Severe Toxicity Free Survival Following Childhood Acute Lymphoblastic Leukemia

The goal of this observational study is to quantify the burden of particularly severe, long-term adverse effects in childhood acute lymphoblastic leukemia (ALL) survivors. The adverse effects include 21 severe health conditions recently selected and defined as Severe Toxicities by an international collaboration of ALL consortia.

The main questions the study aims to answer for childhood ALL patients are:

• What is the chance of surviving without any Severe Toxicities during the first 5 years after ALL diagnosis?
• What is the average cumulative burden of different Severe Toxicities during the first 5 years after ALL diagnosis? The study uses standard-care follow-up data for childhood ALL patients from an international collaboration of five ALL consortia from Europe, the US, and Australia.

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoblastic Leukemia

Detailed Description

Background:

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer comprising around 25% of all childhood cancers. Stepwise modifications of antileukemic therapy have led to a rise in 5-year survival probability from less than 30% in the 1970s to above 90% today. Cure, however, comes at a price; survivors are burdened by acute as well as long-term toxicities, that is, adverse effects of treatment. Among survivors, the cumulative incidence of severe, disabling, life-threatening, or fatal chronic health conditions was recently reported to be 21.1% at 20 years from ALL diagnosis, which is substantial, not least when considering the peak incidence of childhood ALL around the age of 3 years, meaning that many 20-year survivors are young adults. Hence, focusing on long-term health sequelae is more relevant than ever. Traditional cancer outcome measures consist of overall survival and cancer-related-event-free survival, but for cancers with high survival probability, such as for childhood ALL, these traditional outcome measures become insufficient since they ignore the burden of therapy. Severe, long-term toxicities should be considered in treatment outcome evaluation, but the lack of internationally standardized capturing and reporting of late effects is a barrier. To address this, an international collaboration of ALL consortia initiated a project aiming to select physician-defined severe toxicities following ALL treatment. This work resulted in consensus definitions of 21 severe health conditions named Severe Toxicities, which could each be considered an unacceptable price for cure. With examples as heart failure, brain damage, and chronic lung disease, the 21 conditions are of such severity that ALL treatment possibly would have been modified if the toxicity had been predictable at time of diagnosis. These Severe Toxicities should be integrated in treatment outcome evaluation alongside the overall survival and the cancer-related event-free survival for a more comprehensive evaluation of treatment protocols.

The occurrence of these 21 Severe Toxicities has not been evaluated before. This international study aims to quantify the occurrence of the Severe Toxicities in 5 large cohorts of childhood ALL patients from Europe, USA, and Australia. Even though the overall survival as well as the cancer-related-event-free survival for different cohorts may be similar, differences in the use and dose-intensity of steroids, chemotherapy, radiotherapy, and hematopoietic stem cell transplantation may lead to different toxicity patterns. The original Severe Toxicity definitions were recently modified to meet statistical requirements for valid analyses and to ensure that the Severe Toxicities can be classified uniformly and prospectively across different cohorts.

Comparing the prevalence and patterns of Severe Toxicities across different treatment protocols will potentially reveal modifiable treatment-related factors associated with risk of individual and/or multiple Severe Toxicities. A global decision to routinely report Severe Toxicity is essential for a more comprehensive knowledge of late effects, which may guide future research towards improved treatment strategies aiming to reduce toxicities, and hereby improving quality of life, without compromising cure.

The 21 Severe Toxicities include the following conditions:

• Hearing loss
• Blindness
• Heart failure
• Arrhythmia
• Coronary artery disease
• Heart valve disease
• Gastrointestinal failure
• Hepatic failure
• Insulin dependent diabetes
• Renal failure
• Pulmonary failure
• Osteonecrosis
• Amputation and physical deformation
• Cognitive dysfunction
• Seizures
• Psychiatric disease
• Paralytic, neuropathic, myopathic, or movement disorders
• Vocal cord paralysis
• Cytopenia
• Immunodeficiency
• Second malignant neoplasm and benign CNS tumor The outcomes considered in the statistical analyses are time-to-event outcomes for each of the 21 Severe Toxicities and the two derived outcomes: the time to first event of death or any of the Severe Toxicities, and the cumulative number of different Severe Toxicities events by time.

Aims:

1. To investigate Severe-Toxicity-Free Survival in childhood ALL survivors
2. To investigate the occurrence of Severe Toxicities in childhood ALL survivors treated on contemporary treatment protocols, investigating the cumulative number of different Severe Toxicities as well as each Severe Toxicity separately Furthermore, the study will explore associations with potential risk factors, e.g., demographic variables such as sex and age at diagnosis, and treatment-related variables such as type of chemotherapy and use of hematopoietic stem cell transplantation with and without total body irradiation.

Data registration:

Data will be collected from medical charts. Medical chart review can be combined with data extraction from existing databases. The method of data capture will vary between centers depending on the degree of already existing toxicity registration and the current use of databases.

Data analysis:

All analyses will use time since diagnosis as the time scale. Severe-Toxicity-Free Survival will be presented graphically by a Kaplan-Meier curve, and exploratory risk factor analyses will be based on Cox regression analyses. Number of different Severe Toxicities by time will be presented graphically as mean cumulative count and exploratory risk factor analyses will be based on Poisson regression models assuming piecewise constant underlying rates and allowing for overdispersion. The cumulative probability of observing each of the Severe Toxicities will be presented graphically using the Aalen-Johansen estimator with death as the competing event, while exploratory risk factor analyses will be based on Cox regression model for the toxicity-specific hazard treating death as a censoring.

In the exploratory risk factor analyses, the linearity assumption for quantitative covariates will be evaluated using linear splines. There are no prespecified hypotheses, all analyses are exploratory, and statistical significance will not be claimed. Estimated associations will be presented with nominal 95% confidence limits, that is, confidence limits that are not adjusted for multiple testing.

Ethics:

All requested data concerns toxicity registration in the protocol period (within 5 years after ALL diagnosis) or potental risk factors such as gender and age at time of diagnosis. The study will be conducted in accordance with Law nr. 502 of 23/05/2018 "Lov om supplerende bestemmelser til forordning om beskyttelse af fysiske personer i forbindelse med behandling af personoplysninger og om fri udveksling af sådanne oplysninger" (The Data Protection Act), Regulation (EU) 2016/679 (GDPR) and other relevant regulation. Each study group is responsible for obtaining relevant local approvals and follow relevant regulation, hereunder GDPR.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Camilla Grud Nielsen, MD; Phone Number: +4528450302; Email: camilla.grud.nielsen@regionh.dk
• Study Contact Backup: Name: Kjeld Schmiegelow, DMSc; Phone Number: +4535451357; Email: kjeld.schmiegelow@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Kjeld Schmiegelow
    • Contact: Kjeld Schmiegelow, M.D.; Phone Number: +45 35451357; Email: kschmiegelow@rh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Children and adolescents treated for acute lymphoblastic leukemia

Description

Inclusion Criteria:

• Diagnosed with ALL ≥5 years ago
• <18 years of age at time of ALL diagnosis

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
NOPHO ALL2008; Children and adolescents treated according to the NOPHO ALL2008 protocol
Australia
Poland
Dutch Childhood Oncology Group
St. Jude

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe-Toxicity-Free Survival	Time from ALL diagnosis to the first event of a Severe Toxicity or death	Within 5 years after ALL diagnosis
Number of different Severe Toxicities	Temporal development of cumulative number of Severe Toxicities	Within 5 years after ALL diagnosis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
21 Severe Toxicities	The occurrence of each of the 21 Severe Toxicities in children and adolescents treated for ALL	Within 5 years after ALL diagnosis

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of 21 Severe Toxicities	Time to occurrence of each of the 21 Severe Toxicities	Within 5 years after ALL diagnosis

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital; Medical University of Lodz; St. Jude Children's Research Hospital; Royal Children's Hospital; Danish Child Cancer Foundation; Aalborg University Hospital; Princess Maxima Center for Pediatric Oncology; Nordic Society for Pediatric Hematology and Oncology
• Investigators: Principal Investigator: Kjeld Schmiegelow, DMSc, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Andres-Jensen L, Attarbaschi A, Bardi E, Barzilai-Birenboim S, Bhojwani D, Hagleitner MM, Halsey C, Harila-Saari A, van Litsenburg RRL, Hudson MM, Jeha S, Kato M, Kremer L, Mlynarski W, Moricke A, Pieters R, Piette C, Raetz E, Ronceray L, Toro C, Grazia Valsecchi M, Vrooman LM, Weinreb S, Winick N, Schmiegelow K; Ponte di Legno Severe Toxicity Working Group. Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia. Lancet Haematol. 2021 Jul;8(7):e513-e523. doi: 10.1016/S2352-3026(21)00136-8.
• Nielsen CG, Thomsen BL, Als-Nielsen B, Conyers R, Jeha S, Mateos MK, Mlynarski W, Pieters R, Rathe M, Schmiegelow K, Andrés-Jensen L (2023) Physician-defined severe toxicities occurring during and after cancer treatment: Modified consensus definitions and clinical applicability in the evaluation of cancer treatment. Front. Pediatr. 11:1155449. doi: 10.3389/fped.2023.1155449

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2023
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: November 24, 2022
• First Submitted That Met QC Criteria: November 26, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): May 26, 2023
• Last Update Submitted That Met QC Criteria: May 25, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: STFS 18.11.2022 v1.0

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No