Introduction to the review series on T-cell malignancies

T-cell malignancies represent a broad, highly heterogeneous grouping of clinicobiological entities, some of which are defined by exclusion. Although T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) derives from T-cell precursors (eg, thymocytes), other entities such as T-cell large granular lymphocyte (LGL) leukemia, human T-cell leukemia virus type 1–positive (HTLV-1⁺) adult T-cell leukemia/lymphoma (ATL), T-cell prolymphocytic leukemia (T-PLL), and most of the peripheral T-cell lymphomas (PTCLs), including angioimmunoblastic T-cell lymphoma (AITL), derive from mature T cells. Historically, these entities have been recognized by histological examination and immunophenotypic evaluation. More recently, molecular cytogenetics, large-scale expression analyses, and next-generation genomics have unraveled the complexity of T-ALL, allowing it to be divided into more homogeneous subtypes, whereas many of the other entities have been better characterized as unique, relatively homogeneous diseases.

Due to molecular complexity, identification of specific biomarkers allowing treatment stratification within entities has been difficult, and although the landscape of oncogenic pathways is now largely identified, clinical targeting is still under investigation. Although genetically modified mice and primary-derived xenografts are available and can be used for preclinical studies in T-ALL, such in vivo models are largely missing in other, more mature, T-cell malignancies inhibiting progress. Nevertheless, there are many promising novel therapeutic strategies in development for these diseases which are discussed within this review series.

The reviews within this series are as follows:

• Toshiki Watanabe, “Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells”

• Thierry Lamy, Aline Moignet, and Thomas P. Loughran Jr, “LGL leukemia: from pathogenesis to treatment”

• Matthew A. Lunning and Julie M. Vose, “Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma”

• Alessandro Broccoli and Pier Luigi Zinzani, “Peripheral T-cell lymphoma, not otherwise specified”

• Tiziana Girardi, Carmen Vicente, Jan Cools, and Kim De Keersmaecker, “The genetics and molecular biology of T-ALL”

• Marta Sanchez-Martin and Adolfo Ferrando, “The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia”

• David I. Marks and Clare Rowntree, “Management of adults with T-cell acute lymphoblastic leukemia”

In the first review, Watanabe provides a detailed overview of the pathogenesis of ATL and discusses current management strategies. ATL is an aggressive T-cell malignancy most prevalent in Japan, an area where HTLV-1 is endemic. The leukemogenesis of ATL involves a multistep process and recent discoveries have served to characterize both the genomic and epigenomic landscape. Within this context, implications for future treatment options, as well as preventive strategies, are explored.

Lamy and colleagues review the rare entity of LGL leukemia, discussing the evolution of its classification and postulating on its pathogenesis. A detailed model is provided which explores the clonal evolution initiated by chronic antigenic stimulation, followed by the constitutive activation of various survival pathways and the resultant dysregulation of apoptosis. Clinically, these patients present a unique challenge. Although the disease course is often indolent, the majority of patients will require intervention due to the frequent development of autoimmune cytopenias.

Lunning and Vose review the rare but complex entity of AITL. Improved molecular insight has led to AITL reclassification within the 2016 World Health Organization (WHO) classification under the category of nodal T-cell lymphomas with T follicular phenotype. Gene expression profiling studies have identified recurrent aberrations, however, their role in the pathogenesis of AITL has not been fully elucidated. Most patients present with advanced-stage disease with minimal bulk lymphadenopathy, and a constellation of signs and symptoms that can mimic infectious or autoimmune conditions. Although a minority of patients can be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, outcomes remain poor and alternative approaches of more intensive strategies and novel agents are being evaluated.

In the fourth review, Broccoli and Zinzani provide a nice overview of the challenge of PTCL, not otherwise specified (NOS). PTCL-NOS is the most common PTCL subtype, likely representing a broad category of biologically and clinically heterogeneous disorders. PTCL-NOS is often a diagnosis of exclusion. Importantly, recurring genetic abnormalities have been identified that may allow for the development of targeted therapeutics. CHOP chemotherapy remains the default treatment of patients with PTCL-NOS, largely extrapolated from historical trials enriched for aggressive B-cell lymphomas. Recently, several novel agents have been approved specifically for the treatment of relapsed PTCL, but how these agents should be combined and integrated into management is under investigation.

In the next review, Girardi and colleagues show how the comprehensive analysis of the T-ALL genome, gene expression profiling, and mouse models have revolutionized the way we see oncogenesis in this disease. Beyond classical transcription factor deregulation, many other mutations contribute to shape a precursor cell as leukemic. Subtypes such as early thymic precursor ALL (ETP-ALL) have been recognized, this last carrying a particular immunophenotypic and molecular profile that suggests a stem cell origin along with a poor prognosis (although the prognosis is still debated and under investigation in current trials in children and adults).

Then, Sanchez-Martin and Ferrando review in depth “The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia.” They nicely integrate many studies that have highlighted, at the genomic and functional levels, the critical importance of an activated NOTCH1 pathway in T-ALL. In this activated program, the MYC oncogene plays a prominent role as a major regulator of leukemia cell growth and metabolism, specifically suggesting therapeutic opportunities.

Finally, in the last article of this series, Marks and Rowntree review the current management of adults with T-ALL. Once the diagnosis of T-ALL has been established, few markers are presently available for treatment stratification. The authors discuss how the immunophenotype for ETP-ALL and genetic analyses at diagnosis are under evaluation to be broadly implemented. This highlights the need for large prospective studies to evaluate the integration of biological markers, especially complex genetic lesions, along with response assessment to treatment. The use of classical therapies, pediatric-inspired therapies, and new treatment options is also discussed.

We hope you find this review series on T-cell malignancies of interest.