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Antihypertensive Agents

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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.

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.

Receives intensive antihypertensive therapy

Intensive Antihypertensive Therapy

Receives conventional antihypertensive therapy

Conventional Antihypertensive Therapy

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).

Symptom Survey

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.

Semi-structured interview

Seth E. Karol, MD

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.

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.

Evaluation of the MRIs defining the primary endpoint will be performed by a blinded radiologist.

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

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

Involvement of \>=30% of the epiphyseal surface of either the hip or knee by prospective MRI during reinduction II

CTCAE grade 2 or high osteonecrosis vs. Total 16 matched controls

Comparison of repeated systolic and diastolic blood pressure measures between randomized treatment arms

Comparison between randomized treatment arms

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma	NCT04401267	Hypertension Osteonecrosis Osteonecrosis D...	Intensive Antih... Conventional An... Symptom Survey Semi-structured...	10 Years -	St. Jude Children's Research Hospital
Hypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma	NCT04401267	Hypertension Osteonecrosis Osteonecrosis D...	Intensive Antih... Conventional An... Symptom Survey Semi-structured...	10 Years -	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for conventional antihypertensive therapy