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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension; Osteonecrosis; Osteonecrosis Due to Drug
• Intervention / Treatment: Drug: Intensive Antihypertensive Therapy; Other: Symptom Survey; Other: Semi-structured interview; Drug: Conventional Antihypertensive Therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive Antihypertensive Therapy; 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; Receives intensive antihypertensive therapy; Other Names: Hypotensive Therapy; Other: Symptom Survey; 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).; Other Names: Survey; Other: Semi-structured interview; 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.; Other Names: Interview
Active Comparator: Conventional Antihypertensive Therapy; 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.	Other: Symptom Survey; 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).; Other Names: Survey; Other: Semi-structured interview; 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.; Other Names: Interview; Drug: Conventional Antihypertensive Therapy; Receives conventional antihypertensive therapy; Other Names: Hypotensive Therapy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Seth E. Karol, MD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• St. Jude Children's Research Hospital
• ClinicalTrials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2020
• Primary Completion (Actual): September 25, 2023
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 19, 2020
• First Posted (Actual): May 26, 2020

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Hypertension; Children; Acute Lymphoblastic Leukemia; Osteonecrosis; Osteonecrosis Due to Drug
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Musculoskeletal Diseases; Bone Diseases; Hypertension; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Osteonecrosis; Antihypertensive Agents
• Other Study ID Numbers: HYPERION; 1K08CA250418 (U.S. NIH Grant/Contract); NCI-2020-03603 (Registry Identifier: NCI Clinical Trial Registration Program)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Data will be made available at the time of article publication.
• IPD Sharing Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No