Introduction to a review series on peripheral T-cell lymphomas: salutary complexity?

Peripheral T-cell lymphomas (PTCLs) are very rare diseases, which in recent years have emerged as perhaps the most vexing clinical challenge of all lymphomas. Many of the paradigm-changing treatments in lymphoma advanced in the last decade (eg, anti-CD19 chimeric antigen receptor T cells, CD3×CD20 bispecific antibodies, PD-1 blockade, small molecule inhibitors of Bruton's tyrosine kinase, BCL-2, etc) are almost exclusively effective in B-cell non-Hodgkin lymphomas and Hodgkin lymphoma. In fact, only 4 drugs have been approved in the United States for PTCL, with one (brentuximab vedotin¹ [BV]) restricted to anaplastic large-cell lymphoma (ALCL), one (romidepsin²) voluntarily withdrawn after failure of its confirmatory study, and the other 2 (pralatrexate³ and belinostat⁴) providing only modest clinical benefits. Today, most newly diagnosed patients with non-ALCL PTCL are treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; a regimen designed over 30 years ago) with or without etoposide, and with or without autologous stem cell transplantation for consolidation (and still with no definitive evidence for or against the benefit of transplantation in this setting). The outcomes of this treatment are poor, with a majority of patients progressing or relapsing; and for those patients with relapsed/refractory disease, the outcomes are dismal.

There are several plausible reasons for this. First, PTCLs are generally more resistant to chemotherapy than their B-cell counterparts. Second, indiscriminate elimination of T cells carries much higher toxicity than elimination of B cells, so the therapeutic index of PTCL therapies is generally narrower. Third, their rarity may discourage drug development. The fourth reason, which is a major focus of this review series, is that PTCLs are complex diseases. Indeed, the term PTCL covers a dauntingly diverse and complex set of diseases which differ in biology, clinical manifestations, treatment and prognosis. This makes it challenging not only to expertly treat the various entities but also to perform successful clinical trials, because one-size-fits-all treatments may not exist, and clinical trials focused on a single subtype of an already rare disease are hard to conduct.

Yet we should perhaps welcome this complexity as a first and essential step to progress. Some of the most important therapeutic advances in PTCL over the last few years are narrowly focused in their targets, including for example: the use of BV in the treatment of ALCL (and CD30⁺ PTCLs)⁵; the greater apparent benefit of epigenetic therapies (histone deacetylase inhibitors and possibly hypomethylating agents) in follicular helper T-cell lymphomas^6,7; the use of ALK inhibitors in Alk⁺ ALCL⁸; the use of L-asparaginase⁹ and PD-1 blockade¹⁰ in extranodal natural killer T-cell lymphoma; and the possible selective benefit of JAK-inhibition in PTCLs with deregulated JAK-STAT signaling.¹¹ Based on these examples, it is tempting to believe that continued progress will require continued “splitting.” This starts at the level of diagnosis, with the imperative need to properly classify the different entities and to accurately diagnose them for individual patients.

This series includes the following articles:

• Laurence de Leval, Philippe Gaulard, and Ahmet Dogan, “A practical approach to the modern diagnosis and classification of T-cell lymphomas”

• Javeed Iqbal, Giorgio Inghirami, and Wing C. Chan, “New insights into the biology of T-cell lymphomas”

• Alison J. Moskowitz, Robert N. Stuver, and Steven M. Horwitz, “Current and upcoming treatment approaches to common subtypes of PTCL (PTCL, NOS; ALCL; and TFHs)”

• Enrica Marchi, Jeffrey W. Craig, and Matko Kalac, “Current and upcoming treatment approaches to uncommon subtypes of PTCL (EATL/MEITL, SPTCL, and HSTCL)”

• Tony Marchand, Thierry Lamy, and Thomas P. Loughran Jr, “A modern view of LGL leukemia”

The review by de Leval, Gaulard, and Dogan provides a deep and comprehensive tour of the recent PTCL pathological classifications. However, even these complex classifications do not fully capture the biological differences and the potentially unique therapeutic vulnerabilities they betray. The review by Iqbal, Inghirami, and Chan provides a deeper dive into the biology of the most common PTCL subtypes and highlights the features that may facilitate their specific therapeutic targeting. The other 3 articles in this series review the treatment of most PTCL entities. Moskowitz, Stuver, and Horwitz review the current treatment of the common PTCL subtypes; Marchi, Craig, and Kalac review the treatment of several uncommon subtypes, while Marchand, Lamy, and Loughran review the modern approach to T-cell large granular lymphocyte leukemia. We are most grateful to all of the authors for their comprehensive reviews, and hope that these articles provide the interested readers with a full, up-to-date understanding of the main scientific and clinical issues in PTCLs, as well as motivate a continued effort to better understand and exploit the complexity of these deadly diseases.

Conflict-of-interest disclosure: P.A. provides consultancy to Merck, Bristol Myers Squibb (BMS), Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, AstraZeneca, Genentech/Roche, Xencor, Foresight, and ATB Therapeutics; receives research funding (institutional) from Kite, Merck, BMS, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM, and AstraZeneca; and receives honoraria from Merck and BMS.