Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma

Study Overview
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Brief Summary
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This is a randomized unblinded Phase II clinical trial evaluating the impact of intensive antihypertensive control (targeted to the 50-75th percentile for age, sex, and height) compared to conventional antihypertensive control (targeted to the 90-95th percentile for age, sex, and height) on the incidence of radiographically extensive osteonecrosis in children and young adults receiving treatment for newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL). Primary Objective Compare the frequency of radiographically extensive osteonecrosis in patients receiving intensive compared to conventional antihypertensive therapy. Secondary Objectives Evaluate the efficacy of intensive antihypertensive control compared to conventional antihypertensive control in the prevention of clinically significant (CTCAE Grade 2 or higher) and radiologically extensive osteonecrosis, overall and stratified by joints. Compare the frequency of clinically significant and radiographically extensive osteonecrosis in patients receiving antihypertensive therapy and historical controls. Compare blood pressures achieved in intensive and conventional arms using both pressures obtained as part of routine patient care and ambulatory blood pressure monitoring. Compare levels of vascular dysfunction as measured physiologically, radiographically, and in blood samples in patients receiving intensive compared to standard antihypertensive therapy. Exploratory Objectives Identify predictive patterns of blood biomarkers which identify patients at high- risk of developing clinically significant osteonecrosis. Identify MRI findings during late induction which correlate with osteonecrosis lesions seen during reinduction. Identify patterns of diurnal blood pressure variation as measured by ambulatory blood pressure monitoring associated with the later development of osteonecrosis. Compare induction blood pressure control and intervention arm to echocardiographic changes at reinduction II. Evaluate patient-reported, health-related quality of life in patients during induction and after 1.5 years of therapy when many experience the symptoms of osteonecrosis.

Detailed Description
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Patient randomization will be stratified based on patient's location (Memphis vs. other), use of antihypertensives prior to randomization, and factors known to influence osteonecrosis risk, specifically sex and self-declared race (non-Hispanic white vs. other). A target systolic blood pressure range will be chosen for each participant based on their randomization arm, age, sex, and height. Patients will be randomized on day 4 of induction therapy to either conventional or intensive blood pressure goals. Patients will be treated with antihypertensive therapy to achieve blood pressure control as indicated by their randomized arm. Therapy will be adjusted every 3-4 days as needed to achieve targeted control based on the mean of blood pressures obtained in that period. Treatment of hypertension to the target will continue until the completion of reinduction II therapy. Patients will be evaluated for osteonecrosis as indicated in their primary therapeutic protocol using MRI during reinduction II. Patients will be asked to complete a symptom survey and a semi-structured interview.

Official Title
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Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma

Conditions
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Hypertension, Osteonecrosis, Osteonecrosis Due to Drug

Intervention / Treatment
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* Drug: Intensive Antihypertensive Therapy
* Drug: Conventional Antihypertensive Therapy
* Other: Symptom Survey
* Other: Semi-structured interview


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is being treated for newly diagnosed acute lymphoblastic leukemia or lymphoma (ALL) on the TOT17 protocol. Patients do not need to be hypertensive to enroll. Patient is 10 years of age or older at the time of enrollment on TOT17. Patient has completed ≤ 4 days of protocol therapy (patients are eligible on Day 4 of TOT17 therapy). Exclusion Criteria: Moderate-severe renal dysfunction (glomerular filtration rate <45 ml/min/1.73m2). Down's syndrome (germline Trisomy 21) or other syndrome resulting in growth delay or alterations in stature. Chronic inability to ambulate. Patients with limitations in movement due to acute complications of leukemia/lymphoma are not excluded. Permanent contraindication to MRI evaluation. Participants who are pregnant or lactating. Males or females of reproductive potential must agree to use effective contraception for the duration of study participation. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive Antihypertensive Therapy<br>Patients will begin Intensive antihypertensive therapy to achieve the targeted blood pressure (targeted to the 50-75th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II. | Drug: Intensive Antihypertensive Therapy<br>* Receives intensive antihypertensive therapy<br>* Other names: Hypotensive Therapy;Other: Symptom Survey<br>* The symptom survey is comprised of the PROMIS Ped 25 profile, PROMIS pain interference 8a, PROMIS physical activity 8a, and PROMIS mobility 8a during induction (day 23-28), during week 17 of continuation (+/- 2 weeks), and continuation week 49 (+/- 3 weeks).<br>* Other names: Survey;Other: Semi-structured interview<br>* Patients will be interviewed by a trained examiner about their treatment and symptom burden on Week 49 of TOT17 Continuation Therapy. The interview will be recorded and will take about 30-45 minutes.<br>* Other names: Interview;|
| Active Comparator: Conventional Antihypertensive Therapy<br>Patients will begin Conventional antihypertensive therapy to achieve the targeted blood pressure (targeted to the 90-95th percentile for age, sex, and height) on day 4 of Remission Induction on TOT17 and continue during steroid containing phases until the completion of reinduction II. | Drug: Conventional Antihypertensive Therapy<br>* Receives conventional antihypertensive therapy<br>* Other names: Hypotensive Therapy;Other: Symptom Survey<br>* The symptom survey is comprised of the PROMIS Ped 25 profile, PROMIS pain interference 8a, PROMIS physical activity 8a, and PROMIS mobility 8a during induction (day 23-28), during week 17 of continuation (+/- 2 weeks), and continuation week 49 (+/- 3 weeks).<br>* Other names: Survey;Other: Semi-structured interview<br>* Patients will be interviewed by a trained examiner about their treatment and symptom burden on Week 49 of TOT17 Continuation Therapy. The interview will be recorded and will take about 30-45 minutes.<br>* Other names: Interview;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extensive radiographic osteonecrosis | Involvement of >=30% of the epiphyseal surface of either the hip or knee by prospective MRI during reinduction II | during reinduction II therapy, approximately 9 months into therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinically significant osteonecrosis | CTCAE grade 2 or high osteonecrosis | any time during leukemia therapy, approximately 2.5 years | 
| Rate of clinically significant osteonecrosis vs. historical control | CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls | any time during leukemia therapy, approximately 2.5 years | 
| Blood pressure control on trial | Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms | first 9 months of therapy | 
| Biomarkers of vascular dysfunction - eNO synthetase (pg/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - Von Willebrand Factor (%) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - TNF-alpha (pg/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - D-dimer (µg/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - PAI-1 (AU/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - E-selectin (ng/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - ICAM-1 (ng/mL) | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 
| Biomarker of vascular dysfunction - Arterial elasticity (ml/mmHg) | Comparison between randomized treatment arms | 3 weeks and 3 months into therapy | 
| Biomarker of vascular dysfunction - Pulse Wave Velocity (m/sec) | Comparison between randomized treatment arms | 3 weeks and 3 months into therapy | 
| Magnetic resonance imaging (MRI) of hip and knee | Comparison between randomized treatment arms | 3 weeks and 9 months into therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic Leukemia, Children, Hypertension, Osteonecrosis, Osteonecrosis Due to Drug