Osteonecrosis (ON) is a common and severe side-effect of modern therapy for acute lymphoblastic leukemia (ALL). It most frequently impacts older children (?10 years old) and young adults, with 15-45% of patients in these groups developing ON symptoms during therapy. Severe ON causes pain and limited mobility, requiring orthopedic surgery including joint replacement. There are currently no interventions which reduce this risk. This award application describes a career development plan to allow me to evolve into a successful independent clinical investigator and achieve my long-term goal of being an independent investigator leading clinical trials which reduce the toxicity of ALL therapy. The short-term goal of this project is to test an intervention for its ability to decrease osteonecrosis. Our preliminary preclinical data showed that intensive antihypertensive therapy reduces ON in this setting without impairing the anti-leukemia effect of chemotherapy. We will now test this in the clinic by evaluating the ability of intensive antihypertensive control (targeted to the 50-75th percentile for age, sex, and height) to reduce ON (as measured by 9 month MRI) compared to standard antihypertensive control (targeted to the 90-95th percentile) by randomizing 160 children and young adults ages 10-18.99 years enrolled on the Total 17 ALL trial to either intensive or standard antihypertensive control (Research Aim 1). Building on our preclinical data, we will also test the ability of biomarkers of vascular dysfunction to identify patients at highest risk of developing ON (Research Aim 2). Finally, we will measure patient-reported quality of life outcomes (PROs) to determine how both the intervention and osteonecrosis impact patients? health-related quality of life (Research Aim 3). This career development award will also prepare me to achieve my long-term goals as an independent investigator. The practical experience of leading the proposed clinical trial, combined with didactic education in clinical trial design and structured mentorship, will increase my expertise as a clinical researcher (Training Aim 1). The award will also support training and mentorship in vascular physiology to improve both the analysis of the planned trial as well as to improve future trials (Training Aim 2). Finally, I will receive training, mentorship, and practical experience in the use of PROs to better implement these tools in future trials to best understand patient complications from therapy (Training Aim 3). This proposal may identify the first intervention to reduce ON in patients with ALL. Such an intervention would have implications for patients with other malignancies or autoimmune diseases who are also at risk of developing ON due to prolonged glucocorticoid treatment. Simultaneously, the training supported by the award will prepare me for a successful career as a clinician scientist to reduce therapy toxicity in children with ALL.
This project will test a novel intervention (intensive antihypertensive control) to determine if it will decrease osteonecrosis in children with acute lymphoblastic leukemia (ALL), while also identifying biomarkers of osteonecrosis risk. This can reduce a side-effect of therapy causing lifelong disability, a crucial goal because more than 90% of children with ALL will become long-term survivors. Identification of both interventions and biomarkers for osteonecrosis will have broad significance as this side-effect complicates therapy not only of ALL but for other cancers and autoimmune diseases which use glucocorticoids.
