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T-cell lymphomas
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NK/T-cell lymphomas Eric Tse, Yok-Lam Kwong∗ Department of Medicine, Queen Mary Hospital, Hong Kong, China
A R T IC LE I N F O
ABS TRA CT
Keywords: NK/T-cell lymphoma Nasal Non-nasal EBV PET/CT Asparaginase Immunotherapy PD1
NK/T-cell lymphomas are extranodal EBV-related malignancies, mostly of NK-cell and occasionally of T-cell lineage. They are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other sites. Disseminated NK/T-cell lymphoma involves multiple organs, and may present with a leukemic phase. Initial evaluation requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. Radiotherapy alone is inadequate with frequent relapses. Anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. For stage III/IV disease, asparaginase-containing regimens are needed. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases. Immunotherapy with antibodies against CD30, programmed cell death protein 1 and CD38 is promising.
Introduction Natural killer (NK) cells are part of the innate immune system [1]. From a common lymphoid progenitor, sequential expressions of transcription regulators NFIL3 and TOX, and then EOMES, TBX21 and ID2, result in the development of NK-cells [1]. NK-cells are strategically distributed at barrier surfaces. They proliferate in response to pathogens, destroying them by secretion of cytotoxic molecules (perforin and granzyme) and cytokines [1]. NK-cells have been demonstrated recently to show antigen-specific and antigen-independent clonal expansion, longevity and recall responses, which are similar to immune memory characteristic of the adaptive immunity [2]. These biologic properties, and residence of NK-cells in extranodal sites including the nasal/oropharyngeal surfaces and skin, are recapitulated by localization of NK-cell malignances to these areas [3]. A clonal receptor gene rearrangement as observed in T-cells and B-cells is not present. Immunophenotypically, NK-cells express CD2, cytoplasmic CD3 epsilon (ε) (but not surface CD3), CD16, CD56, CD94, and cytotoxic molecules (perforin, granzyme, T-cell intracellular antigen 1, TIA-1) [4]. Malignancies of putative NK-cell derivation Lethal midline granuloma referred to rare destructive midline facial lesions that would progress inexorably to death. Although this entity encompassed different diseases, one lesion was shown by modern pathological techniques to be a lymphoid neoplasm [5]. The neoplasm is infiltrated by a polymorphic population of abnormal lymphoid cells, inflammatory cells, and eosinophils, leading to
∗
Corresponding author. Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail address: [email protected] (Y.-L. Kwong).
https://doi.org/10.1016/j.beha.2019.06.005 Received 29 April 2019; Accepted 11 June 2019 1521-6926/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Eric Tse and Yok-Lam Kwong, Best Practice & Research Clinical Haematology, https://doi.org/10.1016/j.beha.2019.06.005
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Fig. 1. Different clinical subtypes of NK/T-cell lymphomas. A. Nasal NK/T-cell lymphoma on presentation, showing involvement of hard platelet and swelling of upper lip. B. Same patient after two cycles of chemotherapy, showing perforation of the central hard palate. Note that on presentation, because of angiodestruction caused by the lymphoma, part of the hard palate had infarcted, so that despite successful treatment, central palatal perforation still ensued. Such a lesion would be described as lethal midline granuloma in the past. C. Typical appearance of cutaneous NK/Tcell lymphoma. D. Aggressive NK-cell leukemia, showing circulating neoplastic cells (arrows) possessing abundant cytoplasm with azurophilic granules.
the morphologic description of polymorphic reticulosis. With the advent of immunohistochemistry, the neoplastic lymphoid cells were initially considered to be of T-cell origin, owing to the detection of the T-cell antigen CD3 with polyclonal anti-CD3 antibodies. Additionally, neoplastic cells often invaded and destroyed blood vessels. Due to these features, the lymphoma was classified as an angiocentric T-cell lymphoma in the REAL classification [6]. However, when monoclonal antibodies became available, angiocentric T-cell lymphomas were found to be negative for surface CD3. Thus, neoplastic cells showed typical feature of NK-cells, viz., surface CD3-negative and cytoplasmic CD3ε-positive. Molecular analysis of the T-cell receptor (TCR) gene showed a germline configuration in the majority of cases [4]. Hence, these lymphomas are of putative NK-cell derivation. Interestingly, occasional cases appear to be of bona fide T-cell derivation, with clonal TCR gene rearrangement [7]. However, different cellular derivations have no apparent influence on clinical features and treatment outcome. In the latest World Health Organization (WHO) classification, these lymphomas are referred to as extranodal NK/T-cell lymphoma, to reflect their putative cellular origins from NK-cells and T-cells [8]. Pathology of NK/T-cell lymphomas NK/T-cell lymphomas are found almost exclusively in extranodal sites. Most cases occur in the nose, nasopharynx, oropharynx, the Waldeyer's ring, and the upper airways and gastrointestinal tract (Fig. 1 A and B). They are clinically referred to as nasal NK/Tcell lymphomas [9]. Occasional cases are found in non-nasal sites, including the skin (Fig. 1C), gastrointestinal tract, testis and salivary glands, and are referred to as non-nasal NK/T-cell lymphomas. Exceptionally, the lymphoma may be disseminated, involving the skin, lymph node, liver, spleen, bone marrow and the peripheral blood (Fig. 1D). Such rare cases are referred to as aggressive NKcell leukemia/lymphoma [9]. Pathologically, lymphoma cells often show angiocentricity and angiodestruction, resulting in zonal necrosis. They are CD2+, surface CD3–, cytoplasmic CD3ε+, CD56+, and cytotoxic molecules (perforin, granzyme, TIA1)+. Cytologically, lymphoma cells resemble large granular lymphocytes. There is an almost invariable infection of lymphoma cells by Epstein Barr virus (EBV), existing in a clonal episomal form not integrated into the host genome [4]. The current WHO classification stipulates demonstration of EBV infection as a pre-requisite for the diagnosis of NK/T-cell lymphoma [8]. In routine practice, EBV is usually detected by in situ hybridization for EBV early RNA (EBER). The presence of EBV is required, but not adequate, for the diagnosis. Either CD56 or cytotoxic molecules should be present. When both are negative, the diagnosis becomes EBV-positive peripheral T-cell lymphoma 2
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(PTCL), not otherwise specified [8]. More recently, very rare cases of aggressive leukemia/lymphoma derived putatively from NK-cells but were EBV-negative had been described [10]. Owing to their extreme rarity, it still remains uncertain if they should be considered together with NK/T-cell lymphoma diagnostically and therapeutically.
Molecular pathology of NK/T-cell lymphomas Conventional karyotyping had shown deletion of chromosome 6q (6q–) to be a recurrent cytogenetic aberration in NK/T-cell lymphoma [11]. Results of comparative genomic hybridization [12] and loss of heterozygosity analyses [13] also demonstrated 6q– to be common. This segment of chromosome 6q might contain putative tumor suppressor genes important in the pathogenesis of NK/ T-cell lymphomas, including HACE1 [14], PRMD1 [15], FOXO3 [16] and PTPRK [17]. Activation of putative oncogenes, including EZH2 [18] and RUNX3 [19], might also be involved. Gene expression profiling (GEP) had revealed that NK/T-cell lymphoma and PTCL of gamma/delta subtype to be similar, consistent with their developmental relationship. GEP had also uncovered other oncogenic mechanisms, including JAK/STAT activation, and over-expression of NK-κB and aurora kinase A [20,21]. Next generation sequencing (NGS) has provided a mutational landscape for NK/T-cell lymphomas. Exome sequencing showed activating JAK3 mutations in about 35% of cases [22], but this observation could not be confirmed by later studies. Instead, activating STAT3 and STAT5B mutations were found in a significant number of cases [23,24]. Later NGS studies identified mutations of the RNA helicase gene DDX3X in about 20% of cases [25]. Other mutated genes included the tumor suppressor gene TP53, found in about 13% of cases [26]; and genes involved in epigenetic pathways, including MLL, ASXL1, ARID1A, and EP300, in 4–18% of cases [26]. The geographic predilection of NK/T-cell lymphoma for Asian and South American populations is not fully explained. A genomewide association study identified four amino acid residues Gly84-Gly85-Pro86-Met87 at the edge of the peptide-binding groove of HLA-DPB1 to be associated with susceptibility to NK/T-cell lymphoma [27]. So far, this association has not been validated in other studies.
Clinical features of NK/T-cell lymphoma Nasal NK/T-cell lymphomas affect mainly the nose and nasal cavity, but the orbit, salivary glands, and paranasal sinuses may be involved. In non-nasal NK/T-cell lymphoma, commonly involved primary sites include the skin [28], gastrointestinal tract [29,30], and testis. It should be noted that when NK/T-cell lymphomas appear to present in non-nasal sites, F18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) ought to be performed [31,32] to define if an occult nasal primary exists. If nasal involvement is documented, these “non-nasal” cases should be regarded as disseminated nasal lymphomas [33]. Aggressive NK-cell leukemia/lymphoma is the rarest form of NK/T-cell malignancy, currently categorized by the WHO classification as aggressive NK-cell leukemia [34]. Patients present with fever, rashes, lymphadenopathy, hepatosplenomegaly, pancytopenia, hyperferritinemia, deranged clotting and liver dysfunction. Active hemophagocytosis is found in the marrow and other reticuloendothelial organs [35]. Few if any patients survive despite intensive chemotherapy or even hematopoietic stem cell transplantation (HSCT).
Circulating EBV DNA as a surrogate biomarker of lymphoma load When NK/T-cell lymphoma cells undergo apoptosis, EBV DNA fragments are released into the blood [36]. Quantification of circulating EBV DNA is an accurate biomarker of lymphoma load [37–39]. Whole blood is not suitable as the starting material, mainly due to the variable presence of circulating memory B-cells that are often infected by EBV, which introduces unpredictable errors. Plasma as a starting material has recently been demonstrated to be superior to whole blood in a study of EBV-related lymphoid malignancies other than NK/T-cell lymphoma [39]. Plasma EBV DNA at diagnosis gives a measurement of the lymphoma load [37]. It provides a real-time assessment of response to treatment [38]. At the end of treatment, detectable EBV DNA reflects residual disease, which portends an unfavorable prognosis [40].
Differential diagnoses of NK/T-cell lymphomas Plasmacytoid dendritic cell neoplasms, formerly mistaken as blastoid NK-cell lymphomas, are localized mainly to the skin but may also involve the bone marrow [41]. It can be differentiated from cutaneous NK/T-cell lymphomas by the absence of CD3, cytotoxic molecules, and EBV infection. NK-cell lymphomatoid gastropathy is a non-neoplastic proliferation of NK-cells [42]. It occurs mainly in the stomach, but may involve the small and large bowels (NK-cell enteropathy) [43]. EBV is absent in lymphomatoid gastropathy/NK-cell enteropathy. Lesions are self-regressing, but occasional cases may relapse. Metastasis does not occur. Chronic lymphoproliferative disorder of NK-cells is a rare condition, currently unclear if reactive or neoplastic. There is no EBV infection. It is indolent and non-progressive [44]. Patients are asymptomatic, and no treatment is required. 3
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Clinical features and evaluation of newly diagnosed NK/T-cell lymphoma patients In addition to routine blood counts and serum biochemistry, trephine biopsy is needed. Morphologic examination should be supplemented with in situ hybridization for EBV encoded early RNA (EBER). The presence of EBER + atypical cells indicates marrow infiltration [4]. Plasma EBV DNA gives information on the presentation tumor load, and provides a biomarker for serial monitoring of treatment efficacy. PET/CT is now regarded as the standard imaging modality for NK/T-cell lymphoma [31,32]. It should be performed for newly diagnosed patients, not only for accurate staging, but also as a baseline with which interim and end-of-treatment scans can be compared, because these comparisons are prognostically important [38,40]. Principles of treatment of NK/T-cell lymphomas Conventional anthracycline-containing (CHOP, cyclophosphamide, adriamycin, vincristine, prednisolone, or CHOP-like) regimens developed for other aggressive lymphomas are ineffective and should not be used for NK/T-cell lymphomas [9], due to expression of the multidrug resistance (MDR) P-glycoprotein on NK lymphoma cells [9]. Instead, an array of more effective nonanthracycline-containing regimens has now been devised for treating NK/T-cell lymphomas [9]. An important advance in the treatment of NK/T-cell lymphoma is the use of asparaginase [9]. Neoplastic NK cells developed rapid apoptosis when treated with L-asparaginase ex vivo [45]. Clinically, L-asparaginase showed significant single-agent activity in relapsed/refractory NK/T-cell lymphoma [9]. Currently, asparaginase or its pegylated form is regarded as an indispensable component of effective regimens in NK/T-cell lymphomas. Risk stratification is a crucial. Prognostic models developed in the era of CHOP or CHOP-like regimens, including the international prognostic index [46] and the Korean prognostic index [47], had become outdated. Two prognostic indices, prognostic index for NK/ T-cell lymphoma (PINK) and PINK with EBV DNA (PINK-E), have been developed for patients treated with non-anthracyclinecontaining regimens [48]. However, PINK only takes into account clinical factors (age > 60 years, stage III/IV disease, distant lymphnode involvement, and non-nasal type disease). It has been shown that at least two other parameters, plasma EBV DNA [38] and PET/ CT scan features [49], are of prognostic importance. PINK-E takes into account presentation EBV DNA (whether detectable), and so has incorporated parameters more advanced than simply clinical ones. It remains to be defined if PET/CT, both interim [38] and endof-treatment [40], can also be incorporated into prognostic scoring systems. Stage I/II diseases have favorable outcomes. However, stage III/IV diseases fare much worse, and require additional efforts to result in durable remission. Hence, an accurate initial staging is of paramount importance. Stage I/II patients should not be treated excessively. On the other hand, stage III/IV patients should receive treatment in addition to chemotherapy so as to improve outcome. Treatment for stage I/II NK/T-cell lymphoma Radiotherapy, chemotherapy and their combination have been used in the treatment for early-stage NK/T-cell lymphoma [9]. Currently, the most widely accepted approach is combined radiotherapy and chemotherapy, which can be given concurrently (chemoradiotherapy) or sequentially. Radiotherapy NK/T-cell lymphoma cells are radiosensitive. However, radiotherapy alone is inadequate, because of unacceptably high risks of systemic relapse [9]. In a retrospective analysis, it was shown that the risk of locoregional relapse increased when the dosage was < 50–52 Gy [50]. The importance of radiation dosage was shown in another study, where in the context of combined chemotherapy and radiotherapy, the 5-year OS was 62% for a dose of > 50 Gy, and 53% for a dose of < 50 Gy [51]. Radiotherapy added to non-anthracycline-containing chemotherapy also led to superior overall survival (OS) and disease-free survival (DFS) [52]. Concurrent chemoradiotherapy Two early trials examined the efficacy of platinum-containing regimens with concurrent radiotherapy for early-stage NK/T-cell lymphoma. In a phase 1/2 multi-center study, concurrent radiotherapy (50Gy) and three cycles of DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin) were evaluated in 33 patients [53]. The complete response rate (CR) and overall response rate (ORR) were 75% and 78%. With a median follow-up of 68 months, the 5-year OS and progression-free survival (PFS) were 73% and 67%. In another phase 2 trial of 30 patients, concurrent radiotherapy (40Gy) and cisplatin (30 mg/m2 weekly) were given, followed by three cycles of VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) as consolidation [54]. The CR and ORR were 80% and 83.3%. The 3-year OS and PFS were 86% and 85%. The addition of L-asparaginase to this strategy was tested in a continuation study, where 30 patients were treated with concurrent radiotherapy (40Gy) and cisplatin (30 mg/m2 weekly), and then 2 cycles of L-asparaginasecontaining chemotherapy VIDL (etoposide, ifosfamide, dexamethasone and L-asparaginase) as consolidation. The CR and ORR were 87% and 90%. With a median follow-up of 44 months, the 5-year OS and PFS were 73% and 60% [55]. Hence, addition of Lasparaginase did not improve the outcome of concurrent chemoradiotherapy. Used outside trials, concurrent chemoradiotherapy appeared to give similar results. In a retrospective analysis of 150 patients, concurrent RT and DeVIC led to CR and ORR of 82% and 89% [56]. With a median follow-up of 5.6 years, the 5-year OS and PFS were 4
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72% and 61%.
Sequential chemotherapy and radiotherapy In most institutes, radiotherapy is not immediately available, and concurrent chemoradiotherapy is difficult to arrange. Chemotherapy followed by radiotherapy is logistically simpler. The use of SMILE (dexamethasone, methotrexate, ifosfamide, Lasparaginase and etoposide), currently the most-employed regimen worldwide, with sandwiched radiotherapy was examined in 29 patients [57]. After 2–3 cycles of SMILE, the CR and ORR were 69% and 86%. After the completion of radiotherapy (50Gy) and 3–4 subsequent cycles of SMILE, CR and ORR were 69% and 90%. Furthermore, the remission was durable with 90% of patients remained in CR during follow-up. The use of other asparaginase-containing regimens including LVP (L-asparaginase, vincristine, prednisolone) [58,59], GELOX (gemcitabine, L-asparaginase, oxaloplatin) [60,61], P-GEMOX (pegaspargase, gemcitabine, oxaliplatin) [62], DICE-L-asp (dexamethasone, ifosfamide, cisplatin, etoposide, L-asparaginase) [63] and MESA (methotrexate, etoposide, dexamethasone, and pegaspargase) [64] followed by radiotherapy also gave comparable results, with CR and ORR at 74–91% and 92–100%. The 5-year OS and PFS were 64–89% and 64–83%. In the largest retrospective study to date, 303 patients treated with various combinations of non-anthracycline-containing chemotherapy and radiotherapy were analyzed. On multivariate analysis, patients treated with concurrent chemoradiotherapy with or without subsequent consolidation chemotherapy had CR, PFS and OS comparable with those of patients treated with sequential chemotherapy and radiotherapy [65]. These results show that when effective chemotherapeutic regimens are used, concurrent chemoradiotherapy and sequential chemotherapy and radiotherapy are equally efficacious. Sequential chemotherapy and radiotherapy have numerous advantages, including immediate availability, logistic ease and better tolerability of chemotherapy and radiotherapy when used singly. Therefore, for stage I/II NK/T-cell lymphoma, sequential chemotherapy and radiotherapy is presently the choice in most centers in the world [66].
Treatment for stage III/IV and relapsed/refractory NK/T-cell lymphoma Stage III/IV diseases have a poor prognosis. With anthracycline-based chemotherapy, there are few if any long-term survivors [9], so that these regimens should no longer be used. L-asparaginase-containing regimens are currently the treatment of choice [9]. In a phase 2 study, 20 newly-diagnosed stage IV patients were treated with SMILE [67]. CR and ORR were 40% and 80%. Grade 3/4 neutropenia occurred in all patients, which in the early part of the study resulted in sepsis-related mortality in 10% of patients. Once routine granulocyte colony stimulating factor was administered, septic deaths did not occur. With a median follow-up of 24 months, the 1-year OS and PFS were both 45%. In another retrospective analysis of 26 patients with newly diagnosed stage IV NK/Tcell lymphoma treated with SMILE, 14 (53.8%) patients achieved CR. The 5-year OS was 47% and the 4-year disease-free survival (DFS) was 60% [57]. For NK/T-cell lymphomas that have relapsed from or are refractory to radiotherapy and/or anthracycline-based chemotherapy, salvage therapy with L-asparaginase-containing regimens has been shown to be highly efficacious. In a retrospectively study of SMILE for relapsed/refractory patients (N = 44, of which 23 had stage III/IV disease), CR and ORR were 66% and 77% [57]. With a median follow-up of 31 months, the 5-year OS was 52% and the 4-year DFS was 68%. Another L-asparaginase-containing regimen, AspaMetDex (L-asparaginase, methotrexate, and dexamethasone) was also studied in the treatment of 19 patients (advanced-stage, N = 7) [68]. After 3 cycles of chemotherapy, CR and ORR were 61% and 78%. With a median follow up of 26 months, the estimated 2-year OS and PFS were both around 40%. The use of pegylated asparaginase in NK/T-cell lymphoma has been investigated. In a retrospective study, 13 patients with relapsed/refractory advanced-stage disease were treated with MEDA (methotrexate, etoposide, dexamethasone and pegylated asparaginase) [69]. After 6 cycles of chemotherapy, the CR and ORR were 62% and 77%. With a median follow up of 20 months, the 1year OS and PFS were 69% and 62%. P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) was examined in a study that included 21 patients with relapsed/refractory disease (advanced-stage, N = 9) [70]. The CR and ORR were 52% and 81%. With a median follow-up of 17 months, the 3-year OS and PFS were 58% and 24%. DDGP (dexamethasone, gemcitabine, cisplatin and pegaspargase) was examined in 22 patients with advanced-stage NK/T-cell lymphoma [71]. The CR and ORR were 71% and 95%. With a median follow up of 14 months, the 1-year OS and PFS were 90% and 86%.
Asparaginase-refractory NK/T-cell lymphoma The outcome for NK/T-cell lymphoma relapsing from or refractory to asparaginase-containing regimens is dismal. In a retrospective study, 20 patients with relapsed/refractory NK/T-cell lymphoma were treated with gemcitabine or its combination with other agents (such as dexamethasone and cisplatin) [72]. Fourteen patients were refractory to L-asparaginase-based chemotherapy (SMILE, N = 11). After gemcitabine-based therapy, CR and ORR were 20% and 40%. The median OS and PFS were 5 months and 2 months. Conventional chemotherapies are therefore largely ineffective in patients failing asparaginase-based treatment. 5
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Immunotherapy in NK/T-cell lymphoma The programmed cell death protein 1 ligand (PDL1) is highly expressed on NK/T-cell lymphoma cells [73,74]. Binding of PDL1 to the inhibitory receptor PD1 on effector T-cells suppresses anti-tumor immunity. Blocking of PD1/PDL1 ligation with anti-PD1 antibody restores effector T-cell targeting of NK/T-cell lymphoma cells. In a preliminary study, the humanized monoclonal anti-PD1 antibody pembrolizumab was used to treat 7 patients with refractory NK/T-cell lymphoma failing L-asparaginase-containing regimens (N = 7) and allogeneic HSCT (N = 2) [75]. After a median of 7 cycles of pembrolizumab, the ORR was 100%. Five patients achieved CR that was sustained after a median follow up of 6 (2–10) months. There were no treatment-related adverse events. In another study of 7 patients with relapsed/refractory NK/T-cell lymphoma treated with pembrolizumab, the ORR was 57% with 2 patients achieving CR after a median of 4 cycles of treatment [76]. One patient has remained in CR with 18 cycles of pembrolizumab, indicating a durable response. There was also a suggestion that the level of PDL1 expression correlated with treatment response. Similarly, the efficacy of another anti-PD1 antibody nivolumab has been demonstrated in a case series of 3 patients with advancedstage relapsed NK/T-cell lymphoma [77]. The ORR was 100% with 1 patient in continuous CR with 9 cycles of treatment. Based on these promising results, the use of pembrolizumab is recommended for the treatment of relapsed/refractory NK/T-cell lymphoma by the National Comprehensive Cancer Network [78]. Prospective studies investigating the role of PD1 immune-checkpoint blockade therapy in NK/T-cell lymphoma are on-going. In addition to anti-PD1 antibody, monoclonal antibodies targeting other antigens expressed on NK/T-cell lymphoma cells have been tested. The efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has been demonstrated in two reported cases of refractory NK/T-cell lymphoma [79,80]. CD38 is expressed on normal NK cells, and 50% of NK/T-cell lymphoma had strong CD38 expression [81]. The efficacy of daratumumab in NK/T-cell lymphoma has been reported in 2 patients with relapsed/refractory disease, with one achieving CR and another achieving partial response [82,83]. Autologous HSCT The benefit of autologous HSCT for NK/T-cell lymphoma at first CR was examined retrospectively in 62 patients [84]. Half of the patients had stage III/IV disease. With a median follow-up of 43 months, the 3-year OS and PFS for early-stage diseases were 68% and 65%, and those of advance-stage diseases were 52% and 40%. These results were not different from non-HSCT patients treated with asparaginase-containing regimens, so that autologous HSCT for NK/T-cell lymphoma at first CR is not warranted. For relapsed NK/Tcell lymphoma after asparginase-based chemotherapy, there are not enough data to support the use of autologous HSCT as salvage. Allogeneic HSCT A retrospective analysis of 82 patients with NK/T-cell lymphoma (early-stage N = 35; advanced-stage N = 22; unknown N = 25) undergoing allogeneic HSCT between 2000 and 2014 was recently reported [85]. Myeloablative HSCT was performed in 38% of patients. With a median follow-up of 36 months, the 3-year OS and PFS of the whole cohort were 34% and 28%. The non-relapse mortality was 30%. The outcomes of allogeneic HSCT in patients previously treated with L-asparaginase containing regimen appeared to be superior. In a retrospective analysis of 18 patients undergoing allogeneic HSCT, SMILE was used as the initial treatment in 14 patients [86]. Thirteen patients had advanced-stage disease at presentation, and 16 patients were at CR prior to HSCT (CR1, N = 9, CR2, N = 7). Myeloablative conditioning was used in 14 patients. With a median follow-up of 21 months, the estimated 5-year PFS and OS were 51% and 57%. The use of SMILE and achieving CR prior to HSCT were associated with a better outcome. The survival of patients transplanted at CR1 and CR2 did not differ, suggesting that allogeneic HSCT for patients in first CR may not be justified. Conclusion and future perspectives With the use of L-asparaginase-containing regimens, stage I/II NK/T-cell lymphoma has become potentially curable in the majority of patients. Treatment of stage III/IV and relapsed/refractory disease remains challenging. The advent of immunotherapy holds much promise. Future research will center on how immunotherapy can be incorporated into conventional strategies to improve outcome. Summary NK/T-cell lymphomas are rare EBV-related malignancies with a predilection for Asian and South American populations. The majority is of NK-cell lineage, and a minority of T-cell lineage. They are predominantly extranodal lymphomas. Clinically, three subtypes can be distinguished: nasal, non-nasal, and disseminated. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract, usually presenting as stage I/II disease. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other soft tissue, often presenting as stage III/IV disease. Disseminated NK/T-cell lymphoma involves multiple organs, may present with a leukemic phase, and is rapidly fatal. Initial evaluation of NK/T-cell lymphoma requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. NK/T-cell lymphomas are radiosensitive, but radiotherapy alone is inadequate with unacceptable relapse rates. Conventional anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently considered the standard of care. For stage I/II disease, 6
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combined chemotherapy and radiotherapy results in very high response rates and cure in a significant proportion of patients. For stage III/IV disease, asparaginase-containing regimens are needed. Interim and end-of-treatment PET/CT scan and circulating EBV DNA are prognostic and useful in the evaluation for additional therapy. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases if a remission can be achieved. Immunotherapy, including the use of antibodies against CD30, programmed cell death protein 1 and CD38, holds promises and should be considered for relapsed/refractory disease. Conflicts of interest The authors have no conflicts of interests to declare. Practice points
• The diagnosis of NK/T-cell lymphoma requires demonstration of Epstein Barr virus (EBV) infection in the lymphoma cells, and either positive CD56 or cytotoxic molecules • Positron emission tomography computed tomography is the standard imaging modality for staging • Plasma EBV DNA should be quantified for assessment of lymphoma load, and monitoring of efficacy of treatment and residual disease • Conventional anthracycline-containing regimens are ineffective and should not be used in NK/T-cell lymphomas • Non-anthracycline-containing regimens incorporating asparaginse are now the standard of care • Combined chemotherapy and radiotherapy, whether concurrent or sequential, is needed for stage I/II NK/T-cell lymphoma • Radiotherapy as the sole treatment modality is inadequate and should not be used • Stage III/IV NK/T-cell lymphomas require systemic chemotherapy, and consideration of allogeneic hematopoietic stem cell transplantation (HSCT) in selected patients • Autologous HSCT is of limited clinical utility • Immunotherapy, including the use of antibodies against CD30, programmed cell death protein 1 and CD38, shows promise in treatment of relapsed/refractory NK/T-cell lymphomas
Research agenda
• Efforts should be made to combine biologic and molecular parameters with clinicopathologic characteristics for the prognostication of NK/T-cell lymphomas • Prospective studies are required to determine if radiotherapy may be omitted in good-risk patients treated with effective asparaginase-containing regimens • Molecular targeting based on genomic alterations in NK/T-cell lymphomas should be explored • The role of immunotherapy in the front-line treatment, as well as in the maintenance of remission, should be defined in high-risk patients
Acknowledgements The authors have no acknowledgements to make. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
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Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/issn/15216926
NK/T-cell lymphomas Eric Tse, Yok-Lam Kwong∗ Department of Medicine, Queen Mary Hospital, Hong Kong, China
A R T IC LE I N F O
ABS TRA CT
Keywords: NK/T-cell lymphoma Nasal Non-nasal EBV PET/CT Asparaginase Immunotherapy PD1
NK/T-cell lymphomas are extranodal EBV-related malignancies, mostly of NK-cell and occasionally of T-cell lineage. They are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other sites. Disseminated NK/T-cell lymphoma involves multiple organs, and may present with a leukemic phase. Initial evaluation requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. Radiotherapy alone is inadequate with frequent relapses. Anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. For stage III/IV disease, asparaginase-containing regimens are needed. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases. Immunotherapy with antibodies against CD30, programmed cell death protein 1 and CD38 is promising.
Introduction Natural killer (NK) cells are part of the innate immune system [1]. From a common lymphoid progenitor, sequential expressions of transcription regulators NFIL3 and TOX, and then EOMES, TBX21 and ID2, result in the development of NK-cells [1]. NK-cells are strategically distributed at barrier surfaces. They proliferate in response to pathogens, destroying them by secretion of cytotoxic molecules (perforin and granzyme) and cytokines [1]. NK-cells have been demonstrated recently to show antigen-specific and antigen-independent clonal expansion, longevity and recall responses, which are similar to immune memory characteristic of the adaptive immunity [2]. These biologic properties, and residence of NK-cells in extranodal sites including the nasal/oropharyngeal surfaces and skin, are recapitulated by localization of NK-cell malignances to these areas [3]. A clonal receptor gene rearrangement as observed in T-cells and B-cells is not present. Immunophenotypically, NK-cells express CD2, cytoplasmic CD3 epsilon (ε) (but not surface CD3), CD16, CD56, CD94, and cytotoxic molecules (perforin, granzyme, T-cell intracellular antigen 1, TIA-1) [4]. Malignancies of putative NK-cell derivation Lethal midline granuloma referred to rare destructive midline facial lesions that would progress inexorably to death. Although this entity encompassed different diseases, one lesion was shown by modern pathological techniques to be a lymphoid neoplasm [5]. The neoplasm is infiltrated by a polymorphic population of abnormal lymphoid cells, inflammatory cells, and eosinophils, leading to
∗
Corresponding author. Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail address: [email protected] (Y.-L. Kwong).
https://doi.org/10.1016/j.beha.2019.06.005 Received 29 April 2019; Accepted 11 June 2019 1521-6926/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Eric Tse and Yok-Lam Kwong, Best Practice & Research Clinical Haematology, https://doi.org/10.1016/j.beha.2019.06.005
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Fig. 1. Different clinical subtypes of NK/T-cell lymphomas. A. Nasal NK/T-cell lymphoma on presentation, showing involvement of hard platelet and swelling of upper lip. B. Same patient after two cycles of chemotherapy, showing perforation of the central hard palate. Note that on presentation, because of angiodestruction caused by the lymphoma, part of the hard palate had infarcted, so that despite successful treatment, central palatal perforation still ensued. Such a lesion would be described as lethal midline granuloma in the past. C. Typical appearance of cutaneous NK/Tcell lymphoma. D. Aggressive NK-cell leukemia, showing circulating neoplastic cells (arrows) possessing abundant cytoplasm with azurophilic granules.
the morphologic description of polymorphic reticulosis. With the advent of immunohistochemistry, the neoplastic lymphoid cells were initially considered to be of T-cell origin, owing to the detection of the T-cell antigen CD3 with polyclonal anti-CD3 antibodies. Additionally, neoplastic cells often invaded and destroyed blood vessels. Due to these features, the lymphoma was classified as an angiocentric T-cell lymphoma in the REAL classification [6]. However, when monoclonal antibodies became available, angiocentric T-cell lymphomas were found to be negative for surface CD3. Thus, neoplastic cells showed typical feature of NK-cells, viz., surface CD3-negative and cytoplasmic CD3ε-positive. Molecular analysis of the T-cell receptor (TCR) gene showed a germline configuration in the majority of cases [4]. Hence, these lymphomas are of putative NK-cell derivation. Interestingly, occasional cases appear to be of bona fide T-cell derivation, with clonal TCR gene rearrangement [7]. However, different cellular derivations have no apparent influence on clinical features and treatment outcome. In the latest World Health Organization (WHO) classification, these lymphomas are referred to as extranodal NK/T-cell lymphoma, to reflect their putative cellular origins from NK-cells and T-cells [8]. Pathology of NK/T-cell lymphomas NK/T-cell lymphomas are found almost exclusively in extranodal sites. Most cases occur in the nose, nasopharynx, oropharynx, the Waldeyer's ring, and the upper airways and gastrointestinal tract (Fig. 1 A and B). They are clinically referred to as nasal NK/Tcell lymphomas [9]. Occasional cases are found in non-nasal sites, including the skin (Fig. 1C), gastrointestinal tract, testis and salivary glands, and are referred to as non-nasal NK/T-cell lymphomas. Exceptionally, the lymphoma may be disseminated, involving the skin, lymph node, liver, spleen, bone marrow and the peripheral blood (Fig. 1D). Such rare cases are referred to as aggressive NKcell leukemia/lymphoma [9]. Pathologically, lymphoma cells often show angiocentricity and angiodestruction, resulting in zonal necrosis. They are CD2+, surface CD3–, cytoplasmic CD3ε+, CD56+, and cytotoxic molecules (perforin, granzyme, TIA1)+. Cytologically, lymphoma cells resemble large granular lymphocytes. There is an almost invariable infection of lymphoma cells by Epstein Barr virus (EBV), existing in a clonal episomal form not integrated into the host genome [4]. The current WHO classification stipulates demonstration of EBV infection as a pre-requisite for the diagnosis of NK/T-cell lymphoma [8]. In routine practice, EBV is usually detected by in situ hybridization for EBV early RNA (EBER). The presence of EBV is required, but not adequate, for the diagnosis. Either CD56 or cytotoxic molecules should be present. When both are negative, the diagnosis becomes EBV-positive peripheral T-cell lymphoma 2
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(PTCL), not otherwise specified [8]. More recently, very rare cases of aggressive leukemia/lymphoma derived putatively from NK-cells but were EBV-negative had been described [10]. Owing to their extreme rarity, it still remains uncertain if they should be considered together with NK/T-cell lymphoma diagnostically and therapeutically.
Molecular pathology of NK/T-cell lymphomas Conventional karyotyping had shown deletion of chromosome 6q (6q–) to be a recurrent cytogenetic aberration in NK/T-cell lymphoma [11]. Results of comparative genomic hybridization [12] and loss of heterozygosity analyses [13] also demonstrated 6q– to be common. This segment of chromosome 6q might contain putative tumor suppressor genes important in the pathogenesis of NK/ T-cell lymphomas, including HACE1 [14], PRMD1 [15], FOXO3 [16] and PTPRK [17]. Activation of putative oncogenes, including EZH2 [18] and RUNX3 [19], might also be involved. Gene expression profiling (GEP) had revealed that NK/T-cell lymphoma and PTCL of gamma/delta subtype to be similar, consistent with their developmental relationship. GEP had also uncovered other oncogenic mechanisms, including JAK/STAT activation, and over-expression of NK-κB and aurora kinase A [20,21]. Next generation sequencing (NGS) has provided a mutational landscape for NK/T-cell lymphomas. Exome sequencing showed activating JAK3 mutations in about 35% of cases [22], but this observation could not be confirmed by later studies. Instead, activating STAT3 and STAT5B mutations were found in a significant number of cases [23,24]. Later NGS studies identified mutations of the RNA helicase gene DDX3X in about 20% of cases [25]. Other mutated genes included the tumor suppressor gene TP53, found in about 13% of cases [26]; and genes involved in epigenetic pathways, including MLL, ASXL1, ARID1A, and EP300, in 4–18% of cases [26]. The geographic predilection of NK/T-cell lymphoma for Asian and South American populations is not fully explained. A genomewide association study identified four amino acid residues Gly84-Gly85-Pro86-Met87 at the edge of the peptide-binding groove of HLA-DPB1 to be associated with susceptibility to NK/T-cell lymphoma [27]. So far, this association has not been validated in other studies.
Clinical features of NK/T-cell lymphoma Nasal NK/T-cell lymphomas affect mainly the nose and nasal cavity, but the orbit, salivary glands, and paranasal sinuses may be involved. In non-nasal NK/T-cell lymphoma, commonly involved primary sites include the skin [28], gastrointestinal tract [29,30], and testis. It should be noted that when NK/T-cell lymphomas appear to present in non-nasal sites, F18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) ought to be performed [31,32] to define if an occult nasal primary exists. If nasal involvement is documented, these “non-nasal” cases should be regarded as disseminated nasal lymphomas [33]. Aggressive NK-cell leukemia/lymphoma is the rarest form of NK/T-cell malignancy, currently categorized by the WHO classification as aggressive NK-cell leukemia [34]. Patients present with fever, rashes, lymphadenopathy, hepatosplenomegaly, pancytopenia, hyperferritinemia, deranged clotting and liver dysfunction. Active hemophagocytosis is found in the marrow and other reticuloendothelial organs [35]. Few if any patients survive despite intensive chemotherapy or even hematopoietic stem cell transplantation (HSCT).
Circulating EBV DNA as a surrogate biomarker of lymphoma load When NK/T-cell lymphoma cells undergo apoptosis, EBV DNA fragments are released into the blood [36]. Quantification of circulating EBV DNA is an accurate biomarker of lymphoma load [37–39]. Whole blood is not suitable as the starting material, mainly due to the variable presence of circulating memory B-cells that are often infected by EBV, which introduces unpredictable errors. Plasma as a starting material has recently been demonstrated to be superior to whole blood in a study of EBV-related lymphoid malignancies other than NK/T-cell lymphoma [39]. Plasma EBV DNA at diagnosis gives a measurement of the lymphoma load [37]. It provides a real-time assessment of response to treatment [38]. At the end of treatment, detectable EBV DNA reflects residual disease, which portends an unfavorable prognosis [40].
Differential diagnoses of NK/T-cell lymphomas Plasmacytoid dendritic cell neoplasms, formerly mistaken as blastoid NK-cell lymphomas, are localized mainly to the skin but may also involve the bone marrow [41]. It can be differentiated from cutaneous NK/T-cell lymphomas by the absence of CD3, cytotoxic molecules, and EBV infection. NK-cell lymphomatoid gastropathy is a non-neoplastic proliferation of NK-cells [42]. It occurs mainly in the stomach, but may involve the small and large bowels (NK-cell enteropathy) [43]. EBV is absent in lymphomatoid gastropathy/NK-cell enteropathy. Lesions are self-regressing, but occasional cases may relapse. Metastasis does not occur. Chronic lymphoproliferative disorder of NK-cells is a rare condition, currently unclear if reactive or neoplastic. There is no EBV infection. It is indolent and non-progressive [44]. Patients are asymptomatic, and no treatment is required. 3
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Clinical features and evaluation of newly diagnosed NK/T-cell lymphoma patients In addition to routine blood counts and serum biochemistry, trephine biopsy is needed. Morphologic examination should be supplemented with in situ hybridization for EBV encoded early RNA (EBER). The presence of EBER + atypical cells indicates marrow infiltration [4]. Plasma EBV DNA gives information on the presentation tumor load, and provides a biomarker for serial monitoring of treatment efficacy. PET/CT is now regarded as the standard imaging modality for NK/T-cell lymphoma [31,32]. It should be performed for newly diagnosed patients, not only for accurate staging, but also as a baseline with which interim and end-of-treatment scans can be compared, because these comparisons are prognostically important [38,40]. Principles of treatment of NK/T-cell lymphomas Conventional anthracycline-containing (CHOP, cyclophosphamide, adriamycin, vincristine, prednisolone, or CHOP-like) regimens developed for other aggressive lymphomas are ineffective and should not be used for NK/T-cell lymphomas [9], due to expression of the multidrug resistance (MDR) P-glycoprotein on NK lymphoma cells [9]. Instead, an array of more effective nonanthracycline-containing regimens has now been devised for treating NK/T-cell lymphomas [9]. An important advance in the treatment of NK/T-cell lymphoma is the use of asparaginase [9]. Neoplastic NK cells developed rapid apoptosis when treated with L-asparaginase ex vivo [45]. Clinically, L-asparaginase showed significant single-agent activity in relapsed/refractory NK/T-cell lymphoma [9]. Currently, asparaginase or its pegylated form is regarded as an indispensable component of effective regimens in NK/T-cell lymphomas. Risk stratification is a crucial. Prognostic models developed in the era of CHOP or CHOP-like regimens, including the international prognostic index [46] and the Korean prognostic index [47], had become outdated. Two prognostic indices, prognostic index for NK/ T-cell lymphoma (PINK) and PINK with EBV DNA (PINK-E), have been developed for patients treated with non-anthracyclinecontaining regimens [48]. However, PINK only takes into account clinical factors (age > 60 years, stage III/IV disease, distant lymphnode involvement, and non-nasal type disease). It has been shown that at least two other parameters, plasma EBV DNA [38] and PET/ CT scan features [49], are of prognostic importance. PINK-E takes into account presentation EBV DNA (whether detectable), and so has incorporated parameters more advanced than simply clinical ones. It remains to be defined if PET/CT, both interim [38] and endof-treatment [40], can also be incorporated into prognostic scoring systems. Stage I/II diseases have favorable outcomes. However, stage III/IV diseases fare much worse, and require additional efforts to result in durable remission. Hence, an accurate initial staging is of paramount importance. Stage I/II patients should not be treated excessively. On the other hand, stage III/IV patients should receive treatment in addition to chemotherapy so as to improve outcome. Treatment for stage I/II NK/T-cell lymphoma Radiotherapy, chemotherapy and their combination have been used in the treatment for early-stage NK/T-cell lymphoma [9]. Currently, the most widely accepted approach is combined radiotherapy and chemotherapy, which can be given concurrently (chemoradiotherapy) or sequentially. Radiotherapy NK/T-cell lymphoma cells are radiosensitive. However, radiotherapy alone is inadequate, because of unacceptably high risks of systemic relapse [9]. In a retrospective analysis, it was shown that the risk of locoregional relapse increased when the dosage was < 50–52 Gy [50]. The importance of radiation dosage was shown in another study, where in the context of combined chemotherapy and radiotherapy, the 5-year OS was 62% for a dose of > 50 Gy, and 53% for a dose of < 50 Gy [51]. Radiotherapy added to non-anthracycline-containing chemotherapy also led to superior overall survival (OS) and disease-free survival (DFS) [52]. Concurrent chemoradiotherapy Two early trials examined the efficacy of platinum-containing regimens with concurrent radiotherapy for early-stage NK/T-cell lymphoma. In a phase 1/2 multi-center study, concurrent radiotherapy (50Gy) and three cycles of DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin) were evaluated in 33 patients [53]. The complete response rate (CR) and overall response rate (ORR) were 75% and 78%. With a median follow-up of 68 months, the 5-year OS and progression-free survival (PFS) were 73% and 67%. In another phase 2 trial of 30 patients, concurrent radiotherapy (40Gy) and cisplatin (30 mg/m2 weekly) were given, followed by three cycles of VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) as consolidation [54]. The CR and ORR were 80% and 83.3%. The 3-year OS and PFS were 86% and 85%. The addition of L-asparaginase to this strategy was tested in a continuation study, where 30 patients were treated with concurrent radiotherapy (40Gy) and cisplatin (30 mg/m2 weekly), and then 2 cycles of L-asparaginasecontaining chemotherapy VIDL (etoposide, ifosfamide, dexamethasone and L-asparaginase) as consolidation. The CR and ORR were 87% and 90%. With a median follow-up of 44 months, the 5-year OS and PFS were 73% and 60% [55]. Hence, addition of Lasparaginase did not improve the outcome of concurrent chemoradiotherapy. Used outside trials, concurrent chemoradiotherapy appeared to give similar results. In a retrospective analysis of 150 patients, concurrent RT and DeVIC led to CR and ORR of 82% and 89% [56]. With a median follow-up of 5.6 years, the 5-year OS and PFS were 4
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72% and 61%.
Sequential chemotherapy and radiotherapy In most institutes, radiotherapy is not immediately available, and concurrent chemoradiotherapy is difficult to arrange. Chemotherapy followed by radiotherapy is logistically simpler. The use of SMILE (dexamethasone, methotrexate, ifosfamide, Lasparaginase and etoposide), currently the most-employed regimen worldwide, with sandwiched radiotherapy was examined in 29 patients [57]. After 2–3 cycles of SMILE, the CR and ORR were 69% and 86%. After the completion of radiotherapy (50Gy) and 3–4 subsequent cycles of SMILE, CR and ORR were 69% and 90%. Furthermore, the remission was durable with 90% of patients remained in CR during follow-up. The use of other asparaginase-containing regimens including LVP (L-asparaginase, vincristine, prednisolone) [58,59], GELOX (gemcitabine, L-asparaginase, oxaloplatin) [60,61], P-GEMOX (pegaspargase, gemcitabine, oxaliplatin) [62], DICE-L-asp (dexamethasone, ifosfamide, cisplatin, etoposide, L-asparaginase) [63] and MESA (methotrexate, etoposide, dexamethasone, and pegaspargase) [64] followed by radiotherapy also gave comparable results, with CR and ORR at 74–91% and 92–100%. The 5-year OS and PFS were 64–89% and 64–83%. In the largest retrospective study to date, 303 patients treated with various combinations of non-anthracycline-containing chemotherapy and radiotherapy were analyzed. On multivariate analysis, patients treated with concurrent chemoradiotherapy with or without subsequent consolidation chemotherapy had CR, PFS and OS comparable with those of patients treated with sequential chemotherapy and radiotherapy [65]. These results show that when effective chemotherapeutic regimens are used, concurrent chemoradiotherapy and sequential chemotherapy and radiotherapy are equally efficacious. Sequential chemotherapy and radiotherapy have numerous advantages, including immediate availability, logistic ease and better tolerability of chemotherapy and radiotherapy when used singly. Therefore, for stage I/II NK/T-cell lymphoma, sequential chemotherapy and radiotherapy is presently the choice in most centers in the world [66].
Treatment for stage III/IV and relapsed/refractory NK/T-cell lymphoma Stage III/IV diseases have a poor prognosis. With anthracycline-based chemotherapy, there are few if any long-term survivors [9], so that these regimens should no longer be used. L-asparaginase-containing regimens are currently the treatment of choice [9]. In a phase 2 study, 20 newly-diagnosed stage IV patients were treated with SMILE [67]. CR and ORR were 40% and 80%. Grade 3/4 neutropenia occurred in all patients, which in the early part of the study resulted in sepsis-related mortality in 10% of patients. Once routine granulocyte colony stimulating factor was administered, septic deaths did not occur. With a median follow-up of 24 months, the 1-year OS and PFS were both 45%. In another retrospective analysis of 26 patients with newly diagnosed stage IV NK/Tcell lymphoma treated with SMILE, 14 (53.8%) patients achieved CR. The 5-year OS was 47% and the 4-year disease-free survival (DFS) was 60% [57]. For NK/T-cell lymphomas that have relapsed from or are refractory to radiotherapy and/or anthracycline-based chemotherapy, salvage therapy with L-asparaginase-containing regimens has been shown to be highly efficacious. In a retrospectively study of SMILE for relapsed/refractory patients (N = 44, of which 23 had stage III/IV disease), CR and ORR were 66% and 77% [57]. With a median follow-up of 31 months, the 5-year OS was 52% and the 4-year DFS was 68%. Another L-asparaginase-containing regimen, AspaMetDex (L-asparaginase, methotrexate, and dexamethasone) was also studied in the treatment of 19 patients (advanced-stage, N = 7) [68]. After 3 cycles of chemotherapy, CR and ORR were 61% and 78%. With a median follow up of 26 months, the estimated 2-year OS and PFS were both around 40%. The use of pegylated asparaginase in NK/T-cell lymphoma has been investigated. In a retrospective study, 13 patients with relapsed/refractory advanced-stage disease were treated with MEDA (methotrexate, etoposide, dexamethasone and pegylated asparaginase) [69]. After 6 cycles of chemotherapy, the CR and ORR were 62% and 77%. With a median follow up of 20 months, the 1year OS and PFS were 69% and 62%. P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) was examined in a study that included 21 patients with relapsed/refractory disease (advanced-stage, N = 9) [70]. The CR and ORR were 52% and 81%. With a median follow-up of 17 months, the 3-year OS and PFS were 58% and 24%. DDGP (dexamethasone, gemcitabine, cisplatin and pegaspargase) was examined in 22 patients with advanced-stage NK/T-cell lymphoma [71]. The CR and ORR were 71% and 95%. With a median follow up of 14 months, the 1-year OS and PFS were 90% and 86%.
Asparaginase-refractory NK/T-cell lymphoma The outcome for NK/T-cell lymphoma relapsing from or refractory to asparaginase-containing regimens is dismal. In a retrospective study, 20 patients with relapsed/refractory NK/T-cell lymphoma were treated with gemcitabine or its combination with other agents (such as dexamethasone and cisplatin) [72]. Fourteen patients were refractory to L-asparaginase-based chemotherapy (SMILE, N = 11). After gemcitabine-based therapy, CR and ORR were 20% and 40%. The median OS and PFS were 5 months and 2 months. Conventional chemotherapies are therefore largely ineffective in patients failing asparaginase-based treatment. 5
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Immunotherapy in NK/T-cell lymphoma The programmed cell death protein 1 ligand (PDL1) is highly expressed on NK/T-cell lymphoma cells [73,74]. Binding of PDL1 to the inhibitory receptor PD1 on effector T-cells suppresses anti-tumor immunity. Blocking of PD1/PDL1 ligation with anti-PD1 antibody restores effector T-cell targeting of NK/T-cell lymphoma cells. In a preliminary study, the humanized monoclonal anti-PD1 antibody pembrolizumab was used to treat 7 patients with refractory NK/T-cell lymphoma failing L-asparaginase-containing regimens (N = 7) and allogeneic HSCT (N = 2) [75]. After a median of 7 cycles of pembrolizumab, the ORR was 100%. Five patients achieved CR that was sustained after a median follow up of 6 (2–10) months. There were no treatment-related adverse events. In another study of 7 patients with relapsed/refractory NK/T-cell lymphoma treated with pembrolizumab, the ORR was 57% with 2 patients achieving CR after a median of 4 cycles of treatment [76]. One patient has remained in CR with 18 cycles of pembrolizumab, indicating a durable response. There was also a suggestion that the level of PDL1 expression correlated with treatment response. Similarly, the efficacy of another anti-PD1 antibody nivolumab has been demonstrated in a case series of 3 patients with advancedstage relapsed NK/T-cell lymphoma [77]. The ORR was 100% with 1 patient in continuous CR with 9 cycles of treatment. Based on these promising results, the use of pembrolizumab is recommended for the treatment of relapsed/refractory NK/T-cell lymphoma by the National Comprehensive Cancer Network [78]. Prospective studies investigating the role of PD1 immune-checkpoint blockade therapy in NK/T-cell lymphoma are on-going. In addition to anti-PD1 antibody, monoclonal antibodies targeting other antigens expressed on NK/T-cell lymphoma cells have been tested. The efficacy of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has been demonstrated in two reported cases of refractory NK/T-cell lymphoma [79,80]. CD38 is expressed on normal NK cells, and 50% of NK/T-cell lymphoma had strong CD38 expression [81]. The efficacy of daratumumab in NK/T-cell lymphoma has been reported in 2 patients with relapsed/refractory disease, with one achieving CR and another achieving partial response [82,83]. Autologous HSCT The benefit of autologous HSCT for NK/T-cell lymphoma at first CR was examined retrospectively in 62 patients [84]. Half of the patients had stage III/IV disease. With a median follow-up of 43 months, the 3-year OS and PFS for early-stage diseases were 68% and 65%, and those of advance-stage diseases were 52% and 40%. These results were not different from non-HSCT patients treated with asparaginase-containing regimens, so that autologous HSCT for NK/T-cell lymphoma at first CR is not warranted. For relapsed NK/Tcell lymphoma after asparginase-based chemotherapy, there are not enough data to support the use of autologous HSCT as salvage. Allogeneic HSCT A retrospective analysis of 82 patients with NK/T-cell lymphoma (early-stage N = 35; advanced-stage N = 22; unknown N = 25) undergoing allogeneic HSCT between 2000 and 2014 was recently reported [85]. Myeloablative HSCT was performed in 38% of patients. With a median follow-up of 36 months, the 3-year OS and PFS of the whole cohort were 34% and 28%. The non-relapse mortality was 30%. The outcomes of allogeneic HSCT in patients previously treated with L-asparaginase containing regimen appeared to be superior. In a retrospective analysis of 18 patients undergoing allogeneic HSCT, SMILE was used as the initial treatment in 14 patients [86]. Thirteen patients had advanced-stage disease at presentation, and 16 patients were at CR prior to HSCT (CR1, N = 9, CR2, N = 7). Myeloablative conditioning was used in 14 patients. With a median follow-up of 21 months, the estimated 5-year PFS and OS were 51% and 57%. The use of SMILE and achieving CR prior to HSCT were associated with a better outcome. The survival of patients transplanted at CR1 and CR2 did not differ, suggesting that allogeneic HSCT for patients in first CR may not be justified. Conclusion and future perspectives With the use of L-asparaginase-containing regimens, stage I/II NK/T-cell lymphoma has become potentially curable in the majority of patients. Treatment of stage III/IV and relapsed/refractory disease remains challenging. The advent of immunotherapy holds much promise. Future research will center on how immunotherapy can be incorporated into conventional strategies to improve outcome. Summary NK/T-cell lymphomas are rare EBV-related malignancies with a predilection for Asian and South American populations. The majority is of NK-cell lineage, and a minority of T-cell lineage. They are predominantly extranodal lymphomas. Clinically, three subtypes can be distinguished: nasal, non-nasal, and disseminated. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract, usually presenting as stage I/II disease. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other soft tissue, often presenting as stage III/IV disease. Disseminated NK/T-cell lymphoma involves multiple organs, may present with a leukemic phase, and is rapidly fatal. Initial evaluation of NK/T-cell lymphoma requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. NK/T-cell lymphomas are radiosensitive, but radiotherapy alone is inadequate with unacceptable relapse rates. Conventional anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently considered the standard of care. For stage I/II disease, 6
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combined chemotherapy and radiotherapy results in very high response rates and cure in a significant proportion of patients. For stage III/IV disease, asparaginase-containing regimens are needed. Interim and end-of-treatment PET/CT scan and circulating EBV DNA are prognostic and useful in the evaluation for additional therapy. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases if a remission can be achieved. Immunotherapy, including the use of antibodies against CD30, programmed cell death protein 1 and CD38, holds promises and should be considered for relapsed/refractory disease. Conflicts of interest The authors have no conflicts of interests to declare. Practice points
• The diagnosis of NK/T-cell lymphoma requires demonstration of Epstein Barr virus (EBV) infection in the lymphoma cells, and either positive CD56 or cytotoxic molecules • Positron emission tomography computed tomography is the standard imaging modality for staging • Plasma EBV DNA should be quantified for assessment of lymphoma load, and monitoring of efficacy of treatment and residual disease • Conventional anthracycline-containing regimens are ineffective and should not be used in NK/T-cell lymphomas • Non-anthracycline-containing regimens incorporating asparaginse are now the standard of care • Combined chemotherapy and radiotherapy, whether concurrent or sequential, is needed for stage I/II NK/T-cell lymphoma • Radiotherapy as the sole treatment modality is inadequate and should not be used • Stage III/IV NK/T-cell lymphomas require systemic chemotherapy, and consideration of allogeneic hematopoietic stem cell transplantation (HSCT) in selected patients • Autologous HSCT is of limited clinical utility • Immunotherapy, including the use of antibodies against CD30, programmed cell death protein 1 and CD38, shows promise in treatment of relapsed/refractory NK/T-cell lymphomas
Research agenda
• Efforts should be made to combine biologic and molecular parameters with clinicopathologic characteristics for the prognostication of NK/T-cell lymphomas • Prospective studies are required to determine if radiotherapy may be omitted in good-risk patients treated with effective asparaginase-containing regimens • Molecular targeting based on genomic alterations in NK/T-cell lymphomas should be explored • The role of immunotherapy in the front-line treatment, as well as in the maintenance of remission, should be defined in high-risk patients
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