vision, pain, or dryness; thus, asymptomatic patients may have been missed, underestimating the incidence of cataract. Second, the difference in TBI methods might affect morbidity. In our hospital, all patients receive the TBI regimen in a hyperfractionated scheme at a maximum total dose of 12 Gy, and ocular shielding is performed when the TBI dose exceeds 8 Gy. In many previous reports, some patients received single or high dose (>12 Gy) TBI [4, 6, 13-16]. Moreover, TBI was performed without eye shielding [15, 18]. Intraocular relapses were observed in four patients, and two patients did not receive TBI (data not shown), which indicates ocular shielding did not increase intraocular relapse. A total dose >8 Gy has been reported to be a significant risk factor for cataract in single-dose TBI [5]. Thus, our TBI regimen seems to be safe, without increasing the risk for cataract and intraocular relapse. Although the use of steroids and TBI was a significant risk factor for cataracts in many reports [4-6, 12-14, 16, 18-20], neither affected cataract formation in this study. On multivariate analysis, age, acute and extensive chronic GVHD, and systemic infection were identified as the risk factors for cataract. The type of infection did not significantly differ between the two groups (P = 0.5, data not shown), which indicates that any systemic infection could be a risk factor for cataract. Although the precise mechanism of cataract formation is not fully understood, oxidative stress has been reported to be an important factor for the development of cataract [21, 22]. The reactive oxygen species are generated in various cells in different settings, including infection and GVHD [23, 24]. Patients who underwent HSCT would be subjected to oxidative stress by various HSCT-associated complications, which may promote the development of cataract. Physical stimuli such as eye rubbing or tapping may also lead to cataract formation, especially in patients with chronic GVHD (e.g., dry eye), just like in patients with atopic dermatitis [25]. Visual acuity improved in all patients who underwent cataract surgery. However, six suffered from visual impairment again because of the development of PCO, and five patients underwent YAG laser capsulotomy. PCO is a common long-term complication of cataract surgery and is reported to occur in 20 to 50% of patients 2 to 5 years after surgery [26, 27]. Although PCO has been reported as one of the most frequent late complications in HSCT recipients [6, 13], the incidence of PCO was not high in our patients compared with that in the general population. All five patients receiving YAG laser capsulotomy improved their visual acuity without sequelae. Thus, these results indicate that the clinical outcomes of cataract surgery following HSCT might be favorable. However, in view of the relatively small number of cataract patients in this study, further investigations will be necessary to confirm the risk factors and the patients' clinical outcomes with a large patient population. A total of 622 patients underwent allogeneic HSCT in our hospital for hematological diseases from 1986 to 2006. Of these, the records of 561 patients were retrospectively reviewed to investigate the clinical features of newly developed ocular complications after HSCT; 61 patients were excluded because of a prior history of ocular complications such as cataract, glaucoma, diabetic retinopathy, or intraocular infection. Ophthalmological examinations were carried out when patients had any ocular symptoms. For the 29 patients who received two or more allogeneic transplantations during the study period, only the first transplantation period was analyzed. Preparative therapies were performed according to the primary disease and type of transplantation. Generally, patients with lymphoid malignancy were conditioned with a fractionated total body irradiation (TBI, 12 Gy) -containing regimen, including cytarabine (8 g/m2) and cyclophosphamide (CY, 120 mg/kg). Fractionated TBI was performed with partial transmission anterior–posterior eye 33% shielding. Patients with myeloid malignancy were conditioned using a non-TBI-containing regimen including busulfan (BU, 16 mg/kg orally or 12.8 mg/kg intravenously) and CY (120 mg/kg). Plasma BU concentrations were not monitored. Total lymphoid irradiation (TLI, 7 Gy) was added to the BU/CY regimen in cases of human leukocyte antigen (HLA)-mismatched or unrelated transplantation. Patients with severe aplastic anemia were also conditioned using a TLI-containing regimen. Prophylaxis for acute GVHD consisted of a short course of methotrexate and cyclosporine A or tacrolimus (FK). FK was used in cases of either unrelated or HLA-mismatched transplantation. Acute and chronic GVHD were diagnosed and graded according to previously established criteria [28, 29]. Continuous baseline characteristics were compared between patients with cataract and patients without cataract using the Mann-Whitney test. Categorical characteristics were compared using the χ2 test. Analyses of risk factors for cataract and the probability of cataract were calculated according to the Kaplan-Meier method. For univariate analysis, the log-rank test was used to compare risk groups for cataract. Multivariate analysis was performed using a Cox's proportional hazard model. The statistical data were obtained using SPSS software (SPSS 11.0, Chicago, IL). All statistical tests were two-sided, and a value of P < 0.05 was considered statistically significant. The authors are very grateful to patients who participated in this study. They also like to thank the staff of the Hematology Division at Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, for their excellent patient care. Yuho Najima*, Kazuhiko Kakihana*, Kazuteru Ohashi*, Narumichi Yamamoto , Takeshi Kobayashi*, Takuya Yamashita*, Hisashi Sakamaki*, Hideki Akiyama*, * Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan, Ophthalmology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.