Saro H. Armenian

Recommendations for Cardiomyopathy Surveillance for Survivors of Childhood Cancer: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549.

Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS)

HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported ≥ 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life-threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population.

Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

Purpose Cardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers. Methods Recommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology. Results A total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. Recommendations It is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.

Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease

Hematopoietic cell transplantation (HCT) recipients may be at an increased risk of developing hypertension, diabetes, and dyslipidemia (referred to as cardiovascular risk factors [CVRFs]); and these factors can potentially increase the risk of cardiovascular disease (CVD). We examined the incidence and predictors of CVRFs and subsequent CVD in 1885 consecutive 1+year survivors of HCT performed at City of Hope between 1995 and 2004. Ten-year cumulative incidence of hypertension, diabetes, dyslipidemia, and multiple (≥ 2) CVRFs was 37.7%, 18.1%, 46.7%, and 31.4%, respectively. The prevalence of CVRFs was significantly higher among HCT recipients compared with the general population; contributed to largely by allogeneic HCT recipients. Older age and obesity at HCT were associated with increased risk of CVRFs. History of grade II-IV acute graft versus host disease was associated with an increased risk for hypertension (relative risk [RR] = 9.1, P < .01), diabetes (RR = 5.8, P < .01), and dyslipidemia (RR = 3.2, P < .01); conditioning with total body irradiation was associated with an increased risk of diabetes (RR = 1.5, P = .01) and dyslipidemia (RR = 1.4, P < .01). There was an incremental increase in 10-year incidence of CVD by number of CVRFs (4.7% [none], 7.0% [1 CVRF], 11.2% [≥ 2 CVRFs], P < .01); the risk was especially high (15.0%) in patients with multiple CVRFs and pre-HCT exposure to anthracyclines or chest radiation.

Late Congestive Heart Failure After Hematopoietic Cell Transplantation

PURPOSE To examine the independent roles of pre-hematopoietic cell transplantation (HCT) therapeutic exposures, transplantation-related conditioning, and comorbidities (pre- and post-HCT) in the development of late congestive heart failure (CHF) after HCT. METHODS This was a nested case-control design. Individuals with late CHF (diagnosed >or= 1 year after HCT) were identified from a cohort of 2,938 1+ year survivors who underwent transplantation at City of Hope National Medical Center, Duarte, CA. This cohort formed the sampling frame for selecting controls (without CHF) matched for age and year of HCT, donor source (allogeneic v autologous), and length of follow-up. RESULTS Sixty patients with late CHF were identified; median age at HCT was 45.3 years (range, 16.6 to 68.6 years); median time to CHF was 3.0 years (range, 1.03 to 18.9 years); 68% received autologous HCT. Median ejection fraction was 36.9% (range, 15% to 53%). Compared with matched controls (n = 166), patients with late CHF received more cycles of pre-HCT chemotherapy (8.6 v 4.9 cycles; P < .01), had greater body mass index at HCT (28.4 v 26.2 kg/m(2); P = .01), greater lifetime anthracycline exposure (285.3 v 175.6 mg/m(2); P < .01), and were more likely to have multiple chronic comorbidities (30.0% v 13.9%; P < .01). Multivariable analysis revealed number of pre-HCT chemotherapy cycles (odds ratio [OR] = 1.2; P < .01), anthracycline dose >/= 250 mg/m(2) (OR = 3.2; P = .05), and two or more chronic comorbidities (OR = 4.3; P = .01) to be independently associated with late CHF. CONCLUSION Pre-HCT exposure to anthracyclines and presence of comorbidities are primarily responsible for the risk associated with late CHF after HCT. Conditioning-related therapeutic exposure does not contribute significantly to the risk. These results form the basis for identifying high-risk individuals for targeted surveillance, as well as developing preventive strategies in the form of aggressive management of comorbidities.

Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

PURPOSE The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. PATIENTS AND METHODS By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. RESULTS By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). CONCLUSION Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.

Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation

Advances in autologous hematopoietic cell transplantation (HCT) strategies have resulted in a growing number of long-term survivors. However, these survivors are at increased risk of developing cardiovascular complications due to pre-HCT therapeutic exposures and conditioning and post-HCT comorbidities. We examined the incidence and predictors of congestive heart failure (CHF) in 1244 patients undergoing autologous HCT for a hematologic malignancy between 1988 and 2002. The cumulative incidence of CHF was 4.8% at 5 years and increased to 9.1% at 15 years after transplantation; the CI for female lymphoma survivors was 14.5% at 15 years. The cohort was at a 4.5-fold increased risk of CHF (standardized incidence ratio = 4.5), compared with the general population. The risk of CHF increased substantially for patients receiving ≥ 250 mg/m(2) of cumulative anthracycline exposure (odds ratio [OR]: 9.9, P < .01), creating a new and lower threshold for cardiac surveillance after HCT. The presence of hypertension among recipients of high-dose anthracycline (≥ 250 mg/m(2)) resulted in a 35-fold risk (OR: 35.3, P < .01) of CHF; the risk was nearly 27-fold (OR: 26.8, P < .01) for high-dose anthracycline recipients with diabetes, providing evidence that hypertension and diabetes may be critical modifiers of anthracycline-related myocardial injury after HCT and creating targeted populations for aggressive intervention.

Burden of morbidity in 10+ year survivors of hematopoietic cell transplantation: report from the bone marrow transplantation survivor study.

Long-term morbidity after hematopoietic cell transplantation (HCT) is unknown. The risk of physical and psychological health in 324 patients who had survived 10 or more years after HCT and a sibling comparison group (n = 309) was evaluated. Using the Common Terminology Criteria for Adverse Events, the 15-year cumulative incidence of severe/life-threatening/fatal conditions was 41% (95% confidence interval, 34% to 48%). HCT survivors were 5.7 times as likely to develop a severe/life-threatening condition (P < .001) and 2.7 times as likely to report somatic distress (P < .001) compared with siblings. Compared with allogeneic HCT recipients with no chronic graft-versus-host disease (GVHD), those with active chronic GVHD were at a 1.8-fold higher risk of severe/life-threatening health conditions (P = .006) and a 4.5-fold higher risk of somatic distress (P = .04); allogeneic HCT recipients with resolved chronic GVHD were not at increased risk of morbidity compared with those with no chronic GVHD. Only 27% of the HCT survivors returned to the transplantation center for their cancer-related care. The burden of long-term physical and emotional morbidity borne by survivors remains substantial, even beyond 10 years after HCT; however, specialized health care is underused. Patients, families, and healthcare providers need to be made aware of the high burden, so they can plan for post-HCT care, even many years after HCT.

Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study

PURPOSE Cardiovascular diseases (CVDs), including ischemic heart disease, stroke, and heart failure, are well-established late effects of therapy in survivors of childhood and young adult (< 40 years at diagnosis) cancers; less is known regarding CVD in long-term survivors of adult-onset (≥ 40 years) cancer. METHODS A retrospective cohort study design was used to describe the magnitude of CVD risk in 36,232 ≥ 2-year survivors of adult-onset cancer compared with matched (age, sex, and residential ZIP code) noncancer controls (n = 73,545) within a large integrated managed care organization. Multivariable regression was used to examine the impact of cardiovascular risk factors (CVRFs; hypertension, diabetes, dyslipidemia) on long-term CVD risk in cancer survivors. RESULTS Survivors of multiple myeloma (incidence rate ratio [IRR], 1.70; P < .01), carcinoma of the lung/bronchus (IRR, 1.58; P < .01), non-Hodgkin lymphoma (IRR, 1.41; P < .01), and breast cancer (IRR, 1.13; P < .01) had significantly higher CVD risk when compared with noncancer controls. Conversely, prostate cancer survivors had a lower CVD risk (IRR, 0.89; P < .01) compared with controls. Cancer survivors with two or more CVRFs had the highest risk of CVD when compared with noncancer controls with less than two CVRFs (IRR, 1.83 to 2.59; P < .01). Eight-year overall survival was significantly worse among cancer survivors who developed CVD (60%) when compared with cancer survivors without CVD (81%; P < .01). CONCLUSION The magnitude of subsequent CVD risk varies according to cancer subtype and by the presence of CVRFs. Overall survival in survivors who develop CVD is poor, emphasizing the need for targeted prevention strategies for individuals at highest risk of developing CVD.