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Review
. 2023 Dec 20;41(36):5579-5591.
doi: 10.1200/JCO.23.01286. Epub 2023 Oct 11.

Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL

Affiliations
Review

Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL

Rob Pieters et al. J Clin Oncol. .

Abstract

Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Stephen P. Hunger

Stock and Other Ownership Interests: Amgen, Merck

Honoraria: Jazz Pharmaceuticals, Servier/Pfizer

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Outcome of Dutch children with ALL from 1972 to 2020. DCLSG, Dutch Childhood Leukemia Study Group; DCOG, Dutch Childhood Oncology Group.
FIG 2.
FIG 2.
Subtyping of B-ALL using whole-transcriptome sequencing. t-SNE depiction of childhood and adult B-ALL adapted from Kimura et al. Subtypes are color-coded and labeled accordingly. t-SNE, t-weighted stochastic neighbor embedding.
FIG 3.
FIG 3.
Frequency of B-ALL subtypes. Histogram of prevalence of B-ALL subtypes according to age. Childhood <15 years; AYA 15-39 years; adult >39 years. AYA, adolescent young adult; HR, high risk; SR, standard risk.
FIG 4.
FIG 4.
Pathways and therapeutic targets in BCR::ABL-like B-ALL. Schematic of genomic subtypes of BCR::ABL-like B-ALL, and potential therapeutic targeting opportunities, grouped according to kinase driver (JAK-STAT pathway, ABL1-class, and other). JAK-STAT, Janus kinase–signal transducers and activators of transcription; mTOR, mammalian target of rapamycin;PI3K, phosphatidylinositol 3-kinase.

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References

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