Molecular-based and antibody-based targeted pharmacological approaches in childhood acute lymphoblastic leukemia

ABSTRACT

Introduction: Despite the significant survival improvement in childhood acutelymphoblastic leukemia (ALL), 15–20% of patients continue to relapse; outcomes following relapse remain suboptimal and have room for further improvement. Advances in genomics have shed new insights on the biology of ALL, led to the discovery of novel genomically defined ALL subtypes, refined prognostic significance and revealed new therapeutic vulnerabilities.

Areas covered: In this review, the authors provide an overview of the genomic landscape of childhood ALL and highlight recent advances in molecular-based and antibody-based pharmacological approaches in the treatment of childhood ALL, from emerging preclinical evidence to published results of completed clinical trials.

Expert opinion: Molecularly targeted therapies and immunotherapies have expanded the horizons of ALL therapy and represent promising therapeutic avenues for high-risk and relapsed/refractory ALL. These novel therapies are now moving into frontline ALL therapy and may define new treatment paradigms that aim to further improve survival and reduce chemotherapy-related toxicities in the management of pediatric ALL.

KEYWORDS:

• Acute lymphoblastic leukemia
• children
• genomics
• immunotherapy
• precision medicine
• targeted therapy

Highlights

• Risk-adapted regimens based on patient’s characteristics, leukemia features, genetic abnormalities and MRD have significantly improved the outcomes of childhood ALL.

• NGS technologies defined novel genomic ALL subtypes that became potentially accessible to molecularly targeted therapies.

• Ph⁺ ALL turned into a highly curable disease in the TKI era and the molecular characterization of specific Ph-like ALL subtypes paved the way to offer effective targeted therapies.

• Effective targeted therapies and immunotherapies improve survival rate as well as quality of life of patients by reducing systemic toxicities.

• Recent trials of antibody- and cell-based immunotherapies changed the landscape of treatment for relapsed and refractory B-ALL and is becoming the new standard of care.

• Challenges remain for other subtypes of childhood ALL and clinical trials are actively investigating the incorporation of immunotherapy into first-line therapy as a genomically agnostic way of improving survival for all children with ALL.

Declaration of interest

H Bittencourt has served as a consultant and speaker for Novartis and has also served as a consultant for and received honoraria from Jazz Pharmaceuticals. TH Tran meanwhile has served as a consultant for and received honoraria from Bayer. The author(s) 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

One reviewer declares that they have received honoraria from Otsuka, as well having served on the advisory board for and received research funding from Novartis. They also have served on an advisory board for Pfizer Inc. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.