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Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers
Stine N Nielsen1, Frank Eriksson2, Susanne Rosthoej2
1Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Insights
Childhood acute lymphoblastic leukemia (ALL) survivors on thiopurine therapy face increased second cancer risk, particularly those with standard-risk ALL receiving prolonged maintenance. No specific genetic factors or TPMT activity identified a higher-risk subset.
Area of Science:
- Pediatric Oncology
- Cancer Epidemiology
- Clinical Pharmacology
Background:
- Improved survival in childhood acute lymphoblastic leukemia (ALL) is threatened by secondary malignancies.
- Thiopurine therapy, a common treatment for ALL, has been linked to an increased risk of developing a second cancer.
Purpose of the Study:
- To investigate the risk of second cancer in childhood ALL survivors treated with varying intensities of thiopurine maintenance therapy.
- To identify specific patient subgroups or treatment factors associated with a higher risk of secondary malignancies.
Main Methods:
- Retrospective analysis of three Nordic Society of Paediatric Haematology and Oncology protocols with escalating thiopurine therapy intensity.
- Exploration of second cancer risk in relation to treatment protocols, risk groups, thiopurine methyltransferase (TPMT) activity, high hyperdiploidy (HeH), and t(12;21) [ETV6/RUNX1] ALL subtypes.
Main Results:
- Among 3,591 patients followed for a median of 9.5 years, 40 developed a second cancer, predominantly in non-high-risk B-cell precursor ALL.
- Standard-risk ALL patients receiving the longest maintenance therapy exhibited the highest adjusted hazard for second cancer.
- No significant associations were found between second cancer risk and protocol, age, white blood cell count, HeH, t(12;21), or low TPMT activity.
Conclusions:
- The incidence of second cancers was highest in low-risk ALL patients.
- This study could not pinpoint a specific subset of childhood ALL patients at significantly higher risk for developing a second cancer beyond the general trend observed in low-risk groups.
Background:
The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy.
Procedure:
We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1].
Results:
After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47).
Conclusions:
The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.
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