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ARTICLE
Impact of Guideline-Driven Approach in Follow-Up of Long-Term Complications After Allogeneic Hematopoietic Cell Transplant: Single Center Experience

Objectives: After allogeneic stem cell transplant, patients may experience psychiatric, endocrinologic, pulmonary, and cardiovascular problems, as well as secondary malignancies and chronic graft-versus-host disease over the long-term follow-up. These long-term complications not only increase mortality and morbidity of transplant survivors but also decrease their quality of life. In this study, we shared our experiences with our guideline-driven approach for follow-up of long-term complications.

Materials and Methods: Our study included 91 patients who received allogeneic hematopoietic cell transplant between July 2009 and March 2016 at our medical center. In accordance with the current guidelines, a screening program was applied to all patients seen between February 2016 and February 2017.

Results: Median posttransplant follow-up duration was 36 months (range, 12-84 mo), and the median follow-up duration after initial diagnosis was 51 months (range, 15-109 mo). Evaluations of patients post­transplant showed ocular complications (50.6% of patients), oral complications (15.4%), respiratory complications (8.8%), cardiac complications (5.5%), metabolic syndrome (37.4%), liver complications (2.2%), skeletal complications (66.7%), endocrine complications (12.1%), secondary cancers (2.2%), psy­chosocial adjustment (27.7%), hypertension (5.5%), and type 2 diabetes mellitus (8.8%).

Conclusions: For long-term follow-up, detailed evaluations of body organs and systems are essential. Early recognition of the aforementioned complications could decrease mortality and morbidity. For patients to be monitored by transplant centers over many years, training and awareness should be provided to ensure adequate follow-up of patients. Based on our results, we believe that the long-term follow-up guidelines used in our clinic are applicable to others.


Key words : Graft-versus-host disease, Morbidity, Mortality, Quality of life

Introduction

Allogeneic hematopoietic cell transplant (allo-HCT) is a curative treatment option for several potentially lethal conditions, including hematological cancers and bone marrow failure. This procedure is being increasingly utilized globally, including in elderly patients, due to improvements in the conditioning regimens and supportive care. Long-term survival rates of patients have increased with new devel­opments in the transplant process. In adults, 3-year median survival following allo-HCT is between 24% and 76% according to the underlying disease.1,2 However, patients who survive early complications of the allo-HCT procedure might experience psychiatric, endocrinologic, pulmonary, or cardiovascular prob­lems, as well as secondary malignancies and chronic graft-versus-host disease (cGVHD), in the long-term follow-up. These long-term complications not only increase the mortality and morbidity of the transplant survivors but also decrease their quality of life.3 The rate of 10-year posttransplant survival was about 30% lower than the 10-year survival of a normal population in the same age group.4-6 Therefore, it is important to monitor posttransplant survivors for any systemic diseases.

International associations have established com­mon guidelines for long-term follow-up of patients after hematopoietic cell transplant.3,7 In line with the guideline published in 2012,3 our patients are screened for long-term complications after the first year of transplant. In this study, we have shared our follow-up experiences.

Materials and Methods

This study was approved by the institutional review board and conducted in accordance with the Declaration of Helsinki. This was a retrospective, observational, case-control study. The patients included in the study had allo-HCT procedures between July 2009 and March 2016 at our medical center. Data were extracted from patient files and stored in electronic format. During this process, all protected information about patients was im­mediately deidentified and kept in the study office of the department, which is a secured room under lock.

All included patients were regularly followed for a minimum of 1 year posttransplant. In accordance with the guidelines published in 2012, a screening program was applied to all cases between February 2016 and February 2017.3 We did not use an institutional side effect/complication recording system. The patients who were less than 1 year posttransplant were not included in the study. The patients who stopped their follow-up visits were also not included in the study.

Transplant procedure
In accordance with the standard criteria, condi­tioning regimens were classified as myeloablative conditioning and reduced-intensity conditioning.8 Prophylaxis for GVHD was provided by giving oral cyclosporine and short-term methotrexate to all patients.

Ocular evaluation
Patients underwent complete ophthalmologic examination by different clinicians. The Schirmer test without anesthesia was performed.9

Respiratory evaluation
All spirometry tests were performed in our pul­monary function test (PFT) laboratory with the use of our standard operating procedures. Measurements of 1-second forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC were evaluated according to the standard criteria.10 Bronchiolitis obliterans syndrome (BOS) and cryptogenic organ­izing pneumonia (COP) were defined according to the standard criteria.11 Patients were included in the analyses if they had ≥ 10% decrease in FEV1 after transplant.

Cardiac evaluation and metabolic syndrome
We used electrocardiogram and echocardiography for cardiac evaluations of patients. Metabolic syndrome was defined according to the standard criteria.12

Liver evaluation
We used enzyme-linked immunosorbent assays to test for anti-hepatitis B surface antibody, anti-hepatitis B surface antigen, and anti-hepatitis B virus. We also checked levels of alanine aminotransferase (ALT), aspartate aminotransferase, total bilirubin, and alkaline phosphatase.

Renal evaluation
Glomerular filtration rate was calculated by using the Cockcroft and Gault formula.13

Skeletal complications
Local bone density tests were performed to check for osteoporosis and osteopenia.14 We used magnetic resonance imaging to search for avascular necrosis in cases with related complaints.

Endocrine complications
Hypothyroidism was evaluated according to the standard criteria.15 Premature ovarian failure (POF) in women was diagnosed according to the standard criteria.16 Male patients were tested for free testos­terone levels. Spermiograms were also performed in male patients who approved the test.

Secondary malignancy evaluation
Patients who had secondary malignancies were noted for our analyses.

Psychosocial and sexual evaluations
Patients were also examined by different psychiatrists working at our center. No tests were performed for evaluation of detailed sexual functions. Verbal infor­mation was obtained regarding sexual reluctance.

General screening and preventative health
Patients were checked for type 2 diabetes mellitus and high blood pressure. Body mass index (BMI) of participants was calculated via the following formula: weight (kg)/height (m)2. Body mass index values were categorized according to the World Health Organization classification.17

Acute and chronic graft-versus-host disease
Acute GVHD and cGVHD were diagnosed according to the standard criteria.18,19

Statistical analyses
Categorical and quantitative variables are presented with descriptive statistics and shown as frequency (percentage) or median (range) values, respectively. Comparisons for statistical significance were made using chi-square analyses for categorical variables.

P ≤ .05 was considered statistically significant. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA).

Results

Our center performed 238 allo-HCT procedures between July 2009 and May 2016. Of these, 89 patients (37.4%) died in the first year posttransplant, and 30 patients (12.6%) died after the first year posttransplant. Of those who died after the first posttransplant year, 17 deaths (7.1%) were due to active disease; the remaining 13 patients (5.5%) died from secondary complications. Our study included 91 patients; 28 patients were not included because they had discontinued their follow-up visits. Of the 91 included patients, 35 (38.5%) were female and 56 (61.5%) were male. The median age of the patients at the time of their evaluation was 39 years (range, 18-64 y). The median posttransplant follow-up duration was 36 months (range, 12-84 mo), and the median follow-up duration after the initial diagnosis was 51 months (range, 15-109 mo). The median count of transplanted CD34-positive stem cells was 7 × 106 (range, 1.86-11.28 × 106). Table 1 summarizes the demographic features of the study cohort.

Table 2 presents the results of evaluations during median posttransplant year 3. We found that 69 patients (75.8%) had ferritin levels lower than 1000 ng/mL and 22 (24.2%) had ferritin levels ≥ 1000 ng/mL. Twenty-four patients (26.4%) had grade 1-2 acute GVHD, and 16 (17.6%) had grade 3-4 acute GVHD. Regarding cGVHD, 7 patients (7.7%) had mild disease, 12 (13.2%) had moderate disease, and 10 (11%) had severe disease.

Immunity and infections
There were 16 patients (17.6%) who received prophylactic antimicrobial treatment because of active cGVHD.

Ocular complications
Ocular sicca syndrome was significantly more frequent in patients with cGVHD (P < .001). There was a significant association between history of total body irradiation (TBI) (P = .059) and more than 3 months of steroid use (P = .43) and cataract develop­ment. One patient with ischemic microvascular retinopathy showed 70% vision loss in the left eye and 90% vision loss in the right eye.

Oral complications
Patients with cGVHD were significantly more likely to have oral complications (P < .001). However, no patients received radiation therapy to the head or neck regions.

Respiratory complications
There was a significant association between diagnosis of BOP or COP and cGVHD development (P < .001). However, there were no significant associations between BOP/COP and TBI and busulfan (P = .828), methotrexate (P = .87), and bleomycin treatment history (P = .475). In addition, busulfan history and ≥ 10% reduction in FEV1 after transplant were not significantly related (P = .205). We did find significant associations between TBI history (P = .028), GVHD development (P = .001), methotrexate treatment history (P = .049), and bleomycin treatment history (P = .029) versus ≥ 10% reduction in FEV1 after transplant.

Cardiac complications and metabolic syndrome
One patient with ferritin level > 1000 ng/mL had cardiac dysfunction. Anthracycline treatment resul­ted in cardiac complications in 2 patients.

Liver complications
Having over 1-fold higher ALT levels (except with viral hepatitis) and having ferritin levels over 1000 ng/mL were significantly related (P < .001), although ALT levels were not significantly associated with having cGVHD (P = .11).

Muscle and connective tissue complications
In patients with myopathy and scleroderma, 1 patient (1.1%) had rheumatoid arthritis and 1 patient (1.1%) had myasthenia graves. Ten patients with sclero­dermoid cGVHD were in remission, but 16 patients with sclerodermoid cGVHD had active disease.

Skeletal complications
Sixty-nine patients (75.6%) received bone mineral densitometry evaluations, and osteopenia or osteoporosis was found in 46 patients (66.6%). Steroid use for longer than 3 months significantly affected bone mineral density results (P = .013). The relation between aseptic necrosis development and steroid use for > 3 months was significant (P = .033), whereas its relation with TBI was not significant (P = .558).

Endocrine complications
No significant differences were shown between hypothyroidism and TBI history (P = .186), busulfan history (P = .446), and cGVHD development (P = .773). Seventeen female patients under 40 years of age were evaluated for POF. The effects of TBI and busulfan history on POF development were not statistically meaningful (P = .266 and P = .11, respectively). Spermiograms were performed in 29 patients, showing normal testosterone levels. Adrenal insufficiency was not detected in any of the patients.

Mucocutaneous complications
Although 11 of 35 female patients (31.4%) had vaginal dryness, no male patients had phimosis. The relationship between vaginal dryness and cGVHD was significant (P = .013).

Secondary cancers
During the study period, 2 patients developed secondary cancers (non-small cell lung cancer and squamous cell skin cancer). Although these patients did not have TBI history, the patient with skin cancer had sclerodermoid skin cGVHD.

Fertility
We evaluated 69 patients (75.8%) who were within reproductive age. Of these, 1 woman and 3 men had children. In the other 65 patients (94.2%) without children, there were significant associations between busulfan history and fertility (P = .008). However, no significant associations were found between fertility and TBI history (P = .381) or cGVHD (P = .113).

Recommended screening
According to BMI, 7 patients (7.7%) were below normal, 41 (45%) were normal, 25 (27.5%) were preobese, 12 (13.2%) were in obese class 1, and 6 (6.6%) were obese class 2.

Discussion

Indications for allo-HCT are mainly because of acute leukemia (constituting 55% to 70% of indications).1 In our patient group, 71.4% of the allo-HCT pro­cedures were due to acute leukemias. Posttransplant cGVHD, which has a cumulative incidence of 30% to 50%, is an important cause of morbitidy and mortality.20,21 In our study, cGVHD was detected in 31.9% of the cases, which is consistent with the literature.

Immunity and infections
Antibody titers of previous vaccines fall after the first year posttransplant; therefore, the risk of infections due to encapsulated bacteria increases. For this reason, most guidelines recommend vaccination of patients in the posttransplant period.22 In our study, vaccination was initiated after the first year post­transplant in accordance with the aforementioned guideline. Immunologic reconstruction is known to develop late in GVHD cases; therefore, prophylactic antimicrobial therapy is recommended in patients with GVHD.3,23 Infection risks of varicella zoster virus, cytomegalovirus, fungi (such as Aspergillus and Candida species), encapsulated bacteria, and Pneumocystis jiroveci exist in patients who are immunosuppressed or have GVHD.24 In our study, we had patients who were being actively treated for Aspergillus-associated fungal infections (1%) and had recovered from varicella zoster virus infection (5.5%).

Ocular complications
Ocular sicca syndrome (known as eye cGVHD) is shown in 5% to 20% and cataract in 30% to 60% of patients after allo-HCT; however, the frequency of ischemic microvascular retinopathy is not clear.3,25-28 Occurrence of ocular illness syndrome in our study was similar to the literature (39.6%) and showed a significant relation with cGVHD (P < .001). Both TBI and steroid use can affect cataract development.3,28 In our study, cataract development was detected in 9.9% of patients. Unlike the literature, the effects of steroid use for >3 months (P = .43) and TBI application (P = .059) on cataract development were not significant. Ischemic microvascular retinopathy is thought to develop due to TBI and cyclosporine treatment.3 In our study, 1 patient with ischemic microvascular retinopathy lost vision. In terms of eye complications, patients need regular examinations by experienced specialists.

Oral complications
Salivary gland dysfunction, impaired taste, xerostomia, and oral GVHD are commonly seen complications after allo-HCT. Radiation therapy to the head-neck region could increase these complications. Oral cGVHD could also cause oral cavity cancers.3,29 In our study, frequency of oral complications was 15.4%, which were mainly oral cGVHD. Oral complications were significantly higher (P < .001) with cGVHD. No patients had oral cavity cancer.

Respiratory complications
Respiratory complications occur in 15% to 20% of patients after allo-HCT and can increase death risk by 15 times compared with that shown in the general population.4 Bleomycin, methotrexate, busulfan, TBI, and cGVHD are risk factors.3,30,31 Patients have poor prognosis, especially with BOS; for patients who do not respond to the first treatment, 5-year survival rate is between 20% and 30%.32,33 The frequency of BOS/COP is between 2% and 14%.19,33,34 In patients diagnosed with cGVHD, it is rational to investigate BOS/COP even if there are no symptoms. Our findings show the importance of intermittent monitoring of pulmonary complications with PFT even without symptoms.

Cardiac complications and metabolic syndrome
Over a 7-year median follow-up, the 10-year cumulative incidences of ischemic heart disease, cardiomyopathy, and all-cause cardiovascular death were shown to be 3.8%, 6%, and 3.7%, respectively.3,34 We found incidences of ischemic heart disease, cardiomyopathy, and all-cause cardiovascular disease of 3.3%, 2.2%, and 2.2%, respectively. Risk factors for cardiac dysfunction include anthracycline, media­stinal radiation therapy, and iron accumulation.3-5,35 In our study, 400 mg/m2 anthracycline resulted in 2 patients with cardiac dysfunction, with 1 patient having ferritin levels > 1000 ng/mL. Our relatively short median follow-up (3 years) may have been the reason for less cardiac complications.

Metabolic syndrome is an important risk factor for cardiovascular diseases. The frequency of metabolic syndrome in Turkey is 35% to 43%.36,37 In a study conducted with 785 allo-HCT patients, rate of metabolic syndrome was 40% in year 1 post­transplant.38 The incidence of metabolic syndrome in our study was 37.4%. These results support the need for patients to change their diet and lifestyle.

Liver complications
Drug toxicity, cGVHD, viral hepatitis, and iron accumulation are risk factors for liver complications.3,39 In our study, 2.2% of patients had chronic hepatitis B virus infection. The relationship between liver complications and > 1000 ng/mL ferritin levels and ALT levels at least 1-fold higher for 3 months (excluding viral hepatitis) was statistically significant (P < .001). Chronic GVHD was also associated with liver disease. In general, iron accumulation should be considered the cause of mild ALT elevations.

Renal and genitourinary complications
Chronic kidney disease can occur in 5.5% to 9% of patients in the long-term after allo-HCT.40 Risk factors for chronic kidney disease in long-term survivors include older age, pretransplant renal function, acute GVHD and cGVHD, history of TBI usage, and certain drug regimens.3,40 No patients had a glomerular filtration rate of < 60 mL/min/1.73 m2 in our study. Intermittent screening is important because chronic kidney disease could develop after allo-HCT.40

Muscle and connective tissue complications
Major late complications include steroid-induced myopathy, fascitis/scleroderma, and polymyositis.3 Myopathy and polymyositis are usually seen at 2 to 5 years posttransplant.40 We only had 1 patient with myopathy detected at screening. Sclerodermic cGVHD is characterized by inflammation and progressive fibrosis of the dermis.19 Sclerotic-type cGVHD can occur in 10% to 15% of patients after allo-HCT.19,41 In our study, 11% had improved sclerotic-type cGVHD and 17.6% had active sclerotic-type cGVHD. Myasthenia gravis can occur with cGVHD.3 In our study, only 1 patient had myasthenia graves. These transplant-related complications could be overlooked if symptom-based questioning is not done carefully.

Skeletal complications
The most important risk factor for skeletal complications is steroid treatment for > 3 months.3,42,43 In our study, osteoporosis was detected in 23.2% and osteopenia in 43.5% of patients. The association between decreased bone density and steroid use for > 3 months was found to be significant (P = .013). Thus, bone density scans are requirements during long-term follow-up.

For avascular necrosis formation, which may occur in 4% to 19% of patients with > 3 months of steroid usage, TBI history and cGVHD were defined as risk factors.3,44 We detected avascular necrosis in 8.8% of patients during a symptom-based screening. Our findings are similar to previous studies.3,44 Although the development of aseptic necrosis was significantly related with over 3 months of steroid usage (P = .033), its relation with TBI was not sig­nificant (P = .558). As suggested in the guidelines, imaging of joints is rational in patients with symptoms.

Central and peripheral nervous system com­plications
In the long term, infection, stroke, leuko­encephalopathy, secondary tumor development, and declines in conscious functions may develop.3 We had 1 patient with central nervous system aspergillosis infection. No special evaluations were performed regarding conscious functions. One patient showed peripheral neuropathy after a complaint-based evaluation. These types of assessments are rational for diagnosis of central and peripheral nervous system complications.

Endocrine complications
Screening is recommended for hypothyroidism, gonadal dysfunction, and primary adrenal insufficiency.3 Hypothyroidism can occur in 7% to 15% of patients after allo-HCT and may be related to TBI history, busulfan history, and cGVHD.3,45 Hypothyroidism (subclinical 9.9%, clinical 2.2%) was detected in 12.1% of our patients, which are similar to rates in the previous studies.

Gonadal dysfunction is highly prevalent after allo-HCT, with rates of 92% for males and 99% for females.3 Both TBI and busulfan usage are main factors that increase the risk of hypergonadotropic hypogonadism in women.3,46 In our study, POF was detected in 88.2% of women under 40 years of age and not significantly related to TBI history (P = .266) or busulfan history (P = .11). Because POF is a major problem during long-term follow-up, at pretransplant, patients should engage the assistance of physicians who specialize in the protection of fertilization and who can assist with reproduction techniques. Some patients may be eligible for oocyte cryopreservation. In males, infertility may develop due to direct germ cell damage.3 In our study, sperm abnormalities that could lead to infertility were detected in 75.9% of the sperm analyses made with spermiogram. This suggests that sperm cryo­preservation is rational in the pretransplant period.

Mucocutaneous complications
Severe genital GVHD has been shown to develop in approximately 12% of women after allo-HCT.47 The initial findings of vaginal cGVHD include vaginal dryness, with dyspareunia and vaginal scarring occurring in the later stages.3,47 In our study, 31.4% of patients had vaginal dryness and dyspareunia, with vaginal dryness significantly associated with cGVHD (P = .013). Phimosis, which could be a finding of genital cGVHD,3 was not shown in any of our male patients. Patients with cGVHD require careful examination for genital cGVHD.

Secondary cancers
In the posttransplant period, the risk of developing solid cancers after allo-HCT is 2 to 3 times higher than in the normal population.48 The rate is 2.2% to 6.4% at 10 years and 2.8% to 3.3% at 20 years posttransplant.49 Radiotherapy, immunosuppressive therapy, and cGVHD are among the known risk factors.3 In our study, 2.2% of patients were diagnosed with secondary cancer. For patients with skin cancer, it is important to have a sclerodermoid skin cGVHD diagnosis.

Psychosocial adjustment and sexual complications
Difficulties in social adjustment and employment after allo-HCT could lead to depression and anxiety.3 In our study, 27.7% of patients had psychiatric diagnosis (10.1% with depression and 17.6% with anxiety). These findings suggest that patients need support for social adjustment. Sexual reluctance may be due to multiple causes, especially hormonal or psychogenic causes.3 In our study, 52.7% of the patients had sexual reluctance. Treatment requires a multidisciplinary approach.

Fertility
Although posttransplant natural pregnancies can occur, the frequency is less than 15%.3 In our study, 5.8% of our patients had children by natural ways after allo-HCT. The relation between TBI history, busulfan use, cGVHD, and infertility is known.3,46 The relation between busulfan use and infertility was significant in our study (P = .008). However, we did not see a significant association between cGVHD and infertility (P = .113) or between TBI history and infertility (P = .381). Patients who want to have children should be referred to specialists.

Recommended screening
Posttransplant follow-up screening is recommended for diseases that concern general public health after allo-HCT.3 For example, 5.5% of patients required hypertension and 8.8% of patients required type 2 diabetes mellitus treatment. In Turkey, according to BMI, rates of being below normal weight, having normal weight, being preobese, and having obesity were reported as 4%, 42.1%, 34.3%, and 19.6%, respectively.50 In our study, these rates were 7.7%, 45%, 27.5%, and 19.8%, respectively.

In conclusion, patients and physicians should remain aware of the long-term complications after allo-HCT. Long-term evaluations should include detailed evaluations of body organs and systems. Early recognition of the complications mentioned in our study could lead to decreased mortality and morbidity after allo-HCT. For patients to be monitored by transplant centers for many years, training should be provided to ensure adequate follow-up of patients. Per previous results, the guideline that we use for long-term follow-up in our clinic3 can be used by others.


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DOI : 10.6002/ect.2018.0007


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From the Hematology and Bone Marrow Transplant Unit, Dr. Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Ankara, Turkey
Acknowledgements: No conflicts of interest were declared by the authors. This study received no financial support.
Corresponding author: Ali Hakan Kaya, Hematology and Bone Marrow Transplant Unit, Dr. Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Mehmet Akif Ersoy Mahallesi, 13 Cadde, No: 56, Yenimahalle, Ankara, Turkey
Phone: +90 530 9249045
E-mail: dr.alihakan@gmail.com