Introduction to a review series on acute lymphoblastic leukemia

Acute lymphoblastic leukemias (ALLs) represent a heterogeneous group of leukemias that affect the lymphoid progenitors of either the B or T lineages. Their prognosis after intensive conventional treatment is extremely variable and depend on the many known oncogenetic subtypes. For example, the very good prognosis of B-lineage ALL in children is based on the preponderance of favorable genetic subgroups in this age group, whereas these subgroups are very rare in older age groups in which many other unfavorable subtypes appear commonly.

This review series includes the following articles:

• Marie Passet, Rathana Kim, and Emmanuelle Clappier, “Genetic subtypes of B-cell acute lymphoblastic leukemia in adults”

• Petri Pölönen, Charles G. Mullighan, and David T. Teachey, “Classification and risk stratification in T-lineage acute lymphoblastic leukemia”

• Talha Badar, Selina M. Luger, and Mark R. Litzow, “Incorporation of immunotherapy into frontline treatment for adults with B-cell precursor acute lymphoblastic leukemia”

• Alexandros Rampotas and Claire Roddie, “The present and future of CAR T-cell therapy for adult B-cell ALL”

The oncogenic landscape of ALL has been broadened considerably by using high-throughput genomic or transcriptomic techniques (whole-genome, whole-exome, or whole-transcriptome sequencing) on diagnostic samples. New subgroups, sometimes frequent, sometimes rare, and more or less correlated with differentiation stages, have been described and compared with clinical data to propose genetic or clinicogenetic prognostic classifications. Functional studies have been able to characterize new oncogenic drivers, which may be potential targets for the development of targeted drugs. In some cases, subtype-founding genomic lesions have made it possible to develop molecular techniques for minimal residual disease monitoring and to compare it with the standard technique based on rearrangements of genes that encode immunoglobulin or T-cell receptor chains. The review by Passet et al, on the one hand, and that by Pölönen et al, on the other hand, provide an overview of currently established ALL subtypes in the B and T lineages, respectively. They address their relevance for risk classification and disease monitoring and underscore their potential to further understand the biology of the disease and guide precision medicine treatment strategies.

Although seemingly unrelated to this comprehensive description of the oncogenic landscape of ALL at first glance, another major advance in the field has been the successful development of new immunotherapy approaches. To date, patients with B-cell precursor ALL have mainly benefited from antibody-based immunotherapies that target surface differentiation molecules, such as CD20, CD19, or CD22, which have proven to be excellent therapeutic targets. It is important to note that immunotherapies active in leukemia are somewhat different from those developed primarily for solid tumors. In fact, likely because of the differences in immunogenicity and microenvironment, ALL has not been the ideal ground for the development of immune checkpoint inhibitors. To achieve an effective immunologic effect in ALL, we rather need to use more sophisticated products capable of forcing immune effectors to act in contact with leukemic cells, like the CD19/CD3 bispecific T-cell engager blinatumomab or chimeric antigen receptor (CAR) T cells. In a more classical way, this proximity is also the basis for the mechanism of action of antibody-drug conjugates like the CD22-targeting inotuzumab ozogamicin. The review by Badar et al discusses how these new therapies progressively moved from the relapsed/refractory field in which they were initially developed to the front line, treatment-naïve field in which they seem to be highly effective. The review by Rampotas and Roddie discusses the current indications, modalities, and toxicity of CAR T-cell therapy and the potential future developments of this fascinating new therapeutic concept in ALL.

We warmly thank all the authors for these reviews and hope that these articles will provide interested readers with a comprehensive and up-to-date understanding of some of the major current scientific and clinical issues concerning ALL and inspire them to continue their efforts to better understand and harness the complexity of these diseases.