Knut B. Smeland

Heart Failure and Asymptomatic Left Ventricular Systolic Dysfunction in Lymphoma Survivors Treated With Autologous Stem-Cell Transplantation: A National Cross-Sectional Study

PURPOSE We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD), including symptomatic (ie, heart failure [HF]) and asymptomatic LVSD in adult lymphoma survivors (LSs) after autologous hematopoietic stem-cell transplantation (auto-HCT) and to identify risk factors for LVSD in this population. PATIENTS AND METHODS All LSs treated with auto-HCT as adults in Norway from 1987 to 2008 were eligible for this national cross-sectional study. Asymptomatic LVSD was defined as left ventricular ejection fraction less than 50% by echocardiography, and HF was defined according to current recommendations. The results in LSs were compared with those found in an age- and sex-matched (1:1) control group. RESULTS We examined 274 LSs (69% of all eligible survivors); 62% were men, the mean (± standard deviation) age was 56 ± 12 years, and mean follow-up time from lymphoma diagnosis was 13 ± 6 years. The mean cumulative doxorubicin dose was 316 ± 111 mg/m(2), and 35% of LSs had received additional radiation therapy involving the heart. We found LVSD in 15.7% of the LSs, of whom 5.1% were asymptomatic. HF patients were symptomatically mildly affected, with 8.8% of all LSs classified as New York Heart Association class II, whereas more severe HF was rare (1.8%). Compared with controls, LSs had a substantially increased LVSD risk (odds ratio, 6.6; 95% CI, 2.5 to 17.6; P < .001). A doxorubicin dose ≥ 300 mg/m(2) and cardiac radiation therapy dose greater than 30 Gy were independent risk factors for LVSD. CONCLUSION LVSD was frequent and HF more prevalent than previously reported in LSs after auto-HCT. Our results may help to identify LSs at increased LVSD risk and can serve as a basis for targeted surveillance strategies.

Valvular Dysfunction in Lymphoma Survivors Treated with Autologous Stem Cell Transplantation A National Cross-Sectional Study

OBJECTIVES This study assessed the prevalence and associated risk factors for valvular dysfunction (VD) observed in adult lymphoma survivors (LS) after autologous hematopoietic stem cell transplantation (auto-HCT), and to determine whether anthracycline-containing chemotherapy (ACCT) alone in these patients is associated with VD. BACKGROUND The prevalence of and risk factors for VD in LS after auto-HCT is unknown. Anthracyclines may induce heart failure, but any association with VD is not well-defined. METHODS This national cross-sectional study included all adult LS receiving auto-HCT from 1987 to 2008 in Norway. VD was defined by echocardiography as either more than mild regurgitation or any stenosis. Observations in LS were compared with a healthy age- and gender-matched (1:1) control group. RESULTS In total, 274 LS (69% of all eligible) participated. Mean age was 56 ± 12 years, mean follow-up time after lymphoma diagnosis was 13 ± 6 years, and 62% of participants were males. Mean cumulative anthracycline dosage was 316 ± 111 mg/m(2), and 35% had received radiation therapy involving the heart (cardiac-RT). VD was observed in 22.3% of the LS. Severe VD was rare (n = 9; 3.3% of all LS) and mainly aortic stenosis (n = 7). We observed VD in 16.7% of LS treated with ACCT alone (n = 177), corresponding with a 3-fold increased VD risk (odds ratio: 2.9; 95% confidence interval: 1.5 to 5.8; p = 0.002) compared with controls. Furthermore, the presence of aortic valve degeneration was increased in the LS after ACCT alone compared with controls (13.0% vs. 2.9%; p < 0.001). Female sex, age >50 years at lymphoma diagnosis, ≥3 lines of chemotherapy before auto-HCT, and cardiac-RT >30 Gy were identified as independent risk factors for VD in the LS. CONCLUSIONS In LS, ACCT alone was significantly associated with VD and related to valvular degeneration. Overall, predominantly moderate VD was prevalent in LS, and longer observation time is needed to clarify the clinical significance of this finding.

A national study on conditional survival, excess mortality and second cancer after high dose therapy with autologous stem cell transplantation for non‐Hodgkin lymphoma

This national population‐based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high‐dose therapy with autologous stem‐cell transplantation (HDT‐ASCT) for non‐Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT‐ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5‐, 10‐ and 20‐year overall survival was 61% (95% confidence interval [CI] 56–64%), 52% (95%CI 48–56%) and 45% (95%CI 40–50%), respectively. The 5‐year survival conditional on having survived 2, 5 and 10 years after HDT‐ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0–13·9), 4·9 (95%CI 4·1–5·9), 2·4 (95%CI 1·8–3·2) and 1·0 (95%CI 0·6–1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT‐ASCT respectively. Of the 281 deaths observed, 77% were relapse‐related. Treatment‐related mortality was 3·6%. The 10‐year cumulative incidence of second malignancies was 7·9% and standardized incidence ratio was 2·0 (95%CI 1·5–2·6). NHL patients treated with HDT‐ASCT were at increased risk of second cancer and premature death. The mortality was still elevated at 5 years, but after 10 years mortality equalled that of the general population.

Høydosebehandling med autolog stamcellestøtte ved lymfom - fra utprøvende til standard behandling

High-dose therapy with autologous stem cell support (HDT) has been a therapeutic option for lymphomas in Norway since as far back as 1987. By restoring bone marrow function through reinfusion of the patients own stem cells, it is possible to administer cancer treatment in higher and otherwise lethal doses, and thereby achieve better treatment results. Originally stem cells were harvested from bone marrow and the high-dose therapy included total body irradiation, but since the mid 1990s stem cells have been harvested by apheresis and the high-dose therapy has consisted of chemotherapy alone (BEAM chemotherapy). In 1995 the treatment was regionalised and since then it has been performed in all health regions. The HDT procedure was introduced as an experimental treatment in clinical studies with international collaboration. The indications have changed over time, and this is now established treatment for a number of types of lymphoma.

Conditional survival and excess mortality after high dose therapy with autologous stem cell transplantation for adult refractory or relapsed Hodgkin lymphoma in Norway

Published under under a Creative Commons Attribution 3.0 License (CC BY 3.0). Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org

Cardiorespiratory fitness in long-term lymphoma survivors after high-dose chemotherapy with autologous stem cell transplantation

Background:Cardiorespiratory fitness as measured by peak oxygen consumption (VO2peak) is a strong predictor of longevity and may be compromised by anticancer therapy, inactivity, and smoking. We compared VO2peak among lymphoma survivors (LSs) with reference data from healthy sedentary subjects, after a 10.2-year (mean) follow-up post high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT). We further examined the association between VO2peak and treatment, physical activity, smoking, pulmonary, and cardiac function.Methods:Lymphoma survivors treated with HDT-ASCT in Norway 1987–2008 were eligible. VO2peak was assessed by cardiopulmonary exercise testing. Pulmonary function testing and echocardiography were also conducted. Data on treatment, physical activity, and smoking were collected from hospital records and questionnaires. VO2peak was compared with age–sex predicted reference data. Linear regression was used to associate clinical factors with VO2peak cross-sectionally.Results:A total of 194 LSs without heart failure were studied. Mean VO2peak was 4.5% and 7.7% below norms in females and males, respectively. Twenty-two percent had impaired (<80% predicted) VO2peak. Decreasing VO2peak was associated with impaired diffusion capacity and current smoking, while physical activity level and VO2peak were positively associated.Conclusion:We suggest increased attention towards physical activity counseling and smoking cessation advice to preserve cardiorespiratory fitness in LSs after HDT-ASCT. Patients with impaired diffusion capacity may benefit from subsequent monitoring to detect pulmonary vascular diseases.

Diffusing capacity impairment is prevalent in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation

Diffusing capacity impairment is prevalent in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation

Obstructive and restrictive pulmonary dysfunction in long-term lymphoma survivors after high-dose therapy with autologous stem cell transplantation

Abstract Background: Obstructive and restrictive dysfunction in long-term lymphoma survivors (LSs) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) has not been addressed systematically previously. Material and methods: LSs treated in Norway 1987–2008 with HDT-ASCT who performed spirometry, measurement of static lung volumes and echocardiography 2012–2014 at either Oslo or St. Olavs University Hospitals was eligible. Smoking data were recorded by questionnaire. Treatment data were collected from medical records or hospital databases. Factors associated with obstructive and restrictive impairments (dichotomous outcomes) were examined by Poisson regression. Linear regression with the margins post-estimation command was used to derive adjusted mean values of forced expiratory volume in 1 s (FEV1). We used the normative reference data recommended by the European Respiratory Society for calculating percent predicted values. Results: A total of 226 LSs were studied, of whom 11.5 and 5.8% had obstructive and restrictive impairment, respectively. For women and men, mean FEV1 was 2.31 and 3.34 l corresponding to 11.4%- and 11.1%-points below that predicted from norms, respectively. In multivariable regression analyses, cumulative doxorubicin dose (400–775 mg/m2) and current smoking were associated with increased risk of obstructive impairment, and chest RT (>13–66 Gy) was associated with increased risk of restrictive impairment. Currently smoking LSs within the highest doxorubicin category (400–775 mg/m2), had the lowest adjusted mean FEV1. Conclusions: Despite intensive cancer treatment, our analysis showed modest reductions in obstructive parameters among long-term LSs after HDT-ASCT compared to normative reference data. To limit obstructive impairments in LSs after HDT-ASCT, we suggest that targeted smoking-cessation advice is directed towards patients who have received high cumulative doses of doxorubicin.

Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation

Abstract Background: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors. Material and methods: Eligible lymphoma survivors were aged ≥18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores ≥−1, between −1 and −2, and ≤−2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (≥−1), osteopenia (between −1 and −2.5), and osteoporosis (≤−2.5). Results: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <−1 and >−2, while 8% and 6% had Z-scores ≤−2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively. Conclusion: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT.