Guidelines for the management of mature T- and natural killer-cell lymphomas (excluding cutaneous T-cell lymphoma): a British Society for Haematology Guideline

This guideline was developed according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are described at http://www.gradeworkinggroup.org. Ovid MEDLINE and PubMed were searched for English language articles up to December 2020 using the keywords: peripheral T-cell lymphoma, T prolymphocytic leukaemia, large granular lymphocyte leukaemia, adult T-cell leukaemia lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, extra-nodal natural killer (NK)/T-cell lymphoma, aggressive NK cell leukaemia, enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma. Review of the manuscript was performed by the BSH Guidelines Committee, Haematology Oncology Task Force and the members of Haematology Oncology sounding board of the BSH. It was also on the members section of the BSH website for comment. The mature or peripheral T-cell neoplasms are a heterogeneous group of rare disorders arising from clonal proliferation of mature post-thymic lymphocytes. Natural killer (NK) cells are part of the innate immune system although they have functional similarities to T cells; neoplasms arising from NK cells are considered within the same broad disease group. The World Health Organization (WHO) classification of haemopoietic neoplasms categorised these diseases into those with predominantly leukaemic (disseminated), nodal, extra-nodal or cutaneous presentation. Further delineation is based on clinical features, morphology, immunophenotype and genetics. The 2016 revision of the WHO classification incorporated scientific advances in cell ontogeny and molecular signatures of certain subtypes.1 Accurate diagnosis of peripheral T-cell lymphomas (PTCLs) is challenging with relatively high discordance rates reported.2 It is essential that PTCL histology is reviewed by haematopathologists with expertise in PTCL diagnostics. Nodal PTCLs are virtually all 18F-fluorodeoxyglucose avid on positron emission tomography-computed tomography (PET-CT) scans. Although baseline PET-CT upstages only a small proportion of cases, additional sites of disease are identified in up to 50%.3 End of treatment PET-CT is increasingly used to guide haematopoietic stem cell transplant (HSCT) decisions. Bone marrow involvement in nodal PTCL occurs in up to 35% of patients but studies report a lower sensitivity of PET-CT in identifying marrow disease compared to Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL).4, 5 Most PTCL subtypes are associated with poor clinical outcomes with conventional chemotherapy, and from the outset, consideration should be given to clinical trial and HSCT options. It is recommended that all PTCL cases, newly diagnosed and relapsed/refractory, are discussed at a regional lymphoma multidisciplinary team (MDT) to include expert pathology review and discussion of treatment options. In addition, young adults aged <25 years should be discussed with a Teenage and Young Adult (TYA) specialist. Excellent outcomes for anaplastic large cell lymphoma (ALCL) have been reported in paediatric series and these protocols may be preferable over adult regimens on a case-by-cases basis considering clinical presentation, individual preferences, and late toxicity risk. T-PLL is rare and accounts for ~2% of all small lymphocytic leukaemias in adults with a median age of 61 years.6 T-PLL typically presents with splenomegaly, lymphadenopathy, and leucocytosis, frequently >100 × 109/l.7 Less commonly, other organs and skin are involved. Up to 30% of patients are asymptomatic at diagnosis.8 The circulating pro-lymphocytes have distinctive morphology and express mature T-cell markers including cluster of differentiation (CD)7 with variable expression of CD4 and CD8. Conventional cytogenetic analysis usually demonstrates complex abnormalities.9 Over 90% of cases show a rearrangement of T-cell leukaemia/lymphoma protein 1A/B (TCL1A/B) and mature T-cell proliferation 1 (MTCP1).10 Abnormalities of chromosome 8 are seen in over half, and the ataxia-telangiectasia mutated serine/threonine kinase (ATM) gene (11q22·3) is frequently disrupted.11 Overall prognosis is poor with a median survival of <2 years from initiation of treatment. A ‘watch-and-wait’ approach is appropriate for asymptomatic T-PLL, although disease progression is invariably seen within 1–2 years. When indicated, the aim of treatment is to achieve a complete response (CR). Early consideration should be given to consolidative allogeneic HSCT (allo-HSCT) for potentially eligible patients. T-PLL is relatively resistant to conventional chemotherapy, with short responses to CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), pentostatin and bendamustine reported.12, 13 Data supporting use of alemtuzumab are derived from single-arm phase II studies, with high overall response rate (ORR; 51–91%) and CR (40–81%), particularly in the first-line setting where a 12-month progression-free survival (PFS) rate of 67%, and a median overall survival (OS) of 24 months are reported.14, 15 Intravenous alemtuzumab, at a dose of 30 mg three times per week after dose escalation (3, 10, 30 mg) in the first week, appears superior to subcutaneous administration, although no direct comparative data exist.14, 16, 17 There are no data to support the use of alemtuzumab maintenance.17 Opportunistic infection prophylaxis (co-trimoxazole and aciclovir) and monitoring for cytomegalovirus (CMV) re-activation using quantitative polymerase chain reaction (qPCR) testing are essential. Treatment options for relapsed/refractory disease are very limited. Clinical trials should be considered if available. Approximately 50% of patients will respond to alemtuzumab re-treatment after a previous clinical response if the cells continue to express surface CD52.18, 19 However, response duration is typically short and cumulative toxicity an important consideration. A phase II study using alemtuzumab with pentostatin in 13 patients with T-PLL produced an ORR of 69%, median OS of 10·2 months and PFS of 7·8 months.20 For patients with poor responses to alemtuzumab, or who have bulky/extranodal disease, the addition of pentostatin to alemtuzumab may be beneficial. Available data on autologous (auto) or allo-HSCT for T-PLL are limited. Although auto-HSCT showed improved OS and PFS compared to historical controls, relapse rates were higher than after allo-HSCT.21 Allo-HSCT is associated with encouraging OS and PFS, although only 30–40% of patients achieve durable disease control and transplant-related mortality (TRM) remains high.22-25 Nevertheless, allo-HSCT is a potential option for achieving long-term remission in carefully selected patients. Auto-HSCT may be an option for those where allo-HSCT is not feasible, but the weak evidence base should be recognised. LGLL is defined as persistent (>6 months) clonal expansion of circulating large granular lymphocytes, usually >2 × 109/l, without a clearly identified cause. The median age at diagnosis is 66 years, with no gender or racial predilection.26, 27 Neutropenia is present in ~80% of patients and the main cause of morbidity and mortality.28 Anaemia and thrombocytopenia occur in ~40% and ~20% of patients respectively. Hepatomegaly and splenomegaly also occur. A strong association exists with rheumatoid arthritis, which is seen in almost a third of patients,29 as well as with other autoimmune conditions.30 T-LGLL has also been associated with clonal B-cell disorders, plasma cell neoplasms and non-haemopoietic tumours.31-33 Most cases are of T-cell origin and usually demonstrate a CD8+ T-cell receptor (TCR) αβ cytotoxic phenotype. Rarer phenotypes express CD4 or TCR γδ or have an NK-cell phenotype. Although a bone marrow biopsy is not mandated within the WHO diagnostic criteria, this is usually helpful in confirming the diagnosis34 and clarifying the mechanism of cytopenias. T-cell clonality should be confirmed, usually by TCR gene rearrangement studies. However, clonal TCR rearrangements can be demonstrated in reactive conditions and results of analysis need to be considered alongside immunophenotypic aberrations and clinical context. Activating mutations in signal transducer and activator of transcription 3 (STAT3) have been identified in 20–50% of patients with LGLL and STAT5b mutations have also been seen in a smaller proportion of patients.35, 36 Up to half of patients may not require therapy at diagnosis with treatment generally reserved for those with symptomatic disease or severe cytopenias.37 The quality of evidence supporting all recommendations is low. Retrospective and single-arm prospective studies have reported efficacy for immunosuppressive (rather than cytotoxic) approaches; low-dose weekly methotrexate,30, 34 low-dose daily cyclophosphamide,38 and ciclosporin (with therapeutic drug monitoring)39 confer response rates of ~40–60%. In T-LGLLs associated with pure red cell aplasia, cyclophosphamide and ciclosporin appear to be active,40, 41 whereas methotrexate may be preferred in cases associated with rheumatoid arthritis and/or neutropenia.29 Importantly, time to response can be slow; treatment should be given for a minimum of 4 months before determining quality of response. A short course of steroids or granulocyte colony stimulating factor (G-CSF) can be considered to support cytopenias whilst awaiting suppression of the T-LGL clone. Response rates with prednisolone monotherapy are low.30 Methotrexate and ciclosporin can be continued indefinitely but cyclophosphamide is often stopped after 8–12 months because of concerns regarding secondary cancers.38 Second-line treatment with alemtuzumab, purine analogues, splenectomy and rituximab has been described in small patient groups.42-45 An increase in large granular lymphocytes is frequently seen in various clinical contexts including after allo-HSCT. Whilst these cases may fulfil the laboratory criteria for T-LGLL, including oligo- or monoclonality, such patients do not typically experience cytopenias or constitutional symptoms and thus should not be necessarily labelled with a T-LGLL diagnosis. ATLL is caused by the retrovirus, human T-cell lymphotropic virus 1 (HTLV-1), which is endemic in many parts of the world. In the UK ATLL is seen predominantly in patients of African-Caribbean or west African descent but with increasing numbers of cases observed from other ethnic groups suggesting that HTLV-1 serology should be undertaken in all cases of PTCL.46 First-degree relatives and partners of those with ATLL should be screened for HTLV-1 infection as they are at increased risk of ATLL and other HTLV-1 related inflammatory disorders.47 ATLL classification remains as per the original Shimoyama classification.48 In the UK >75% cases are lymphoma subtype, with a median age at presentation of 53 years. More recently a distinct primary cutaneous entity, without blood or lymph node involvement, has been recognised.49 The prognosis for acute and lymphoma type ATLL remains unchanged with a median survival of only 8·3 and 10·6 months. The median OS of indolent subtypes (chronic and smouldering) remains 2–4 years, with 50% of patients transforming to an aggressive generally fatal subtype at a median of 18-months follow-up and with no plateau in the survival curve.50, 51 Three prognostic indices have been developed [Japan Clinical Oncology Group-Prognostic Index (JCOG-PI), ATLL-PI, modified ATLL-PI] but even in the low-risk groups the prognosis remains poor and no subgroups of patients have been identified who would not benefit from allo-HSCT.52-54 ATLL cells have a characteristic morphology (‘flower cells’), although such cells may be infrequent. The immunophenotype is CD3+, CD4+, CD26–, C-C chemokine receptor 4 (CCR4)+, CD7– expressing a dominant TCRvB.55 Monoclonal integration of HTLV-1 pro-viral DNA is found in all cases and is useful in distinguishing ATLL from other PTCL in a HTLV-1 carrier,56 which is essential due to differing transplant strategies. A United Kingdom Accreditation Service (UKAS) accredited pro-viral load monitoring and clonality assays are available at Imperial College (further information www.htlv.eu). Patients are immunocompromised, opportunistic infections are common and suitable prophylaxis is required. Routine strongyloides serology and treatment of seropositive cases is recommended at diagnosis. Recommended treatment options have been recently summarised in an International Consensus Report.46 As OS remains dismal with current therapies, all patients should be considered for allo-HSCT and referred promptly at diagnosis. Better outcomes are associated with early transplant (<100 days from diagnosis) and whilst in CR.57 Prophylactic central nervous system (CNS) therapy should be considered for all patients with aggressive ATLL subtypes.46 Nodal disease (lymphoma or acute subtypes with lymphadenopathy) should be treated with a chemotherapy-based approach. CHOP-like protocols remain standard of care.46 Whilst intensive protocols may increase CR rates, the PFS and OS are not significantly improved58 and concurrent zidovudine/interferon-α may be less well tolerated. The combination of the anti-retroviral drug AZT with IFN-α has demonstrated significant activity in patients with ATLL and improved clinical outcome, particularly in leukaemic subgroups59 but also in aggressive subtypes.60 In the aggressive form of acute ATLL higher initial doses of AZT/IFN-α are used before reducing to maintenance dosing in responding patients.61 Lower dosing is also used in chronic/smouldering ATL or when given concurrently with chemotherapy in the lymphoma subtype. G-CSF support is usually required. The addition of the integrase inhibitor, raltegravir, to transplant conditioning protocols to reduce de novo infection of donor stem cells has been recently incorporated into clinical practice, although the evidence supporting this strategy is limited.46 Patients with acute/lymphoma type ineligible for transplant should continue with maintenance AZT/IFN-α indefinitely. Oral etoposide-containing maintenance chemotherapy, such as PEP-C (prednisolone, etoposide, cyclophosphamide, procarbazine) is an option for those who do not tolerate AZT/IFN-α.46 Mogamulizumab, a monoclonal antibody targeting CCR4, has demonstrated activity in relapsed or refractory ATLL. In addition, mogamulizumab is licensed in Japan in combination with chemotherapy in first-line therapy, resulting in improved CR rates (52% vs. 33%) but no improvement in PFS or OS.62 Recent retrospective data suggest that patients harbouring activating CCR4 mutations are those most likely to respond.63 However, there is a significant risk of severe steroid-refractory acute graft-versus-host disease when mogamulizumab is used prior to allo-HSCT and it is contraindicated within 50 days of transplant.57 Mogamulizumab responses display a compartment effect (effective in blood, intermediate in skin, and poor in lymph nodes) and thus therapy is most active in leukaemic disease. The latest WHO Classification recognises four distinct subtypes of ALCL: primary systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative disease, primary cutaneous types and breast-implant associated. These subtypes have differences in immunophenotype, genetics, and clinical behaviour.1 ALCL comprises ~3% of all adult non-Hodgkin lymphomas and 10–20% of childhood lymphomas. ALK+ ALCL typically occurs in children and young adults with a median age of 30 years, whereas ALK− ALCL occurs in older adults (median age, 55 years). For both types, most patients are male and present with advanced stage disease, often with B symptoms. Extra-nodal, especially cutaneous, involvement frequently occur.64 The International Prognostic Index (IPI) is useful in risk stratifying patients with systemic ALCL (sALCL) and age is a strong factor underpinning the prognostic difference between ALK+ and ALK− ALCL.65 Age <40 years and a low β2-microglobulin (<3 mg/dl) have been identified as favourable prognostic factors.66 Recurrent chromosomal rearrangements involving the dual specificity phosphatase 22-interferon regulatory factor 4 (DUSP22-IRF4) locus on 6p25·3 have been reported as identifying a subset of ALK− ALCL with favourable outcomes but numbers are small and not all studies have reached the same conclusion.67-69 Rearrangement of tumour protein p63 (TP63) occurs in 8% of cases and may be associated with particularly poor outcomes.68, 69 Most patients with sALCL present with advanced-stage disease and there are few reported studies involving limited stage. Whilst favourable outcomes have been reported with short-course (three to four cycles) CHOP-based chemotherapy and consolidation radiotherapy70 there is insufficient evidence to recommend abbreviated chemotherapy over standard full-course treatment. Previously, CHOP-like chemotherapy represented the standard of care for advanced-stage ALK+ and ALK− ALCL. Post hoc and registry studies have suggested benefit for the addition of etoposide to CHOP, particularly in ALK+ ALCL.71, 72 First-line treatment with CHP-BV (cyclophosphamide, doxorubicin, prednisolone and brentuximab vedotin) has recently been shown to significantly improve both PFS and OS compared to CHOP73 and is now considered standard of care for systemic ALCL. The role of high-dose chemotherapy [e.g. BEAM (carmustine, cytarabine, etoposide, melphalan) or similar] conditioned auto-HSCT consolidation in first complete remission (CR1) is unclear. The favourable outcomes of low-risk ALK+ ALCL (IPI < 2 and/or age <40 years) suggest auto-HSCT consolidation should not be performed in CR1. The Nordic group prospective phase II trial (NLG-T-01) included 31 patients with ALK− ALCL and showed a 5-year PFS of 61% and 5-year OS of 70%.74 In the ECHELON2 study consolidative transplant was permitted, but a censored analysis found no advantage in PFS or OS.73 The number of patients with ALCL transplanted (~20%) in these studies was too low to evaluate the role of transplantation in CR1. In a phase II trial of single agent brentuximab vedotin in 58 patients with relapsed or refractory sALCL the ORR was 86% and CR in 66% of patients with impressive long-term outcomes seen in those achieving a CR.75 Patients responding to CHP-BV as first-line therapy for sALCL who subsequently experience relapse, remain eligible for re-treatment with brentuximab vedotin monotherapy, with high response rates reported.76 Alternatively, in those who are refractory to or experience only a short response following brentuximab vedotin, multiagent non-cross-resistant chemotherapy is appropriate [further detailed under PTCL-not otherwise specified (NOS)]. The role of transplantation in nodal PTCL, including sALCL, is also reviewed under PTCL-NOS. BIA-ALCL is a rare lymphoma associated with textured breast implants. Early diagnosis is crucial as surgical resection is usually curative. It is recommended that possible BIA-ALCL cases are managed in line with recent UK BIA-ALCL guidelines.77 The 2016 WHO classification update1 recognises two provisional new entities [‘follicular T-cell lymphoma’ and ‘nodal peripheral T-cell lymphoma with a T-follicular helper (Tfh) phenotype’] with a common cell of origin78-80 and overlapping mutational signatures81, 82 with AITL. Whilst assessing Tfh markers in PTCL-NOS cases is now part of routine diagnostic evaluation, there are as yet insufficient data to guide treatment decisions specifically for these entities. Accordingly, this guideline will refer to the 2008 categories of PTCL-NOS and AITL only when discussing treatment recommendations. However, it is possible that future clinical trial eligibility and treatment decisions will be based on Tfh derivation. Prognosis is poor with 5-year failure-free survival (FFS) and OS of 20% and 30% respectively. The conventional IPI score is predictive of outcome. Several specific risk scores have been validated in PTCL-NOS and AITL that may better identify a subgroup with relatively favourable clinical outcomes.83, 84 The standard of care remains CHOP chemotherapy. A randomised phase II study comparing CHOP with GEM-P (gemcitabine, methylprednisolone and cisplatin) failed to show an improved CR rate with GEM-P.85 In AITL specifically, a first-line phase II single-arm trial of fludarabine and cyclophosphamide (FC) with thalidomide maintenance failed to demonstrate significant activity.86 Data to support the addition of etoposide to CHOP (CHOEP) are inconclusive. A retrospective German analysis reported that younger patients with a normal serum lactate dehydrogenase treated with CHOEP had a superior 3-year event-free survival (EFS), but no OS advantage was observed.71 The Nordic NLG-T-01 study of 160 patients (58% had either PTCL-NOS or AITL) treated with six courses of CHOEP-14 (CHOP-14 if aged >60 years) followed by auto-HSCT in responding patients reported a 5-year PFS of 44%, although this is an inherently selected group who also underwent auto-HSCT.74 A large retrospective study from South Korea failed to demonstrate a benefit when etoposide was added to CHOP.87 Alternative dose-intensive chemotherapy strategies have been investigated as a way of improving results of CHOP. Whilst some studies have reported encouraging outcomes in single-centre randomised88 or non-randomised studies,89 others have not demonstrated improved outcomes90 and as such dose-intensified strategies cannot be currently recommended. The ECHELON-2 (detailed in the ALCL section) trial included only small cohorts of CD30+ PTCL-NOS and AITL impeding meaningful interpretation.73 CHP-BV is currently not licensed for PTCL-NOS and AITL in Europe. A large international randomised trial comparing romidepsin-CHOP against CHOP presented in abstract form reported a failure of the experimental arm to improve PFS.91 The role of CNS prophylaxis is not well studied. In a recent study of 600 cases of PTCL, the overall incidence of CNS relapse was 1·8% in PTCL-NOS and 0·7% in AITL at 5 years.92 Involvement of more than one extra-nodal site was the only significant factor identified to be associated with increased risk, but the few events precludes definitive conclusions. In frail patients unfit for combined chemotherapy, high-dose corticosteroids may be useful to control symptomatic disease and can achieve remissions.93 Stage I and II AITL and PTCL-NOS are rare with a paucity of robust data to inform treatment decisions. Compared to limited-stage DLBCL, clinical outcomes are poor with 5-year PFS of 52% recently reported.94 The role of high-dose therapy with auto-HSCT as consolidation in first remission is controversial and there are no randomised trials reported. Several prospective studies have shown encouraging results, on an intention-to-treat basis, with long-term disease-free survival rates of 30–55%.74, 95-97 However, these studies have variable inclusion criteria, end-points and follow-up duration, making comparisons and conclusions difficult. A systematic review and meta-analysis reported a PFS rate of 33% (95% confidence interval 14–56%).98 Comparative, non-randomised, analyses and retrospective studies have also been attempted.99-101 These data are all hampered by disease/treatment heterogeneity, unbalanced treatment groups, and different statistical approaches yielding conflicting results. In summary, the contribution of auto-HSCT to survival outcomes, beyond that achieved by conventional chemotherapy, remains unclear. Allo-HSCT has theoretical advantages over auto-HSCT including a graft free of tumour cells and a donor T-cell mediated graft-versus-lymphoma effect. An international trial randomised patients to auto- versus allo-HSCT after chemotherapy induction.102 The study was hampered by 38% of participants not undergoing HSCT, largely due to disease progression. Patients proceeding to HSCT had similar 3-year EFS and OS. The auto-HSCT group had lower TRM but higher relapse rates with the converse reported for the allo-HSCT group. There are few other reports of allo-HSCT transplantation exclusively in first remission. There are no randomised studies to guide the optimal therapy for patients with relapsed PTCL-NOS or AITL. Dexa-BEAM and GDP (gemcitabine, dexamethasone, cisplatin) chemotherapy demonstrated ORRs of 69% and 64% with a median PFS of 6·4 months and 5·4 months respectively.103, 104 Bendamustine monotherapy achieved an ORR of 50% with a median PFS of 3·6 months.105 Thus, no clear recommendation for a specific chemotherapy regimen can be made; decisions should be made on individual patient- and treating centre-related factors. Various non-chemotherapy options have been studied, usually in patients with multiply relapsed disease. Three single-agent therapies currently are approved in the United States (romidepsin, belinostat and pralatrexate) but modest response rates, PFS benefit and lack of comparative trial data have precluded these drugs receiving European or UK approval.106-108 In AITL specifically, low-quality data have suggested activity of ciclosporin, thalidomide, lenalidomide and azacitidine.109-112 The lack of prospective trials or even formal retrospective studies at present prevents recommendation of these agents until prospective data are available. The outcomes of patients with relapsed PTCL are very poor with a median PFS and OS of only 3·1 months and 5·5 months respectively in patients with PTCL-NOS/AITL relapsing after initial therapy.113 For younger patients with no or few co-morbidities, HSCT is usually considered as consolidation when in second remission. The evidence supporting auto-HSCT in this setting is weak, largely comprising retrospective series.114-117 Allo-HSCT has been more extensively reported in the relapse setting but most studies are retrospective and include patients with a variety of histologies.118-121 One of the largest studies described allo-HSCT, largely performed beyond first remission, conferring 3-year PFS and OS rates of 36% and 47% respectively. An international registry study focussed on the outcome of allo-HSCT for relapsed AITL specifically.122 Only 45 patients were included, but the 3-year PFS and OS rates were 53% and 64% respectively. Outcomes appeared better with chemosensitive disease prior to transplantation. To conclude, allo-HSCT is a valid option for suitable patients with chemosensitive-relapsed PTCL-NOS and AITL. This is an aggressive, largely extra-nodal lymphoma, usually of NK-cell type (CD2+, CD56+, CD3ε+), with recognised cytotoxic CD8+ T-cell variants. These very rare tumours are commoner in East Asia and South America, where they may represent up to 28% of all PTCLs. They present at median age of 50–60 years and have a male preponderance. Epstein−Barr virus (EBV) is implicated in all cases regardless of ethnicity. The condition almost invariably presents in extra-nodal sites, classically in the nasal structures with or without disease elsewhere. Extra-nasal disease in the absence of overt primary nasal involvement is recognised. Accurate staging is critical, given the therapeutic implications. Magnetic resonance imaging (MRI) is valuable in establishing extent and informing radiotherapy field for localised disease. PET-CT scanning is useful in detecting occult extra-nodal disease sites. Nasal endoscopy with biopsies may demonstrate clinically inapparent nasal involvement. EBV should be routinely demonstrated in the biopsy material. Latent membrane protein 1 (LMP1) immunostaining lacks sensitivity for EBV detection whereas EBV-encoded small RNAs in situ hybridisation (EBER-ISH) is highly sensitive and the established ‘gold standard’. Peripheral blood EBV DNA should be quantitated and has value as a response biomarker.123 CNS involvement is relatively uncommon (5–10%) and insufficient data are available to support routine examination of the CNS or prophylactic therapy. An ENKTL-specific CNS risk model has recently been proposed.124 The major determinant of long-term clinical outcome is the presence of extra-nasal involvement. A recent analysis reported a median PFS of 72 versus 10 months and 5-year OS of 56% versus 34% for nasal and extra-nasal cases respectively.125 A novel prognostic index (PINK) delineated three patient groups with 3-year OS of 81%, 62%, and 25% respectively.123 Inherent chemoresistance is common, with poor efficacy of CHOP/CHOP-like schedules.126, 127 Involved field radiotherapy (IFRT) typically given at doses of ≥50 Gy is a central component of first-line therapy.128 Combined chemoradiation protocols, comprising non-anthracycline platinum-based chemotherapy, with/without asparaginase, are an effective strategy. Radiation is typically delivered concurrently with, ‘sandwiched’ between cycles, or immediately after chemotherapy. A prospective phase II trial of 66 patients using a ‘sandwich protocol’ comprising two cycles of LVDP (L-asparaginase, etoposide, cisplatin, dexamethasone), 56 Gy radiotherapy, followed by a further two to four cycles of chemotherapy reported a 3-year OS of 70%.129 GELOX (gemcitabine, oxaliplatin, L-asparaginase) followed by radiotherapy resulted in a 5-year survival of 86%.130 A concurrent chemoradiotherapy approach using the DeVIC regimen (carboplatin, etoposide, ifosfamide, dexamethasone) achieved a 5-year OS of 61%.131, 132 The optimal timing of radiotherapy remains unclear but early delivery in the first weeks after initial chemotherapy appears key for localised ENKTL.133 Anthracycline-based chemotherapy is considered inadequate for the treatment of ENKTL.125 A recent prospective trial of the SMILE regimen (dexamethasone, methot