Impact of body mass index on outcome, toxicity and pharmacokinetics in patients with acute lymphoblastic leukemia

Background: Overweight and obesity are growing health problems. Obesity has been associated with both a higher risk of contracting cancer and increased cancer-related mortality in adults. The impact in children with cancer, and more specifically with acute lymphoblastic leukemia (ALL), is less explored. Body mass index (BMI) may be an additional risk factor for poor outcomes that warrants consideration in risk stratification for ALL treatment assignment. This study aimed to retrospectively study the association between BMI and ALL treatment in children and young adults treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols and explore possible factors underlying adverse outcomes. Methods: Patients with B-cell-precursor (BCP) and T-cell ALL from the Nordic countries, Estonia and Lithuania were included. Detailed data on weight and height at diagnosis, as well as patient and disease characteristics, were retrieved from the NOPHO leukemia registries. In Study I, we used data collected retrospectively on children aged 2-<18 years and treated according to the NOPHO ALL92-, ALL2000, or ALL2008 protocols between 1992 and 2016, and for consecutive studies we included patients only from the NOPHO ALL2008 protocol (Studies II, III and IV) and also comprised of young adults (18-<46 years, Study V). In children, BMI was calculated and converted according to the International Obesity Task Force classification into BMI standard deviation scores (SDS), and age and sex-related BMI cut-offs for thinness, healthy weight, overweight, and obesity. The impact of BMI on the following outcomes in children and young adults were analyzed: event-free survival, relapse, overall survival, and treatment-related toxicity and mortality (Studies I, II and V). In children, mean BMI change between diagnosis and the end of treatment, together with identifying risk factors for weight gain were investigated (Study IV). Further, the relation between BMI and delayed high-dose methotrexate (HD-MTX) excretion was explored using data on HD-MTX pharmacokinetics gathered from medical charts from children treated in Stockholm and Uppsala (Study V). Results: In Study I (n =2558), we explored the impact of BMI on survival outcomes in children. Obese children aged 10-18 years at the time of their ALL diagnosis had higher relapse rate and consequently a more than six-fold increased risk of dying from their disease compared to healthy weight patients. Underweight and overweight were also associated with an increased risk of relapse, compared to healthy weight in this age category. However, BMI had no significant impact on outcomes in younger children aged 2-<10 years. In Study II, we compared the risk of specific severe adverse events and treatment delays in different BMI categories in a cohort of 1443 children with non-high-risk ALL. A similar age trend was observed in this study; only older obese children aged ≥10 years had a significantly increased incidence rate ratio for one or more specific severe adverse events, compared to healthy weight children. Older children also had a three-fold higher incidence rate ratio of asparaginase truncation, compared with older healthy weight children. Study III shows, that BMI SDS increased for many children during ALL therapy (n=765). An increase in BMI SDS was more prevalent in those who were young (2-<6 years) or underweight/healthy weight at diagnosis, compared to other age or BMI groups. To evaluate how BMI influences pharmacokinetics and associated toxicities, one cornerstone of the antileukemic treatment—HD-MTX—was explored in Study IV. The results, comprising 182 children and 1401 HD-MTX courses, indicate that children with substantial weight loss during induction had an increased risk of delayed methotrexate excretion. The results did not support changed pharmacokinetics of HD-MTX as a contributing factor to decreased survival in overweight and obese children. In Study V, the role of BMI on outcomes was further examined in young adults, to explore age-related differences in metabolic status and its impact on outcome. Out of the 416 young adults with non-high-risk ALL, only the severely obese patients (BMI ≥35 kg/m2, n=234) had inferior event-free survival due to relapses. Severe obesity had no effect on toxicity nor treatment delays compared to healthy weight patients. Conclusions: In obese patients, the poor outcomes are primarily linked to a higher risk of relapse, which may be related to undertreatment or chemotherapy resistance. When trying to improve survival, there is a fine balancing act between intensifying treatment in unhealthy BMI groups with the potential risk of Increased toxicity. For obese patients with ALL, novel strategies with individualized frontline therapy approaches are needed to reduce toxicity while further improving outcomes. Achieving optimal dosing strategies requires further exploration through pharmacokinetic trials. Furthermore, it is crucial to recognize that nutritional status is a modifiable risk factor, where physical activation and dietary interventions, possibly combined with drugs targeting the metabolic pathways, may contribute to better outcomes

Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols

Objectives High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0-17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut-offs: underweight, = 30 kg/m(2). Results In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10-17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24-6.78],P = .01; overweight, HR: 1.95 [1.11-3.43],P = .02, and obese HR: 4.32 [95% 2.08-8.97],P <.001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.Peer reviewe

Changes in body mass index during treatment of childhood acute lymphoblastic leukemia with the Nordic ALL2008 protocol

Funding Information: Christina Egnell is supported by funding from the Swedish Childhood Cancer Foundation (Barncancerfonden, grant numbers TJ2018‐0093; PR2019‐0075; TJ2019‐0048). This work is part of the Danish nation‐wide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by the Danish Cancer Society (R‐257‐A14720) and the Danish Childhood Cancer Foundation (2019‐5934 and 2020‐5769). Publisher Copyright: © 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.Objectives: Children with acute lymphoblastic leukemia (ALL) have a tendency to gain weight during treatment. As overweight and obesity associate with health problems, prophylactic interventions are warranted. Therefore, it is important to identify the children most prone to gain weight. Methods: Patients aged 2.0–17.9 years at ALL diagnosis were identified from the NOPHO ALL2008 registry. Registry data was complemented with height and weight at the end of therapy from questionnaires. Body mass index (BMI) was classified according to international age- and sex-adjusted International Obesity Task Force BMI cut-offs. BMI values were transformed into standard deviation scores (SDS) to calculate the difference in BMISDS during treatment. Results: Data on BMI change were available for 765 children. Overweight and obesity doubled during treatment: 9.7% were overweight and 2.1% obese at diagnosis and 21.8% and 5.4% at the end of therapy, respectively. The mean BMISDS change was +0.64. Younger (2.0–5.9 years) and healthy weight children were most prone to become overweight (mean change in BMI SDS +0.85 and + 0.65, respectively). Conclusions: Younger children (2.0–5.9 years) with healthy weight at diagnosis were most prone to becoming overweight and therefore are an important group to target while considering interventions.Peer reviewe

Long-Term Prognostic Value of Dobutamine Stress CMR

ObjectivesThe aim of this study was to assess the long-term value of high-dose dobutamine cardiac magnetic resonance (DCMR) for the prediction of cardiac events in a large cohort of patients with known or suspected coronary artery disease.BackgroundHigh-dose DCMR has been shown to be a useful technique for diagnosis and intermediate-term prognostic stratification.MethodsClinical data and DCMR results were analyzed in 1,463 consecutive patients undergoing DCMR between 2000 and 2004. Ninety-four patients were lost to follow-up. The remaining 1,369 patients were followed up for a mean of 44 ± 24 months. Cardiac events, defined as cardiac death and nonfatal myocardial infarction, were related to clinical and DCMR results.ResultsThree-hundred fifty-two patients underwent early revascularization (≤3 months of DCMR) and were excluded from analysis. Of the remaining 1,017 patients, 301 patients (29.6%) experienced inducible wall motion abnormalities (WMA). Forty-six cardiac events were reported. In those with and without inducible WMA, the proportion of patients with cardiac events was 8.0% versus 3.1%, respectively, p = 0.001 (hazard ratio: 3.3; 95% confidence interval: 1.8 to 5.9 for the presence of inducible WMA; p < 0.001). A DCMR without inducible WMA carried an excellent prognosis, with a 6-year cardiac event-free survival of 96.8%. In all 1,369 patients in the patient group with stress-inducible WMA, those patients with medical therapy demonstrated a trend to a higher cardiac event rate (8.0%) than those with early revascularization (5.4%) (p = 0.234). Patients with normal DCMR and medical therapy or early revascularization demonstrated similar cumulative cardiac event rates (3.1% vs. 3.2%, p = 0.964).ConclusionsIn a large cohort of patients, DCMR has an added value for predicting cardiac events during long-term follow-up, improving the differentiation between high-risk and low-risk patients. Patients with inducible WMA and following early revascularization, demonstrate lower cardiac event rates than patients with medical therapy alone

Impact of body mass index on outcome and treatment-related toxicity in young adults with acute lymphoblastic leukemia

Background: Data on outcome for patients in different body mass index (BMI) categories in young adults with acute lymphoblastic leukemia (ALL) are scarce. We explored survival and toxicities in different BMI categories in young adults with ALL. Material and methods: Patients aged 18–45 years, diagnosed with ALL between July 2008 and June 2022 in the Nordic countries, Estonia, or Lithuania, and treated according to the NOPHO ALL2008 protocol, were retrospectively enrolled and classified into different BMI categories. Endpoints were overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse as well as incidence rate ratio (IRR) of severe predefined toxic events, and treatment delays. Results: The group comprised 416 patients, of whom 234 (56%) were stratified to non-high-risk (non-HR) treatment. In the non-HR group, patients with severe obesity, BMI ≥35 kg/m2 had worse EFS due to relapses but there was no effect on toxicity or treatment delays compared with the healthy-weight patients. There was no association between BMI category and OS, overall toxicity, or treatment delays in the patients with high-risk treatment. Conclusion: Severe obesity is associated with worse EFS in young adults treated according to the non-HR arms of the NOPHO ALL2008 protocol. Poorer outcome is explained with a higher risk of relapse, possibly due to under treatment, and not caused by excess therapy-related mortality