Trial Title:
Severe Toxicity Free Survival Following Childhood Acute Lymphoblastic Leukemia
NCT ID:
NCT05639673
Condition:
Acute Lymphoblastic Leukemia
Conditions: Official terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Retrospective
Summary:
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.
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.
Criteria for eligibility:
Study pop:
Children and adolescents treated for acute lymphoblastic leukemia
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
- Diagnosed with ALL ≥5 years ago
- <18 years of age at time of ALL diagnosis
Exclusion Criteria:
- None
Gender:
All
Minimum age:
0 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Kjeld Schmiegelow
Address:
City:
Copenhagen
Zip:
2100
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Kjeld Schmiegelow, M.D.
Phone:
+45 35451357
Email:
kschmiegelow@rh.dk
Start date:
June 15, 2023
Completion date:
November 1, 2025
Lead sponsor:
Agency:
Rigshospitalet, Denmark
Agency class:
Other
Collaborator:
Agency:
Danish Child Cancer Foundation
Agency class:
Other
Collaborator:
Agency:
Aarhus University Hospital
Agency class:
Other
Collaborator:
Agency:
Odense University Hospital
Agency class:
Other
Collaborator:
Agency:
Aalborg University Hospital
Agency class:
Other
Collaborator:
Agency:
Royal Children's Hospital
Agency class:
Other
Collaborator:
Agency:
St. Jude Children's Research Hospital
Agency class:
Other
Collaborator:
Agency:
Princess Maxima Center for Pediatric Oncology
Agency class:
Other
Collaborator:
Agency:
Nordic Society for Pediatric Hematology and Oncology
Agency class:
Other
Collaborator:
Agency:
Medical University of Lodz
Agency class:
Other
Source:
Rigshospitalet, Denmark
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05639673
