होम Biology of Blood and Marrow Transplantation Frequency of Abnormal Findings Detected by Comprehensive Clinical Evaluation at 1 Year after...
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CLINICAL RESEARCH Frequency of Abnormal Findings Detected by Comprehensive Clinical Evaluation at 1 Year after Allogeneic Hematopoietic Cell Transplantation Stephanie J. Lee,1 Travis Seaborn,1 Frances J. Mao,1 Susan C. Massey,1 Ngoc Q. Luu,1 Mary A. Schubert,3 Jason W. Chien,2 Paul A. Carpenter,1 Carina Moravec,3 Paul J. Martin,1 Mary E. D. Flowers1 Consensus guidelines recommend various screening examinations for survivors after allogeneic hematopoietic cell transplantation (HCT), but how often these examinations detect abnormal findings is unknown. We reviewed the medical records of 118 patients who received comprehensive, standardized evaluations at 1 year after allogeneic HCTat Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Abnormal findings were common, including moderate to severe pulmonary dysfunction (16%), fasting hyperlipidemia (56%), osteopenia (52%), osteoporosis (6%), and active chronic graft-versus-host disease (cGVHD) (64%). Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases. Only 3% of patients had no abnormal findings. We conclude that comprehensive evaluation at 1 year after allogeneic HCT detects a high prevalence of medical problems. Longer follow-up is needed to determine whether early detection and intervention affect later morbidity and mortality. Biol Blood Marrow Transplant 15: 416-420 (2009) Ó 2009 American Society for Blood and Marrow Transplantation KEY WORDS: Late effects, Allogeneic hematopoietic cell transplantation, Chronic graft-versus-host disease, Recurrent malignancy, Hypothyroidism, Osteoporosis, Immunity INTRODUCTION Numerous observational studies have documented the spectrum of late effects after allogeneic hematopoietic cell transplantation (HCT) in adults [1-8] and children [9,10]. Several position statements have provided recommendations about appropriate patient follow-up after allogeneic HCT [11-14]. These recommendations emphasize detection and management of procedure-related complications and other la; te effects in HCT survivors. For example, screening for secondary cancers and abnormalities of endocrine, cardiovascular, pulmonary, renal, and hepatic function is advised. Clinicians also are encouraged to discuss psychosocial issues and general health maintenance. From the 1Divisions of Clinical Research; 2Pulmonary and Critical Care, Fred Hutchinson Cancer Research Center, Seattle, Washington; and 3Long-Term Follow-Up Unit, Seattle Cancer Care Alliance, Seattle, Washington. Financial disclosure: See Acknowledgments on page 419. Correspondence and reprint requests: Stephanie J. Lee, MD, MPH, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D5-290, Seattle, WA 98109 (e-mail: firstname.lastname@example.org). Received November 19, 2008; accepted December 21, 2008 Ó2009 American Society for Blood and Marrow Transplantation 1083-8791/09/154-0001$36.00/0 doi:10.1016/j.bbmt.2008.12.502 416 Subspecialist evaluations by dentists, ophthalmologists, and gynecologists are recommended. The frequency with which these late effects and general health screening recommendations are followed, the likelihood of detecting abnormalities that result in medical interventions, and the ultimate impact of compliance with these screening recommendations on the health of HCT survivors are unknown. For 3 decades, the Long-Term Follow-Up (LTFU) program at Fred Hutchinson Cancer Research Center (FHCRC) has offered a comprehensive onsite evaluation to allogeneic HCT recipients at 1 year after transplantation (Table 1). Because the results of these evaluations are not comprehensively collected in a research database, we reviewed medical records for 118 of the 1-year evaluations of adults who had undergone allogeneic HCT in 2005 to identify the frequency of abnormal findings. STUDY DESIGN All adult patients who had undergone allogeneic HCT at FHCRC/Seattle Cancer Care Alliance (SCCA) in 2005 and were seen by the LTFU program 1 year later were eligible for the study. A single year was chosen for study, because a detailed retrospective Biol Blood Marrow Transplant 15:416-420, 2009 Table 1. Routine 1-Year Comprehensive Evaluation at FHCRC/Seattle Cancer Care Alliance Category Evaluations History and physical exam Chronic GVHD–focused review of systems and examination Complete skin examination Range of motion testing, if indicated Weight, height, vital signs, medical photographs List of all medications and supplements Complete blood cell count with differential Reticulocyte count Comprehensive chemistry panel Fasting lipid panel Virology screen (hepatitis, cytomegalovirus) Immunization titers Endocrine evaluations (thyroid, sex hormones) Iron tests Immunosuppressive drug levels ABO typing (if ABO-mismatched) Chimerism testing Bone marrow aspirate and biopsy Skin biopsy Pulmonary function tests Schirmer’s test Dual energy X-ray absorptiometry Chest X-ray (chest computed tomography scan if indicated) Mammogram (if age > 35 years) Pap smear (if age > 21 years or sexually active) Prostate specific antigen (if age > 45 years) Colonoscopy (if age > 50 years) Stool for occult blood (if age > 40 years) Ophthalmology Oral medicine (dentist) Gynecology Laboratory testing Other studies Secondary cancer screening Subspecialist exams GVHD indicates graft-versus-host disease. chart review was required. FHCRC’s Institutional Review Board approved the study design. Summary letters from FHCRC and laboratory results from the 1-year LTFU evaluation were reviewed to collect data on medical history, current abnormal findings, treatment recommendations, vaccinations and immunity, and current medications. Data were not collected on the patients’ pretransplantation medical status. Diagnoses of hyperlipidemia (elevated fasting cholesterol, triglycerides, or low-density lipoprotein), thyroid abnormalities (abnormal thyroidstimulating hormone, free thyroxine, or total thyroxine), iron abnormalities (abnormal ferritin, serum iron, total iron-binding capacity, or transferrin saturation), and immunity (preimmunization titers against specific pathogens) were based on laboratory results. Diagnosis of recurrent malignancy was based on radiologic studies, tissue biopsy analyses, and blood, urine, and bone marrow tests. Chronic graft-versus-host disease (cGVHD) was diagnosed based primarily on clinical criteria . Thirty charts (25%) were selected at random for second abstraction to confirm the accuracy of 20 key variables; the median number of abstraction errors was 1 (5%; range, 0 to 6). Evaluation of HCT Survivors 417 Results are reported as medians and ranges for continuous variables and as percentages for categorical variables. Wilcoxon’s rank-sum test was used to compare continuous variables, and the c2 or Fisher’s exact test was used to compare categorical variables. RESULTS Subject Characteristics A total of 258 adults underwent allogeneic HCT in 2005. Among these, 113 died and 11 experienced recurrent malignancy before 1 year and did not return for LTFU evaluation. Of 134 patients who survived at least 1 year and were alive without active malignancy, making them eligible to return for their comprehensive evaluation, 118 (88%) were included in this study. Sixteen eligible patients (12%) did not return for 1-year evaluation. There were no statistically significant differences in age, sex, donor type, graft source, number of transplantations, conditioning regimen, or frequency of second transplantations between the patients who returned for LTFU evaluation and those who did not. Information on insurance coverage was not available, and it is possible that lack of insurance or limitations on return visits to the transplantation center could differ between those who did and did not return. The study cohort included 69 men (58%), 47 patients (40%) who had received reduced-intensity conditioning (RIC), 62 (53%) who had undergone HCT from an unrelated donor, 105 (89%) who had received a granulocyte colony-stimulating factor (G-CSF)– mobilized peripheral blood graft, and 18 (15%) who had undergone a second transplantation. The median age at HCT was 47 years (range, 19 to 69 years). Forty-eight of the patients (41%) lived in Washington. Most of the patients (n 5 102; 86%) spent 2 to 4 days in Seattle for testing and consultation as part of their LTFU evaluation; 16 (14%) provided results of diagnostic testing performed elsewhere. These outside test results were reviewed in lieu of testing at FHCRC. Most patients were followed by their primary oncologist and usually were not seen by the LTFU clinical service at FHCRC/SCCA between day 100 and 1 year, even if they lived locally. Medication Usage At the time of the 1-year LTFU evaluation, the patients were taking a median of 6 systemic medications (interquartile range, 4 to 9) (Table 2). Most (94%) were still taking prophylactic antibiotics, 71% were taking an immunosuppressive medication (56%, a calcineurin inhibitor; 50%, a corticosteroid), 30% were taking a bisphosphonate, 27% were receiving hormone therapy, 26% were taking an antidepressive drug, 418 S. J. Lee et al. Biol Blood Marrow Transplant 15:416-420, 2009 Table 2. Medication Use at 1 Year after Allogeneic HCT in 118 Patients n (%) Anti-infective agent Calcineurin inhibitor Corticosteroid Antihypertensive agent Bisphosphonate Hormone replacement therapy Antidepressive agent Diabetes medication Thyroid replacement therapy Lipid-lowering agent 111 (94) 66 (56) 59 (50) 38 (32) 35 (30) 32 (27) 31 (26) 18 (15) 15 (13) 11 (9) 15% were taking antidiabetes medication, 13% were on thyroid hormone replacement, 38% were taking an antihypertensive agent (7% with an angiotensionconverting enzyme inhibitor or an angiotensin II receptor blocker), and 9% were taking a lipid-lowering agent (7% with a 3-hydroxy-3-methyl-glutaryl–CoA reductase inhibitor). We did not collect information about medication usage before HCT. Prevalence of Problems and Frequency of Recommendations Table 3 shows the prevalence of selected problems after HCT. Among the 106 patients who had no previous evidence of disease relapse after HCT (90%), 4 (4%) were diagnosed with recurrent malignancy during the LTFU visit. Before the LTFU visit, 56% of patients had active cGVHD, 18% had inactive or resolved cGVHD, and 31% did not have cGVHD. Of the patients without previous cGVHD, 9 (29%) were diagnosed with cGVHD during the LTFU visit; thus, the overall prevalence of active cGVHD was 64%. Pulmonary function tests were available for 116 subjects. Only 26 (22%) had a normal modified lung function score (mLFS) according to forced expiratory volume for 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO) adjusted for hemoglobin . Seventy-two (62%) had mild pulmonary dysfunction (mLFS 3 to 5), 16 (14%) had moderate dysfunction (mLFS 6 to 9), and 2 (2%) had severe pulmonary dysfunction (mLFS 10 to 12). Compared with pulmonary function tests conducted before HCT (n 5 115), 56 patients (49%) did not change categories and 6 (5%) improved by at least 1 category. In contrast, 46% worsened by either 1 category (n 5 50; 43%) or 2 categories (n 5 3; 3%). Gynecologic exam results were available for 45 of 49 women (92%). Pap smears were abnormal (n 5 10) or insufficient (n 5 1) in 24%, and led to recommendations for retesting before 1 year for 6 women (13%) and interventions for 2 women (4%). Twentyfive underwent mammography, all of which were normal. Vulvovaginal cGVHD was diagnosed in 20 women (47%), judged to be mild in 12 (29%), moderate in 5 (11%), and severe in 3 (7%). Overall, 26 of 45 women (58%) had 1 or more abnormal gynecologic findings, leading to recommendations for altered screening schedules, therapeutic interventions, or medication changes in 20 of these 26 women (77%). Only 4 patients (3%) had no abnormal findings. Most of the patients had either 2 (n 5 29; 25%) or 3 (n 5 40; 34%) abnormal findings. The median number of treatment recommendations provided by FHCRC was 2 (n 5 50 [42%]; interquartile range, 2 to 3); only 1 patient (1%) did not receive a new recommendation after the LTFU evaluation. Active cGVHD and abnormal bone mineral density were the major problems that led to a dosage change or new medication for affected patients, whereas moderate to severe pulmonary dysfunction usually led to recommendations for more frequent pulmonary function testing. Abnormal laboratory studies (serum iron, fasting lipids, and thyroid function tests) were least likely to result in changes to treatment or monitoring. There was no statistical difference in the frequency of abnormal findings and treatment recommendations between patients who had received RIC and those who had received myeloablative conditioning. Vaccination and Immunity Almost all patients received routine immunizations at the 1-year LTFU visit. Some physicians did not give immunizations to patients who were currently ill or known to have very low B cell numbers, although this practice was not standardized. Lack of protective antibodies was documented for pneumococcus in 45% of patients, haemophilus influenza B in 79%, tetanus in 64%, and hepatitis B in 74%; additional doses of at least 1 vaccine were recommended for 95% of patients. DISCUSSION Although our patients were all evaluated at approximately 1 year after HCT, our findings are consistent with the literature regarding the overall incidence of late effects. Specifically, our rates of osteoporosis, osteopenia, hyperlipidemia, diabetes, gynecologic abnormalities, and pulmonary function deficits are similar to those reported in survivors at later times after HCT [2-4,6,7,9,17,18]. Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases. Detection of new cases of cGVHD did not result from implementation of the new NIH Consensus Criteria, because the new standards are more restrictive than previous definitions . Several problems, such as hyperlipidemia, iron abnormalities, and thyroid function abnormalities, were less likely to be noted in the medical records or to generate a treatment recommendation. We hypothesize that physicians may have believed that these laboratory abnormalities would resolve with time, or they may Biol Blood Marrow Transplant 15:416-420, 2009 Evaluation of HCT Survivors 419 Table 3. Prevalence of Abnormal Findings and Frequency of Recommendations at 1 Year after Allogeneic HCT Recommendations for Affected Patients Problem Prevalence Continuation of Current Management Abnormal iron tests Active chronic GVHD Abnormal gynecologic findings Elevated fasting lipid levels Osteopenia + osteoporosis Abnormal thyroid tests Moderate to severe pulmonary dysfunction Recurrent malignancy 71% 64% 58% 56% 52% + 6% 22% 16% 4%* 24% 19% 28% 38% 42% 52% 22% 0% Dosage Change, New Medication, or Change in Monitoring Schedule No Recommendation or No Discussion in Medical Records 17% 79% 77% 18% 44% 16% 78% 100% 59% 2% 0% 44% 14% 32% 0% 0% HCT, hematopoietic cell transplantation; GVHD, graft-versus-host disease. *In patients with no previous evidence of disease. have been reluctant to recommend a new medication or intervention given the number of medications already taken by the patients. Reports of late cardiovascular and other complications after allogeneic HCT suggest that more aggressive management of laboratory abnormalities may be warranted [8,17]. The high rate of abnormal findings in our study suggests that it is reasonable to use the 1-year anniversary of the graft infusion as a simple, easily remembered reminder to conduct a comprehensive evaluation. In fact, earlier screening may be warranted for some conditions for which interventions can be applied within the first posttransplantation year. Our experience is that using the transplantation anniversary date helps physicians track scheduled screening examinations and ensures that recommended testing is completed. Testing can be done by the transplantation center or by the patient’s oncologist or primary physician. The present study identified some routine tests that do not appear to be justified based on clinical use of the information. For example, results from routine chest X-rays, Schirmer’s tests, and skin biopsy analyses appeared to have little effect on treatment and monitoring recommendations unless supported by clinical symptoms ; thus, these tests would be better reserved for symptomatic patients or situations in which there is a defined clinical or research question. Limitations of this study include the retrospective study design and the assessment of practices only in a single year at a single institution, which might not be representative of other time periods or other institutions. We reviewed chart notes and electronic medical records including laboratory data, but these sources may not have fully captured medical problems, medical decision-making processes, and physician recommendations. Sixteen patients (12%) did not return for LTFU evaluation. Although we did not identify any differing characteristics, these patients may have had their LTFU evaluations done locally or may differ in important ways from the returning cohort. For example, a patient with no apparent transplantation-related medical problems at 1 year might have felt that there was no need to return for a comprehensive evaluation. We conclude that routine comprehensive LTFU evaluation at 1 year after allogeneic HCT detects a high prevalence of medical problems necessitating intervention or adjustment of therapy. Although the ultimate effect on health outcomes is unknown, our findings suggest that systematic evaluation as early as 1 year after HCT is an important aspect of early detection and monitoring for late effects. Continued longitudinal study of this group of patients is needed to determine whether serious late effects and late treatment-related mortality (TRM) can be prevented through continued screening and appropriate early interventions [19,20]. ACKNOWLEDGMENTS Financial disclosure: This work was supported by National Cancer Institute Grant CA018029. We thank our colleagues, the nurses, and the clinical staff of the LTFU program at FHCRC/Seattle Cancer Care Alliance, as well as our patients, for their valuable contributions to the clinical and research program. REFERENCES 1. Stern JM, Sullivan KM, Ott SM, et al. Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow Transplant. 2001;7:257-264. 2. Socie G, Salooja N, Cohen A, et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood. 2003;101: 3373-3385. 3. Baker KS, Gurney JG, Ness KK, et al. Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study. Blood. 2004;104:1898-1906. 4. Savani BN, Montero A, Srinivasan R, et al. 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