Peripheral T- and natural killer-cell lymphomas: ESMO-EHA Clinical Practice Guideline for diagnosis, treatment, and follow-up

Peripheral T-cell and natural killer (NK)-cell lymphomas (PTCLs) represent a heterogeneous group of neoplasms derived from post-thymic T- or NK cells, with diverse morphological patterns, phenotypes, and clinical presentations. The International Consensus Classification and World Health Organization (WHO) classification of lymphoid and hematopoietic neoplasms recognize >30 PTCL entities^{1, 2} (Supporting Information: Table S1 and Supporting Information Section 1). The incidence and epidemiology of PTCL are described in Supporting Information Section 2. This clinical practice guideline (CPG) covers PTCLs with primary nodal, extranodal, and leukemic presentation. Guidelines for primary cutaneous T-cell lymphomas are reported elsewhere.³

Accurate identification and diagnosis of PTCL is mandatory for adequate clinical management, as treatment should be adapted for each entity. Several entities present with a wide pathological spectrum and there is substantial overlap in morphology, immunophenotype, and mutational landscape between diseases. The differential diagnosis of PTCL is broad and includes various reactive conditions, particularly primary immune deficiencies, inflammation, autoimmune diseases, infections, Hodgkin lymphoma, and, in some instances, B-cell lymphomas.⁴ Overtly malignant PTCLs must be distinguished from the recently recognized indolent clonal T- or NK-cell lymphoproliferative disorders.^{1, 2} Given the low prevalence of PTCLs, most pathologists have insufficient experience to confidently diagnose them; therefore, diagnosis should be established or confirmed by a hematopathologist with expertise in PTCL who has access to all slides and ≥1 representative paraffin block of the biopsy.^{5, 6}

Clinicopathological correlation is critical for diagnosis, incorporating imaging findings, symptoms, and laboratory information. Anatomical localization can pre-sort for specific entities (e.g., hepatosplenic T-cell lymphoma [HSTCL], Epstein–Barr virus [EBV]-associated extranodal NK- or T-cell lymphoma [ENKTCL] nasal type, enteropathy-associated T-cell lymphoma [EATL], and breast implant-associated anaplastic large-cell lymphoma [BIA-ALCL]). Autoimmune and inflammatory diseases (e.g., celiac disease and inflammatory bowel disease), immunocompromised status, ethnicity, origin from endemic regions (e.g., within Asia, Africa, or South America for adult T-cell leukemia or lymphoma [ATLL]) or infection (e.g., EBV in tumor cells, human T-cell lymphotropic virus type 1 [HTLV-1]) may further support identification of entities.

Diagnosis should rely on surgical excisional or incisional biopsy whenever possible⁵ to allow adequate histopathological assessment and provide sufficient tissue for immunohistochemistry (IHC) and molecular studies. When surgery is not possible, core needle biopsy or biopsies may be adequate for initial management⁵; however, their accuracy is substantially lower than surgical biopsies for diagnosis and subclassification.^{7, 8} Several cores are warranted to anticipate future needs for archived biopsy material. In addition to IHC, flow cytometry has a role in diagnosing and staging PTCL in fluids (blood, ascites, pleural effusion, and cerebrospinal fluid).

The indication of the neoplastic nature of a T-cell population is based on (i) morphology (including overall tissue architecture), atypical cytology and microenvironment features; (ii) aberrant T-cell phenotype; and (iii) presence of a disease-associated genetic alteration, pathogenic mutation(s) or clonally rearranged T-cell receptor (TCR) genes.⁹ Morphological clues, immunophenotypical markers, and genetic molecular studies are summarized in Supporting Information: Tables S2 and S3. Various phenotypic aberrancies occur in PTCLs. Loss or reduced expression of one or more pan-T-cell antigens (cluster of differentiation [CD]2, surface CD3, CD4, CD5, CD7, CD8, and TCR) is common across various entities. Coexpression of CD30 is a defining feature of anaplastic large-cell lymphoma (ALCL), but is also observed in many other entities. Demonstration of differentiation markers related to follicular helper T cells (CD10, B-cell lymphoma 6, programmed cell death protein 1 [PD-1], CXC chemokine ligand 13, inducible T-cell costimulatory) is key for diagnosing follicular helper T-cell-derived lymphoma (TFHL). Cytotoxic markers (cytotoxic granule-associated RNA binding protein, granzyme B, and perforin) are useful for the characterization of extranodal T-cell neoplasms and PTCL not otherwise specified (PTCL-NOS). The latter may be further defined according to the expression of markers of type 1 T helper cells (CXC chemokine receptor 3 and T-box transcription factor 21) and type 2 T helper cells (C–C chemokine receptor type 4 [CCR4] and GATA binding protein 3). FISH is commonly used to assess frequent gene rearrangements or fusions, notably for genetic subtyping of anaplastic lymphoma kinase (ALK)-negative ALCL based on DUSP22 with or without TP63 rearrangement. The detection of gene variants may rely on targeted assays for certain hotspots (e.g., RHOA p.G17V or IDH2 p.R172 mutations, which both support a diagnosis of TFHL) but is more commonly achieved by high-throughput sequencing (HTS) of panels of genes. Many of the recurrent aberrations found in PTCLs involve genes related to epigenetic regulation (TET2, DNMT3A, IDH2, ARID1A, SETD2, and INO80), components of the TCR, nuclear factor kappa B and Janus kinase (JAK)–signal transducer, and activator of transcription signaling pathways (CD28, CARD11, RHOA, PIK3CD, PLCG1, JAK1, JAK3, STAT3, and STAT5B) or genes involved in the regulation of cell cycle and apoptosis (ATM, CDKN2A, FAS, and TP53).⁹ HTS complements classical TCR gene rearrangement studies to determine clonality, given that TCR gene-based assays may give false-positive results for non-malignant clones or false-negative polyclonal results in T-cell malignancies. HTS may also assist therapeutic decisions, as some PTCL-associated genetic lesions may support a rationale for subtype-specific intervention.¹⁰ An overview of the main defining features of common PTCL entities is presented in Supporting Information: Table S4. The diagnostic approach to nodal PTCLs is summarized in Supporting Information: Figure S1 and Supporting Information Section 3.

Bone marrow (BM) is often the main tissue source providing conclusive diagnostic documentation in leukemic entities such as T-cell prolymphocytic leukemia (T-PLL), T-cell large granular lymphocytic leukemia (T-LGL), NK-cell large granular lymphocytic leukemia (NK-LGL), aggressive NK-cell leukemia (ANKL), and ATLL. HSTCL is the only non-leukemic PTCL with evidence of BM involvement in almost all cases. BM involvement is characterized by a typical intrasinusoidal lymphoid infiltrate, and its diagnosis often relies on BM biopsy.¹¹ When primary BM diagnosis is required in rare cases of extranodal lymphomas presenting with isolated BM disease, PTCL diagnosis can be particularly challenging.¹²

All patients with PTCL should be offered the opportunity to participate in a clinical trial whenever possible. An overview of first-line treatment strategies is shown in Figure 1 (nodal PTCL), Figure 2 (extranodal PTCL), and Figure 3 (leukemic PTCL). Complementary and subtype-specific algorithms can be found in the Supporting Information as outlined below.

Patients with r/r PTCL have a poor prognosis, with a study reporting median PFS and OS of 3.1 months and 5.5 months, respectively.⁷³ Algorithms for the management of r/r PTCL are shown in Figure 4 (r/r nodal PTCL), Figure 5 (r/r extranodal PTCL), and Figure 6 (r/r leukemic PTCL).

Response evaluation and follow-up in patients with PTCL are described in Supporting Information Section 7.

This CPG was developed in accordance with the ESMO standard operating procedures for CPG development (http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology). The relevant literature has been selected by the expert authors. The FDA/EMA or other regulatory body approval status of new therapies/indications is reported at the time of writing this CPG. Levels of evidence and grades of recommendation have been applied using the system shown in Supporting Information: Table S6. Statements without grading were considered justified standard clinical practice by the authors. For future updates to this CPG, including eUpdates and Living Guidelines, please see the ESMO Guidelines website: https://www.esmo.org/guidelines/guidelines-by-topic/haematological-malignancies/peripheral-t-cell-lymphomas.

All authors conceptualized, performed the literature search, and reviewed and edited the manuscript. Francesco d'Amore and Massimo Federico performed the literature review and development of clinical recommendations. Francesco d'Amore and Laurence de Leval visualized the work. Francesco d'Amore, Laurence de Leval, Massimo Federico, François Lemonnier, Olivier Hermine, Fredrik Ellin, and Joost S. P. Vermaat wrote the original draft. The following authors contributed to section-specific contributions: epidemiology, staging and risk assessment, follow-up—Fredrik Ellin, Massimo Federico, and Francesco d'Amore; diagnosis and pathology—Laurence de Leval and Joost S. P. Vermaat; primary treatment—Francesco d'Amore, François Lemonnier, Olivier Hermine, Massimo Federico, Won Seog Kim, Gerald Wulf, and Fredrik Ellin; treatment of relapsed/refractory disease—Francesco d'Amore, François Lemonnier, Olivier Hermine, Massimo Federico, Won Seog Kim, Gerald Wulf, and Fredrik Ellin.

F. d. A. reports institutional fees for an advisory role from Frost; institutional fees as local principal investigator (PI) from Genmab; institutional fees for the implementation of a clinical trial as coordinating PI from Servier; non-remunerated membership of the Scientific Committee for the European School of Haematology and the Clinical Advisory Committee for the WHO (T-cell lymphoma working group); and non-remunerated roles as project lead for the European Union's HARMONY Alliance (contact person of associated member institution Aarhus University Hospital), lead author of ESMO−EHA CPG for T-cell lymphomas, Chairman of the Nordic Lymphoma Group (NLG) T-cell lymphoma working group and PI for the RESILIENCE trial at Aarhus University Hospital.

M. F. reports no potential conflicts of interest.

L. D. L. reports institutional fees for advisory board membership from AbbVie, Blueprint Medicines, and Novartis; and institutional fees for expert testimony and travel support from Roche.

F. E. reports institutional fees for writing educational material from Roche Sweden; and a non-remunerated role as local PI for Celgene (observational study).

O. H. reports personal fees from AB Science (as consultant, co-founder, and for scientific support); personal stocks and shares from AB Science (co-founder); personal ownership interest in Inatherys (co-founder); institutional fees for advisory board membership from Bristol Myers Squibb (BMS), Celgene and Novartis; and institutional funding from AbbVie, AB Science, Alexion, Blueprint, BMS, Celgene, Novartis, Roche, and Takeda.

W. S. K. reports personal and institutional fees as a coordinating PI from BeiGene, Boryong, Kyowa-Kirin, Roche, and Sanofi; and a non-remunerated advisory role for Celltrion (regular consulting).

F. L. reports personal fees for advisory board membership from BMS, Kiowa, and Miltenyi; personal fees as an invited speaker from AstraZeneca and Takeda; and personal travel grants from Gilead, Janssen, and Roche.

J. S. P. V. reports no potential conflicts of interest.

G. W. reports personal fees for advisory board membership from Clinigen, Novartis, and Takeda; personal fees as an invited speaker from Gilead and Takeda; an institutional role as local PI from Gilead, Janssen, Miltenyi, Novartis, Roche, and Verastem; non-remunerated speaker for the German Society of Hematology and Medical Oncology (DGHO); non-remunerated membership of the DGHO, Experimental Cancer Research (AEK), German Cancer Aid (DKH), and German Lymphoma Alliance (GLA); and has received product samples from Gilead and Roche.

C. B. reports personal fees for advisory board membership from AbbVie, BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, Lilly Deutschland GmbH, MorphoSys, Novartis, Pfizer, Regeneron, Roche, and Sobi; personal fees as an invited speaker from AbbVie, BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, Lilly Deutschland GmbH, MorphoSys, Novartis, Pfizer, Regeneron, Roche, and Sobi; and institutional funding from AbbVie, Amgen, Bayer, Celltrion, Janssen, MSD, Pfizer, and Roche (all for investigator-sponsored clinical trials and registries).

M. D. reports personal fees as an advisory board member from AbbVie, AstraZeneca, BeiGene, BMS/Celgene, Gilead, Janssen, Lilly/Loxo, Novartis, and Roche; personal fees as an invited speaker for AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; institutional research grants from AbbVie, Bayer, Celgene, Gilead/Kite, Janssen, Lilly, and Roche; and non-renumerated membership of the American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH; subcommittee), DGHO (prior Board member), European Hematology Association (EHA; Executive Board), ESMO (Faculty), and the Lymphoma Research Foundation (Mantle Cell Lymphoma Consortium).

M. J. reports personal fees for advisory board membership from Genmab, Gilead, and Roche; personal fees as an invited speaker from AbbVie; institutional funding from AbbVie, AstraZeneca, Celgene, and Roche; an institutional role as coordinating PI from BioInvent; and non-remunerated membership of ASCO, ASH, and the EHA.

No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO (for Annals of Oncology) and EHA (for HemaSphere) from central funds.