Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients' lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient's specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.

Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP‐BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia

“…Advances in ALL therapy includes the development of targeted therapy, such as tyrosine kinase inhibitors, and the introduction of immunotherapies 1 . The promise of these novel approaches is to improve cure rates, to overcome chemotherapy resistance, and, being target‐specific, to confer limited toxicity to normal tissues 33–36 . Pharmacological strategies, including the analysis of the proactive monitoring of drug metabolites and important predictive pharmacogenetic markers, could represent additional valuable tools for a rational use of “old” drugs to personalize therapy with the same purposes.…”

A Novel ELISA-Based Peptide Biosensor Assay for Screening ABL1 Activity in vitro: A Challenge for Precision Therapy in BCR-ABL1 and BCR-ABL1 Like Leukemias

“…However, none of these genetic methods can give functional information about the aberrant kinase activity or about blasts sensitivity to TKI. This highlights the importance of having functional assays for TKs with key pathogenic role rather than genomic characterization as tools of precision therapy in BCR-ABL1 like ALL patients (Franca et al, 2018). Functional TK assays would represent an important tool for clinicians also for BCR-ABL1 CML and ALL: they could be used to guide the choice of TKI for the best target therapy and to identify primary TKI resistance in a timely manner at diagnosis.…”

Pharmacogenetics of thiopurines

“…In ALL, thiopurines are always used in the context of a polychemotherapeutic protocol that comprises glucocorticoids, vincristine, asparaginase, cytarabine, anthracyclines, cyclophosphamide and tyrosinekinase inhibitors such as imatinib; in particular, MP is used in combination with methotrexate [13][14][15] . Specific ALL polychemotherapeutic approaches differ across worldwide protocols in terms of drugs, dosages and combinations; however, they consistently share the therapeutic scheme with an initial remission-induction phase to eradicate the burden of tumoral cells and restore normal hematopoiesis, followed by a remissionconsolidation therapy and then by a long-term maintenance regimen (up to 24 months after diagnosis) to eliminate minimal residual leukemic cells.…”