The development of targeted new agents to improve the outcome for children with leukemia

ABSTRACT

Introduction: Survival rates in pediatric leukemia have greatly improved in the last decades but still a substantial number of patients will relapse and die. New agents are necessary to overcome the limitations of conventional chemotherapy and hematopoietic stem cell transplantation and to reduce their undesirable long-term toxicities. The identification of driving molecular alterations of leukemogenesis in subsets of patients will allow the incorporation of new-targeted therapies.

Areas covered: In this article the authors present a detailed review of the most recent advances in targeted therapies for pediatric leukemias. A comprehensive description of the biological background, adult data and early clinical trials in pediatrics is provided.

Expert opinion: Clinical trials are the way to evaluate new agents in pediatric cancer. The development of new drugs in pediatric leukemia must be preceded by a solid biological rationale. Agents in development exploit all possible vulnerabilities of leukemic cells. Drugs targeting cell surface antigens, intracellular signaling pathways and cell cycle inhibitors or epigenetic regulators are most prominent. Major advances have occurred thanks to new developments in engineering leading to optimized molecules such as anti-CD19 bi-specific T-cell engagers (e.g. blinatumomab) and antibody-drug conjugates. The integration of new-targeted therapies in pediatric chemotherapy-based regimens will lead to improved outcomes.

KEYWORDS:

• Anticancer drug development
• children
• leukemia
• relapse

Article highlights

• Leukemia is the most frequent type of cancer in children. Survival rates have improved in the last decades but still a substantial number of patients will succumb to their disease. New agents are necessary to overcome the therapeutic imitations of conventional chemotherapy and hematopoietic stem cell transplantation and to reduce their long-term toxicity.

• Pediatric research platforms for the identification of molecular alterations and novel targeted therapies have been developed, such as the Pediatric Pre-clinical Testing Program and the Therapeutically Applicable Research to Generate Effective Treatments project in the United States or the Innovative Therapies for Children with Cancer Consortium in Europe. A close collaboration between pharma, regulators and academic groups is necessary to incorporate these therapies into clinical practice.

• New agents have been developed to target pathogenic molecular alterations at different cell levels: cell surface receptors, tyrosine-kinases, signaling pathways and the cell cycle. Immunotherapy in leukemia is key and new promising agents are being developed such as antibodies or CAR-T cells.

• The introduction of targeted agents in particular subsets of children with leukemia harboring individual molecular alterations has radically changed their outcome, such as BCR-ABL fusion gene in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. The identification of driving targetable molecular alterations in clonal leukemic cells will allow individualizing treatments while sparing patients of undesirable side effects.

This box summarizes key points contained in the article.

Acknowledgments

The authors are grateful to their colleagues from the Innovative Therapies for Children with Cancer (ITCC) group.

Declaration of interest

L Moreno has received funding/honoraria for their consultancy/advisory role from Amgen Inc, AstraZeneca, Bayer, Mundipharma, Novartis and Roche Genentech.

CM Zwaan has received funding/honoraria for their consultancy/advisory role from Bristol-Myers Squibb, Celgene, Novartis and Sunesis. P Kearns has received funding for their consultancy/advisory role from Genzyme. 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.

Additional information

Funding

This manuscript has not been funded.