A review of current induction strategies and emerging prognostic factors in the management of children and adolescents with acute lymphoblastic leukemia

ABSTRACT

Introduction

Acute lymphoblastic leukemia is the most frequent hematologic malignancy in children. Almost 95% of children potentially achieve a complete remission after the induction treatment, but over the last years, new insights in the genomic disease profile and in minimal residual disease detection techniques have led to an improvement in the prognostic stratification, identifying selected patients’ subgroups with peculiar therapeutic needs.

Areas covered

According to a comprehensive search of peer-review literature performed in Pubmed, in this review we summarize the recent evidences on the induction treatment strategies comprised in the children acute lymphoblastic leukemia scenario, focusing on the role of key drugs such as corticosteroids and asparaginase and discussing the crucial significance of the genomic characterization at baseline which may drive the proper induction treatment choice.

Expert opinion

Current induction strategies already produce durable remissions in a significant proportion of standard-risk children with acute lymphoblastic leukemia. A broader knowledge of the biologic features related to acute lymphoblastic leukemia subtypes with worse prognosis, and an optimization of targeted drugs now available, might lead to the achievement of long-term molecular remissions in this setting.

KEYWORDS:

• Acute lymphoblastic leukemia
• children
• adolescents
• induction strategies
• minimal residual disease
• dexamethasone
• asparaginase
• tyrosine kinase inhibitors

Article highlights box

• The overall survival of children affected by acute lymphoblastic leukemia (ALL) is approximately 80%, but some acute lymphoblastic leukemia subtypes (unfavorable genetic abnormalities, slow induction, and consolidation response) show a lower cure rate.

• The identification of specific clinical/biological features influencing prognosis highlighted the significance of risk-adapted therapy.

• Dexamethasone has shown a greater antileukemic activity compared with prednisone in randomized trials. The use of dexamethasone-induced a lower relapse-rate and better EFS especially in patients with T-acute lymphoblastic leukemia.

• Asparaginase is a key drug as part of induction treatment. By administering the appropriate doses, it is possible to determine an adequate asparagine depletion thereby ensuring an asparaginase activity.

• PEG-asparaginase might replace the use of native E. coli asparaginase because it is associated with a lower allergy and silent inactivation rate.

• AYA patients treated with high-intensity pediatric or pediatric-like regimens show promising long-term outcome. In this age group (15-39 years), the allogenic transplant approach in first complete remission when minimal residual disease is low (<10⁻⁴ using a qPCR assay) is no longer recommended.

• In Philadelphia positive acute lymphoblastic leukemia, the current induction approaches comprising TKIs provide a high rate of negative minimal residual disease (MRD) achievement. The role of allogenic stem cell transplant remains an intriguing issue. The ongoing European Intergroup of patients with Philadelphia positive ALL/Children’s Oncology Group (EsPhALL2017/COGAALL1631) study restricts transplant indications to patients with poor MRD response (EudraCT No.: 2017-000705-20).

• Philadelphia-like acute lymphoblastic leukemia is a current treatment challenge among children and adolescents. The standardization of diagnostic technologies is still ongoing and the treatment role of tyrosine kinase inhibitors and Janus kinase inhibitors in this setting is currently under investigation.

• The outcome of acute lymphoblastic leukemia in Down syndrome children is worse, compared with the general pediatric population mainly due to the therapy-related toxicities and higher relapse-rate. Further strategies including better supportive care, reduced intensity regimens in some low-risk patients, and novel immunomodulating agents might improve the outcome of these patients.

• Acute lymphoblastic leukemia in infants is a very rare event, with unfavorable prognosis probably related to the high frequency of KMT2A gene rearrangements and overexpression of fms-like tyrosine kinase 3. The suitable treatment modalities in this setting are still debated. A broader knowledge of the biological profile is warranted to identify the proper therapeutic strategy.

Declaration of interest

S Chiaretti is on the advisory board for Amgen, Incyte, Shire, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.