Hematopoietic Cell Transplantation Survivors Research Articles

Prevalence and Associated Factors for Arterial Hypertension in Adults Following Hematopoietic Stem Cell Transplantation

Background: Survivors of hematopoietic stem cell transplantation (HSCT) are 2 to 4 times more likely to develop cardiovascular diseases, accounting for 2-11% of mortality among long-term survivors. Early diagnosis and treatment of modifiable risk factors, such as arterial hypertension, are imperative in this group of patients. The aim of this study is to evaluate the prevalence and associated factors for arterial hypertension following HSCT in a Colombian population. Methods: A retrospective study was conducted in 220 consecutive adult HSCT recipients who underwent transplantation between 2009 and 2017 at a third level referral center in Colombia. Blood pressure data, from two different measures, were collected at 7 time points: day of mobilization for autologous HSCT (auto-HSCT) and day 0 before infusion for allogeneic HSCT (allo-HSCT), day 7, and months 1, 3, 6 and 12 post-HSCT. Arterial hypertension was defined as a systolic blood pressure 140mmHg and/or a diastolic blood pressure 90 mmHg. Patients with history of arterial hypertension were excluded. Descriptive statistics were used to analyze patient's demographic data. Bivariate and multivariate analyses were performed to assess the association between clinical characteristics and arterial hypertension. Results: One hundred and seventy-one patients were included, with a median age of 45 years (range 18-71). Eighty-nine patients (52.1%) were male. One hundred and fifteen patients (67.3%) underwent auto-HSCT and 56 (32.7%) allo-HSCT. The most common indication for HSCT were lymphomas (39.8%), followed by leukemia (28.6%) and multiple myeloma (23.4%). Thirty-six patients (21.1%) developed arterial hypertension by the end of the first year of follow-up. Prevalence of hypertension at each time point was 2.3% on day 7 post-HSCT, 4.7%, 5.3%, 5.5% and 8.1% at 1, 3, 6 and 12 months respectively. Allo-HSCT (P<0.001), diagnosis of leukemia (P<0.001) or lymphoma (P<0.05), therapy with calcineurin inhibitors (P=0.004), prophylactic treatment for GvHD with mycophenolate (P<0.05) and acute GvHD (P<0.001) were significantly associated with the development of arterial hypertension. After performing multivariate regression analysis to identify arterial hypertension associated factors, patients with allo-HSCT were found to be 3 times more likely to develop arterial hypertension than patients with auto-HSCT (95% CI 1.85-8.60, P=0.000). Conclusions: Screening for arterial hypertension is warranted in HSCT survivors since it is a modifiable cardiovascular risk factor. Similar to previously reported findings, we found an association between post-HSCT arterial hypertension and allo-HSCT, use of calcineurin inhibitors and mycophenolate, and development of acute GvHD. Patients undergoing allo-HSCT are at increased risk of developing hypertension. Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Primary Care Physician Perspectives on Caring for Adult Survivors of Hematologic Malignancies and Hematopoietic Cell Transplantation

BackgroundPrimary care physicians (PCPs) may face barriers to caring for hematologic malignancy and hematopoietic cell transplantation (HCT) survivors. MethodsA Web-based survey consisting of 40 questions and 2 case scenarios was administered to 302 PCPs at 2 large integrated health care systems. The questionnaire assessed perceived barriers to delivery of care to hematologic malignancy/HCT survivors, resources available to care for cancer survivors, practices for care coordination with hematologist-oncologists, and preferred models of care delivery. ResultsOverall response rate was 30% (n = 86). PCPs reported several barriers such as lack of resources to facilitate care (69%), lack of awareness of screening/prevention guidelines (55%) and psychosocial needs of survivors (65%), inadequate time (65%), and patient preference to follow up with their oncologists (66%). They expressed confidence in caring for general medical issues (84%) and general cancer screening (73%), but they preferred that oncologists manage cancer-related medical issues (42%) as well as screen for cancer recurrence (52%) and secondary cancers (55%). In multivariable analysis, PCPs who had previously cared for a large number of hematologic malignancy/HCT survivors and those with a longer time since graduation from medical school had greater confidence in managing cancer-related medical issues. ConclusionPCPs report several barriers in providing care to hematologic malignancy/HCT survivors. Clinical experience with this patient population is associated with greater confidence in providing survivorship care. Several barriers identified by PCPs in providing survivorship care to hematologic malignancy/HCT survivors are potentially addressable by education and clinical decision support tools and guidelines, thereby enhancing the patients’ clinical experience and care coordination with hematologist-oncologists.

Trial in Progress: A Phase 3 Study of Itacitinib or Placebo in Combination with Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease (GRAVITAS-309)

Background Allogeneic hematopoietic cell transplantation (HCT) is indicated for several hematologic malignancies and nonmalignant disorders. Chronic graft-versus-host disease (cGVHD) develops in 30%-70% of long-term survivors of HCT and is a significant cause of nonrelapse mortality. Corticosteroids (CS) are the recommended first-line treatment for cGVHD; however, up to 60% of patients treated with CS require additional cGVHD therapy within 2 years. Furthermore, long-term exposure to CS is associated with a wide range of toxicities and increased risk of infection. Novel safe and effective therapies are needed to treat cGVHD and reduce CS dependence. Janus kinases (JAKs) mediate the signaling of proinflammatory cytokines involved in the pathogenesis of cGVHD. Itacitinib is a JAK-1 selective inhibitor that improved graft-versus-host disease (GVHD) and survival without affecting engraftment of donor leukocytes in murine models. In a phase 1 clinical study, itacitinib 200 or 300 mg once daily (QD) was well tolerated in patients with steroid-refractory or steroid-naive acute GVHD (aGVHD). Here we describe the trial design of the first clinical study evaluating the safety and efficacy of itacitinib for the treatment of cGVHD. Study Design and Methods GRAVITAS-309 (NCT03584516) is a 2-part phase 3 study of itacitinib or placebo in combination with CS as initial treatment for cGVHD. Patients aged ≥18 years who underwent allogeneic HCT from any donor type and graft source, with evidence of myeloid and platelet engraftment, and who have active, moderate, or severe cGVHD per National Institutes of Health Consensus Criteria are eligible to participate. Patients are excluded if they received >1 prior HCT (except autologous), had >3 days of systemic CS treatment for cGVHD, received any other systemic treatment for cGVHD, have presence of active uncontrolled infection, or had treatment with a JAK inhibitor within 8 weeks of randomization (patients who previously received a JAK inhibitor for aGVHD are eligible only if they achieved a complete or partial response). Part 1 is a randomized, open-label study to determine optimal dosing of itacitinib in combination with CS (~20 patients randomized 1:1 to itacitinib 200 mg QD or 300 mg QD; Figure 1). The primary endpoints for Part 1 are dose-limiting toxicities (DLTs) through Day 28 as well as clinical safety and laboratory assessments. Main secondary endpoints include pharmacokinetic (PK) parameters and efficacy outcomes (Table 1). After 20 patients have completed 28 days of treatment, an external data monitoring committee will review the data and provide a recommendation for an appropriate dose for Part 2 based on emergent adverse events, clinical laboratory parameters, PK data, and DLTs. Part 2 is a randomized, double-blind, placebo-controlled study using the dose selected in Part 1 to assess the efficacy and safety of itacitinib plus CS vs placebo plus CS (~246 patients stratified by cGVHD severity and randomized 1:1; Figure 1). Patients randomized to the placebo group will be permitted to cross over to the itacitinib group after completion of the primary analysis. The primary endpoint is overall response rate (proportion of patients with complete or partial response) at 6 months. Secondary endpoints include changes in symptom scores using health-related quality-of-life measures, additional efficacy outcomes, PK parameters, and clinical safety assessments (Table 1). Exploratory biomarker analyses will evaluate the effects of JAK inhibition on circulating inflammatory cells (ie, T-cell subsets, B cells, natural killer cells, cytokines) and biomarkers of GVHD in peripheral blood after transplant. Patients will remain on study for a total of 37 months, which includes treatment period, safety follow-up, and posttreatment GVHD follow-up, unless confirmed GVHD progression, start of a new GVHD therapy, or relapse/recurrence of underlying hematologic disease occurs earlier. Efficacy analyses will be performed on the intent-to-treat population; safety analyses will be conducted on all randomized patients who receive ≥1 dose of study drug. The PK-evaluable population will include all patients who receive ≥1 dose of study drug and provide ≥1 postdose plasma PK sample. Disclosures Morariu-Zamfir: Incyte Corporation: Employment. Bleam:Incyte Corporation: Employment. Yan:Incyte Corporation: Employment.

Diagnostic Predictive Model for Diagnosis of Heart Failure after Hematopoietic Cell Transplantation (HCT): Comparison of Traditional Statistical with Machine Learning Modeling

Background: Therapy-related heart failure (HF) is a leading cause of morbidity and mortality in patients who undergo successful HCT for hematological malignancies. To eventually help improve management of HF, timely and accurate diagnosis of HF is crucial. Currently, no established method for diagnosis of HF exist. One approach to help improve diagnosis and management of HF is to use predictive modeling to assess the likelihood of HF, using key predictors known to be associated with HF. Such models can, in turn, be used for bedside management, including implementation of early screening approaches. That said, many techniques for predictive modeling exist. Currently, it is not known if Artificial Intelligence machine learning (ML) approaches are superior to standard statistical techniques for the development of predictive models for clinical practice. Here we present a comparative analysis of traditional multivariable models with ML learning predictive modeling in an attempt to identify the best predictive model for diagnosis of HF after HCT. Methods: At City of Hope, we have established a large prospective cohort (>12,000 patients) of HCT survivors (HCT survivorship registry). This registry is dynamic, and interfaces with other registries and databases (e.g., electronically indexed inpatient and outpatient medical records, national death index [NDI]). We utilized natural language processing (NLP) to extract 13 key demographics and clinical data that are known to be associated with HF. For the purposes of this project, we extracted data from 1,834 patients (~15% sample) who underwent HCT between 1994 to 2004 to allow adequate follow-up for the development of HF. We fit and compared 6 models [standard logistic regression (glm), FFT (fast-and-frugal tree) decision model and four ML models: CART (classification and regression trees), SVM (support vector machine), NN (neural network) and RF (random forest)]. Data were randomly split (50:50) into training and validation samples; the ultimate assessment of the best algorithm was based on its performance (in terms of calibration and discrimination) in the validation sample. DeLong test was used to test for statistical differences in discrimination [i.e. area under the curve (AUC)] among the models. Results: The accuracy of NLP was consistently >95%. Only the standard logistic regression model LR (glm) resulted in a well-calibrated model (Hosmer-Lemeshow goodness of fitness test: p=0.104); all other models were miscalibrated. The standard glm model also had best discrimination properties (AUC=0.704 in training and 0.619 in validation set). CART performed the worst (AUC=0.5). Other ML models (RF, NN, and SVM) also showed modest discriminatory characteristics (AUCs of 0.547, 0.573, and 0.619, respectively). DeLong test indicated that all models outperformed CART model (at nominal p<0.05 ), but were statistically indistinguishable among each other (see Figure). Power of analysis was borderline sufficient for the glm model and very limited for ML models. Conclusions: None of tested models showed optimal performance characteristics for their use in clinical practice. ML models performed even worse than standard logistic models; given increasing use of ML models in medicine, we caution against the use of these models without adequate comparative testing. Figure Disclosures No relevant conflicts of interest to declare.

Predictors of Loss to Follow-Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors: A Report from the Center for International Blood and Marrow Transplant Research.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

Cardiotoxicity of mediastinal radiotherapy.

To explore available recent literature related to cardiotoxicity following mediastinal radiation. Radiotherapy-related heart injury is well documented, with no apparent safety threshold dose. The number of long-term cancer survivors exposed to mediastinal radiotherapy at some point of their treatment is increasing. Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures. In October 2018, we identified articles published after 1990 through a PubMed/MEDLINE database search. The authors examined rough search results and manuscripts not relevant for the topic were excluded. We extracted clinical outcomes following mediastinal radiotherapy of childhood cancers, lymphoma, medulloblastoma, thymic cancers and hematopoietic cell transplantation survivors and evaluated treatment planning data, whenever available. A total of 1311 manuscripts were identified in our first-round search. Of these manuscripts, only 115 articles, matching our selection criteria, were included. Studies uniformly show a linear radiation dose-response relationship between mean absorbed dose to the heart (heart-Dmean) and the risk of dying as a result of cardiac disease, particularly when heart-Dmean exceeds 5Gy. Limited data are available regarding dose-volume predictors for heart substructures and the risk of subsequent cardiac toxicity. An individual patient's cardiotoxicity risk can be modified with advanced treatment planning techniques, including deep inspiration breath hold. Proton therapy is currently showing advantages in improving treatment planning parameters when compared to advanced photon techniques in lymphoma, thymic malignancies, malignant mesothelioma and craniospinal irradiation.

Parent proxy assessment of sibling quality of life following pediatric hematopoietic cell transplantation

BackgroundWhen a child undergoes hematopoietic cell transplantation (HCT), the impact extends to the entire family, including siblings. Assessment of the quality of life (QoL) of siblings is challenged by their general lack of availability for regular assessment by clinical providers. Thus, the use of parent proxy reporting may be useful. Our aim was to describe the QoL of siblings of HCT survivors, as reported by their parents, as well as to identify parent and family factors associated with lower sibling QoL.MethodsA cross-sectional study was utilized to assess parent-reported QoL of the HCT recipient’s sibling (Short Form (SF)-10 Health Survey for Children and the Pediatric Symptom Checklist (PSC)-17). Parent QoL was assessed using the SF-12. Multivariable linear regression was used to explore hypothesized predictors of sibling QoL, including parent QoL, family impact/function (Impact on Family Scale, Family Adaptability and Cohesion Evaluation Scales, IV, and a question asking about financial problems) while adjusting for demographic and HCT characteristics.ResultsNinety-seven siblings (55% males) with a mean age of 12 years (standard deviation [SD] 4 years) were assessed, representing HCT survivors, who were an average of 5 years (SD 4 years) post-HCT. Neither sibling psychosocial (mean 49.84, SD 10.70, p = 0.87) nor physical health scores (mean 51.54, SD 8.42, p = 0.08) differed from norms. Parent proxies reported behavioral/emotional problems (PSC-17 total score > 15) in 24% of siblings. While parental ratings of their own physical health (SF-12 were higher than norms (mean 53.04, SD 8.17, p = 0.0005), mental health scores were lower (mean 45.48, SD 10.45, p < 0.0001). In multivariable analysis, lower parent emotional functioning and adverse family function were associated with lower sibling QoL, as reported by parents.ConclusionsWhile proxy-reported QoL of siblings did not differ significantly from normative data, both parent QoL and family function were associated with sibling QoL. Future research is needed to understand how siblings themselves perceive their QoL following HCT.

Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplantation

Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown. Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation. We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research. Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67). Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review. These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.

Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell transplantation

Early cardiovascular disease is relatively common among childhood cancer survivors (CCS). A high risk of accelerated atherosclerosis and a 8.2-fold higher cardiac mortality rate have been reported (1). Arterial stiffness, an independent risk factor for cardiovascular morbidity and mortality in adults, seems to increase in young adult CCS (2). In hematopoietic cell transplantation (HCT) survivors, the risk of cardiovascular death is 2–4 fold higher than the general population, and cardiovascular adverse events occur earlier than average (3).

Lung evaluation in 10year survivors of pediatric allogeneic hematopoietic stem cell transplantation.

There is little data on the long-term respiratory development of children after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We describe the respiratory assessment 10years after allo-HSCT of 35 children transplanted between 2000 and 2004. During this period, 90 children were transplanted at our center. Twenty-five children died, thirty were lost to follow-up, and thirty-five came to have a pulmonary investigation. The thirty-five participants answered a questionnaire asking if they had pulmonary symptoms, and pulmonary function tests (PFTs) were performed. The median age of these children 10years after the transplant was 16years old. Just over a third of them had pulmonary symptoms. Among them, 5/13 (38%) had bronchiolitis obliterans syndrome (BOS). The majority of children (62.8%) did not have respiratory symptoms. PFTs were abnormal in one-third of asymptomatic children, revealing restrictive lung disease that was always mild to moderate (p = 0.02).Conclusion: In the long term, research at the time of the medical examination for the presence of chronic cough, shortness of breath on exertion, or wheezing helps to guide the clinician as to the need for further lung exploration. Similarly, informing patients and their families about these symptoms, which can be underestimated, should allow for more specific management.What is Known:• Pulmonary complications are a major cause of hematopoietic stem cell transplantation (HSCT) morbidity and mortality.• A long time after allogeneic HSCT, pulmonary function tests abnormalities may occur in children, but it is not always related to symptoms.What is New:• The occurrence of respiratory symptoms: cough, dyspnea on exertion, chronic bronchitis, and wheezing should be systematically investigated in the follow-up of allografted patients, even at a distance.• The presence of respiratory symptoms should lead to a respiratory functional investigation to detect the presence of an obstructive syndrome.

Early Prediction of Cardiovascular Risk after Hematopoietic Cell Transplantation: Are We There Yet?

Cardiovascular (CV) events have emerged as a major cause of morbidity and mortality among hematopoietic cell transplantation (HCT) survivors. Accumulating evidence supports the presence of increased CV risk in HCT recipients. Most studies have focused mainly on traditional CV risk factors, such as the metabolic syndrome and hypertension. However, detection of these factors suggests the development of irreversible overt clinical atherosclerosis. Therefore, earlier prediction of CV risk is needed to prevent CV morbidity and mortality in these patients. In the field of CV research, endothelial dysfunction is considered an early event in the pathophysiology of CV risk factors, and a number of markers have been proposed for its assessment. In addition, markers of subclinical target organ damage have been introduced to implement CV risk prediction and early preventive or intensive therapeutic interventions. Furthermore, a number of CV models have been suggested aiming for optimal stratification of patients. Preliminary studies have indicated excess CV risk using these early markers in HCT recipients. However, their role in the pathophysiology and clinical practice in HCT survivors remains largely understudied. Taking into account the need for increased awareness from treating physicians in this evolving setting, we conducted a state-of-the-art review aiming to summarize current knowledge on endothelial dysfunction, subclinical target organ damage, and CV risk prediction in HCT survivors.

Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation

AbstractWe examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMNs) in the era of reduced-intensity and nonmyeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4905 1-year survivors of allogeneic HCT for hematologic malignancies (N = 4500) or nonmalignant disorders (N = 405) who received transplants between 1969 and 2014, we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMNs by 30 years after HCT was 22.0%. Compared with age-, sex-, and calendar year–matched Surveillance, Epidemiology, and End Results (SEER) population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR, 28.8), oral cavity (SIR, 13.8), skin (SIR, 7.3), central nervous system (SIR, 6.0), and endocrine organs (SIR, 4.9). The highest excess absolute risks (EARs) were seen with breast cancer (EAR, 2.2) and cancers of the oral cavity (EAR, 1.5) and skin (EAR, 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1000 cGy) or high-dose fractionated (1440-1750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still twofold higher than in the general population. These data demonstrate a strong effect of TBI dose, dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMNs increases with follow-up time; thus, HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.

Late infectious complications in hematopoietic cell transplantation survivors.

7046 Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p &lt; 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p &lt; 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p &lt; 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.

Patient-reported outcomes (PROs) in adult survivors of childhood hematopoietic cell transplant (HCT): A report from the St. Jude lifetime cohort study.

10049 Background: We examined PROs including symptom prevalence and quality of life (QOL) in adult survivors of childhood HCT compared to those treated with conventional therapy and non-cancer controls, and risk factors of impaired PROs. Methods: Physical and psychological symptoms and QOL were reported by 112 survivors of hematologic malignancies treated with HCT, 1106 treated with conventional therapy, and 242 non-cancer controls. PROs were self-reported using a survey, which included demographics, Brief Symptom Inventory and 36-Item Short Form Survey. Each participant completed a clinical physical health assessment and chronic health conditions (CHCs) were graded using a modified Common Terminology Criteria for Adverse Events. Multivariable logistic regression was conducted to estimate odds ratios (OR) and 95% confidence intervals (CI) for PROs using demographics and CHCs as predictors. Results: HCT and conventional therapy survivors’ mean age at survey and time since diagnosis were 28 and 29 years, and 19 and 20 years, respectively. The mean age at survey for non-cancer controls was 35 years. HCT survivors reported high prevalence of pain (64%), sensory (39%) and memory problems (29%), anxiety (29%), and depression (24%), which was not significantly different from survivors treated with conventional therapy. Compared to non-cancer controls, HCT survivors had more sensory (OR 3.2; 95% CI 1.5-6.8), motor (OR 4.3; 95% CI 1.2-15.4), and memory (OR 3.7; 95% CI 1.5-8.9) problems, and worse physical QOL (OR 5.4; 95% CI 1.6-18.6). Presence of PROs were associated with organ-specific CHCs (grade 3-4 vs. grade 0-2) not receipt of HCT: cardiac symptoms with cardiovascular CHCs (OR 3; 95% CI 1.8-4.9), pulmonary symptoms with pulmonary CHCs (OR 2.5; 95% CI 1.4-4.3), nausea with gastrointestinal CHCs (OR 2; 95% CI 1.2-3.1), and sensory (OR 1.9; 95% CI 1.2-3.1) and motor (OR 3.3; 95% CI 2-5.5) problems with neurological CHCs. Conclusions: Prevalence of symptoms and impaired QOL in HCT survivors is comparable to survivors treated with conventional therapy, but higher than non-cancer controls. PROs may have a role in facilitating identification of adverse events in survivors.

Ocular instillation of vitamin A–coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD

AbstractChronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.

The experience of dysgeusia in allogeneic haematopoietic cell transplantation survivors: a qualitative study.

Taste disorders are one of the most common side effects of treatment in oncology patients and often occur after allogeneic haematopoietic cell transplantation (allo-HCT). Dysgeusia does not receive close medical attention, and information about this disorder is largely based on the clinician's own experience. However, taste disorders can have an impact on the quality of life and nutritional status of survivors of allo-HCT. The number of performed annual transplantations is growing, as the number of older long-term survivors increases, but only few research studies examine survivors of allo-HCT with taste disorders. We conducted a qualitative descriptive study to explore experiences of dysgeusia in patients undergoing allo-HCT and to examine what strategies they used to mitigate it. Using purposeful sampling, survivors of allo-HCT were recruited. Audiotape interviews were conducted until data saturation was achieved. Each interview was transcribed verbatim, and content analyses were performed to extract significant themes and subthemes. Three major themes embracing various aspects of allo-HCT survivors' experiences were identified: (1) the shape of taste; (2) everything is irritating and it is arduous to eat; (3) finding new strategies to overcome the problems. Together, they highlight the experiences of survivors showing how the taste disorders can affect the physical, psychological and social dimensions of a person. A cumulative burden is the result of dysgeusia and its clinical course reinforced also by related symptoms. Healthcare professionals must focus their attention on the management of these symptoms and offer interventions to safeguard the patient's social, physical and psychological well-being.

Effects of smoking on outcomes of hematopoietic cell transplantation: a systemic review and future directions.

Hematopoietic cell transplantation (HCT) survivors are at risk of increased mortality compared to the general population. Smoking by HCT survivors has been reported to impact a variety of health outcomes, resulting in an increased risk for infections, cardio-pulmonary diseases, and cancer. The purpose of our study was to conduct a systematic literature search to determine the relationship between tobacco smoking pre-HCT and post-HCT outcomes. We conducted an electronic literature search from all languages from multiple peer-reviewed databases of studies that evaluated the effects of tobacco smoking prior to HCT on clinical outcomes. Data were extracted from the studies according to a strict selection criterion. Due to differences in primary endpoint and different populations evaluated in different studies, a meta-analysis was not possible, and a descriptive quantitative analysis is provided. Out of the 447 publications fulfilling the selection criteria for the electronic search, 17 articles were included in the final sample. The studies varied in terms of study design, patient characteristics, and HCT type. Considerable variability in definition of smoking was observed. We found that smoking pre-HCT was associated with a higher incidence of cardiovascular diseases, new infections, pulmonary complications, and cancers in comparison to non-smokers. Moreover, smoking pre-HCT was significantly associated with increased risks of both relapse and non-relapse mortality, and inversely related to median overall survival. Smoking adversely affects mortality in all HCT survivors by increasing the risks of both malignant and non-malignant complications. Thus, guidelines are urgently needed to formulate lifestyle factor modifications for HCT survivors focusing on smoking cessation strategies and abstinence maintenance in former smokers. Given the strength of these findings, guidelines should include systematic definitions of smoking for use in clinical trials as well as in standardized data reporting.

Treatment exposures stratify need for echocardiographic screening in asymptomatic long-term survivors of hematopoietic stem cell transplantation.

We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽-2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score -2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3-99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.

Implementing Recommended Long Term Follow up Screening and Preventive Practices in an Allogeneic Hematopoietic Cell Transplant Survivorship Clinic

The number of allogeneic hematopoietic cell transplantation (HCT) survivors is projected to increase and guidelines for screening and management of late effects have been established. Although the value of a systematic process for the long-term care of HCT survivors and screening of late effects is increasingly recognized, best practices for the implementation of survivorship care delivery has not been well described. In October 2016, we established a Survivorship Clinic for allogeneic HCT recipients in our Blood and Marrow Transplant (BMT) Program. A consultative model aimed to augment care provided by the patient's primary transplant and primary care physician was felt to best fit our program's needs. Patients (pts) are seen by a Nurse Practitioner (NP) and social worker (SW) at day 100 and 1 year visits. Visits include a comprehensive history and physical, symptom assessment, and graft-versus-host disease evaluation, as well as review and provision of a treatment summary and care plan. 1-year recommended assessments include: bone density scan, vitamin D, TSH, lipid panel, HbA1c, Ferritin, pulmonary function tests (PFTs), ophthalmic exam, and mammogram and pelvic exam (women). We performed a formal review of follow up with recommended screening guidelines among pts seen in our Survivorship Clinic from 2016-2018. Since its establishment, 161 pts received allogeneic HCT in our Program, of whom 131 pts have been seen at day 100 and 42 have been seen at 1-year. Patients not seen at day 100 were due to relapse, death or acute illness where they were not able to attend the clinic visit. Among pts seen at day 100 but not at 1 year, 7 were international, 2 were deferred due to relapse, 12 died prior to one year follow up, one transferred care to another facility and 67 have not reached their 1-year follow up. Of 42 pts seen at 1 year, all have received a complete treatment summary and care plan at both day 100 and 1 year. 35 pts had an evaluation and follow up with their transplant SW for psychosocial assessment. 41 pts had a bone density scan completed. All 42 pts completed a screening TSH, vitamin D, lipid panel, HbA1c, Ferritin, and PFTs. 36 saw ophthalmology for a yearly exam. Of the 20 women seen at 1 year, all 20 had mammograms done and 19 had gynecologic exams. In summary, this review of our NP run BMT survivorship clinic demonstrates feasibility and a high rate of adherence to recommended late effects screening practices for HCT survivors. As the survivorship program continues to grow, further integration of patient-reported outcomes and interventional research on late effects to improve the well-being of long-term survivors is planned.

Patient Reported Review of Symptoms in Survivorship Clinic

Allogeneic hematopoietic cell transplant (HCT) is a potentially curative treatment for many hematologic malignancies. Survivors of HCT have a variety of side effects from chemotherapy, graft-versus-host disease, as well as late effects including cardiovascular disease, diabetes and osteoporosis. Patient report of symptoms has been demonstrated to be a more accurate measure of health status, and can enhance patient-physician communication. Within our survivorship program, we collect a comprehensive assessment of core symptoms at day 100 and 1 year. These patient reported symptoms presents an opportunity to screen and detect potential complications early. All allogeneic HCT recipients are seen within our survivorship program and asked to complete a systematic and comprehensive screening questionnaire to evaluate a variety of symptoms related to skin, eyes, mouth, gastrointestinal tract, cardio/pulmonary, musculoskeletal, sexual functioning, work, substance use, exercise, cognition and performance status at day 100 and 1-year post HCT. From 2016-2018 161 patients had an allogeneic HCT and 42 patients completed survivorship appointments at day 100 and 1-year.We performed a review of patient assessments of their symptoms. Patients reported more symptoms at 1 year compared to day 100 (Figure). The most common symptoms reported were involving the musculoskeletal system (N=35 at both day 100 and 1-year) and cognitive functioning (N= 29 at day 100 and N=24 at 1 year). Musculoskeletal complaints included tremors and leg weakness, more common at day 100; and numbness, joint stiffness, decreased range of motion and joint pain more commonly at 1-year. Difficulties with memory and having to cut back on activities due to fatigue were prevalent day 100 and 1-year after HCT. Many symptoms reported were related to acute and chronic GVHD (17 developed acute GvHD by day 100 and 21 had chronic GVHD at 1 –year). In summary, this review demonstrates a continued high burden of symptoms in transplant survivors even at 1 year—with persistent or even new symptoms occurring. This emphasizes the need for continued follow up of late-effects and importance of patient self-report. Through our survivorship program, we hope to continue to capture patient-reported outcomes to better measure health status and late effects.