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. Author manuscript; available in PMC: 2023 Apr 1.
Published in final edited form as: Clin Lymphoma Myeloma Leuk. 2021 Oct 16;22(4):e250–e260. doi: 10.1016/j.clml.2021.10.004

Characteristics and Outcome of Extranodal NK/T-cell Lymphoma in North America: A Retrospective Multi-Institutional Experience

N Nora Bennani 3,*, Aung M Tun 3,12,*, Kenneth R Carson 1,2, Jessica L Geiger 3, Lauren S Maeda 4, Kerry J Savage 5, Jim Rose 5, Lauren Pinter-Brown 6, Matthew A Lunning 7, Jeremy S Abramson 8, Nancy L Bartlett 2, Julie M Vose 7, Andrew M Evens 9, Sonali M Smith 10, Steven M Horwitz 11, Stephen M Ansell 3,#, Ranjana H Advani 4,#
PMCID: PMC8977231  NIHMSID: NIHMS1757125  PMID: 34794912

MicroAbstract

Extranodal natural killer/T-cell lymphoma is rare in the Western world. Clinical characteristics and outcomes remain unclear. We report on 121 cases from major centers in North America. The majority of patients present with early stage disease, and CMT appears to provide optimal outcomes for appropriate candidates. Patients did poorly overall, regardless of race/ethnicity, highlighting need for further advances in the field.

Introduction

Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare subtype of mature T-cell and NK-cell lymphoma in Western countries, representing less than 1% of all non-Hodgkin lymphomas (NHL).1 It is far more common in Eastern Asia as well as Central and South America, where it accounts for 5 to 15% of all NHL.2–4 Pathologically, ENKTL is characterized by neoplastic cells of natural killer cell lineage (less commonly T-cell), which by immunohistochemistry are CD2+, surface CD3−,cytoplasmic CD3E+, CD56+, and express cytotoxic markers (granzyme B, perforin and TI1A).5–7 Neoplastic cells are Epstein-Barr virus (EBV) positive and in-situ hybridization for EBV encoded RNA (EBER) is a diagnostic requirement.8,9 The most commonly involved site is the nasopharynx and surrounding structures, often with palatal destruction.2,10 The disease is localized in ~ 60% of patients at time of diagnosis. There is a male predominance with roughly a 2:1 male to female ratio, and the median age at time of initial diagnosis is 52 years.11,12

While current treatment paradigms in North America are based on the Asian literature,13 little is known about patient demographics, patterns of care, and outcomes of ENKTL patients in North America. Additionally, there are limited data available on outcomes of Asian patients residing in North America who develop ENKTL. To evaluate characteristics and outcomes, we collected data in a multi-institutional effort, on a retrospective cohort of patients with ENKTL, all diagnosed and treated in North America. We sought to assess differences in treatment patterns and outcomes according to era of treatment and ethnic origin.

Methods

Patients with ENKTL were retrospectively identified by the North America T-cell consortium working group, an informal coalition of T-cell investigators at various academic centers. All institutions had local institutional review board approval prior to patient selection and data collection. Patients with a local pathology report consistent with angiocentric lymphoma under the Revised European-American Lymphoma (REAL) classification or ENKTL under the World Health Organization (WHO) classification (after 2001), and documented CD56+ expression in the tumor cells by immunohistochemistry (IHC) were included. Review of pathology reports was performed by expert hematopathologists at each participating academic site. There was no provision for central pathology review in this study. Medical records were assessed at each contributing site to determine patient race/ethnicity, disease characteristics, treatments, and outcomes including dates of progression or death. Since this study was intended to evaluate treatment patterns and survival, those who elected to pursue hospice care or had palliative chemotherapy or radiotherapy were excluded from the cohort. Similarly, patients with no information on stage of disease were excluded.

Results of EBV testing on tumor tissue by fluorescent in-situ hybridization (FISH) or IHC were recorded, when available. Chemotherapy regimens were compared based on era of treatment, and the stratification was made between patients who were diagnosed before 2007 and during/after 2007 since platinum-based regimens were first used in 2007, followed by the introduction of asparaginase- and gemcitabine-containing regimens. We also analyzed survival outcomes based on anthracycline-versus non-anthracycline-containing chemotherapy and L-asparaginase-versus non-asparaginase-based regimens.

Statistical Analyses

Descriptive statistics were used to compare baseline clinicopathologic characteristics. The reverse Kaplan-Meier method was used to obtain median follow-up time.14,15 Progression free survival (PFS) was defined as the time between the date of diagnosis and the date of progression, relapse, or death from any cause. Overall survival (OS) was defined as the time from the date of diagnosis to the date of death from any cause. Survival curves were constructed using the methods of Kaplan and Meier.16 Two year survival point estimates and confidence intervals (CI) were calculated. Univariate Cox proportional hazards models were used to evaluate the impact of clinical characteristics and treatment variables on PFS and OS. Multiple variable Cox proportional hazards models, adjusting for age, sex, and era of diagnosis, were also constructed. All statistical analyses were performed using JMP Pro v14.1 (SAS Institute, Cary, NC).

RESULTS

We identified 143 patients with ENKTL diagnosed between June 1990 and November 2012 across various academic and United States Veterans Health Administration centers in North America. The final data cutoff for the study was made on November 30, 2012. We excluded 14 patients with missing data on age or stage and 1 patient who proceeded directly to hospice care. Additional 7 patients who were treated with single agent palliative chemotherapy (cyclophosphamide, chlorambucil, and nitrogen mustard) or palliative radiotherapy were also excluded, leaving the final cohort of 121 patients (Supplemental Figure 1). Baseline characteristics are presented in Table 1. The median age at diagnosis was 52 years (range 19 to 88 years) and 66% of patients were male (n=80). Fifty-three percent of patients (n=64) were diagnosed before 2007, and the remaining 47% (n=57) were diagnosed during or after 2007. Thirty-three percent of cases (n=40) had B symptoms at presentation. Most patients had stage I/II disease at time of diagnosis (n=83, 69%). Fifty-nine percent (n=71) were Caucasian, 21% (n=25) were of Asian ethnicity and 21% (n=25) were of other racial background or unknown. EBV testing on tumor tissue was positive in 74% of cases (n=89), negative in 14% of cases (n=17), and unknown or unassessed in the remaining 12% of cases (n=15). Note that EBV testing on tumor tissue was done by IHC for EBV-encoded proteins or FISH for EBER. The median follow-up time for the entire cohort was 51 months with a range of 0.5 to 137 months (4.3 years; range 0.04 to 11.4 years). The median PFS and OS for the entire cohort were 10 months (95% CI: 6–19) and 23 months (95% CI: 12–37), respectively. Five-year PFS and OS were 28% (95% CI: 19–37) and 33% (95% CI: 23–43), respectively (Figure 1A).

Table 1.

Demographic and Clinical Characteristics

Characteristic Number of Patients (%)
N 121
Median Age and range 52 (19 – 88)
Gender
 Male 80 (66)
 Female 41 (34)
Year of diagnosis
 Before 2007 64 (53)
 During and after 2007 57 (47)
B symptoms
 Yes 40 (33)
 No 78(64)
 Missing 3 (2)
Stage
 I/II 83 (69)
 III/IV 38 (31)
Race
 White 71 (59)
 Asian 25 (21)
 Black 3 (2)
 Hispanic/American India 20 (17)
 Unknown 2 (2)
EBV status (tissue biopsy)
 Positive by Fish or IHC1 89 (74)
 Negative2 17 (14)
 Unknown 15 (12)
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EBV, Epstein-Barr virus; FISH, fluorescent in-situ hybridization; IHC, immunohistochemistry.

1

Positive EBV status was determined by FISH in 69 patients, IHC in 19 patients, and an unknown testing modality in 1 patient.

2

Negative EBV status was determined by FISH in 8 patients, IHC in 1 patient, and an unknown testing modality in 8 patients.

Figure 1.

Figure 1

Figure 1

Figure 1

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A. 5-year progression free survival and overall survival for the overall study population

B. 5-year progression free survival in patients with stage I vs stage II disease

C. 5-year overall survival in patients with stage I vs stage II disease

Outcomes according to Stage

Stage I and II disease

Sixty-four percent (n=53) of patients with stage I or II disease received CMT, 19% (n=16) received radiation monotherapy (RT), and 17% (n=14) received CT (Supplemental Table 1). Overall, the median PFS and OS were 18 months (95% CI: 8–36) and 37 months (95% CI: 21–83), respectively. No differences in outcomes were seen when comparing stage I and stage II (5-year PFS 35% vs 28% (p=0.53) and 5-year OS 42% and 38% (p=0.11), respectively)(Figure 1B and 1C). Similarly, no differences in outcomes were observed in patients treated with CMT, compared to those treated with RT alone (2-year PFS 53% vs 47%; HR: 0.96; 95% CI: 0.46–2.24; p=0.91) and OS (67% vs 67%; HR: 0.79; 95% CI: 0.37–1.90; p=0.58) (Table 2).

Table 2:

Univariate Cox analyses

Characteristic 2-year PFS (95% CI) HR for PFS (95% CI) p-value 2-year OS (95% CI) HR for OS (95% CI) p-value
All patients (n=121) 35% (26–44) 49% (40–59)
Age (+10 years) NA 1.05 (0.93–1.19) 0.42 NA 1.11 (0.97–1.28) 0.14
Sex
 Male (n=80) 36% (24–47) 1.00 50 (38–61) 1.00
 Female (n=41) 35% (20–50) 0.93 (0.60–1.44) 0.74 49 (33–65) 0.86 (0.52–1.41) 0.54
Race
 Non-Asian (n=94) 33% (23–44) 1.00 48% (37–59) 1.00
 Asian (n=25) 40% (19–61) 0.83 (0.48–1.43) 0.49 47% (26–69) 0.72 (0.39–1.35) 0.30
Race/Ethnicity
 Asian/Hispanic/American Indian (n=45) 44% (29–59) 1.00 49% (33–65) 1.00
 White/Black(n=74) 30% (19–41) 1.47 (0.93–2.33) 0.09 48% (36–60) 1.52 (0.91–2.55) 0.10
Stage
 Advanced(n=38) 19% (6–32) 1.00 29% (14–44) 1.00
 Early (n=83) 43% (32–55 0.61 (0.39–0.94) 0.03 59% (48–70) 0.48 (0.30–0.77) 0.004
Chemo Regimen (All Stages)
 Non-Anthra (n=30) 39% (19–58) 1.00 39%(18–59) 1.00
 CHOP/Anthra (n=72) 33% (21– 44) 1.13 (0.65–1.97) 0.66 47% (35–59) 0.84 (0.48–1.49) 0.57
Chemo Regimen (Early-Stage Disease)
 Non-Anthra (n=16) 63% (39–86) 1.00 59% (33–85) 1.00
 CHOP/Anthra (n=51) 39% (25–53) 1.57 (0.66–3.75) 0.28 58% (44–72) 0.98 (0.40–2.42) 0.97
Chemo Regimen (Late-Stage Disease)
 Non-Anthracycline (n=14) 18% (0–39) 1.00 25% (1–49) 1.00
 CHOP/Anthracycline (n=21) 17% (0–33) 1.16 (0.54–2.48) 0.70 21% (3–40) 1.13 (0.52–2.44) 0.76
Chemo Regimen
 Non-Asparaginase-based regimen (n=87) 32% (22–42) 1.00 45% (34–56) 1.00 0.95
 Asparaginase-based regimen (n=15) 53% (28–79) 0.72 (0.33–1.58) 0.39 53% (27–78) 0.98 (0.44–2.17)
Treatment Category (Early-Stage Disease)
 Radiation alone (n=16) 47% (22–73) 1.00 67% (43–91) 1.00
 Combined modality therapy (n=53) 53% (38–67) 0.96 (0.46–2.24) 0.91 67% (53–80) 0.79 (0.37–1.90) 0.58
BMT status
Patients achieving complete remission
 No Transplant in CR1 (n=53) 50% (36–65) 1.00 73% (60–86) 1.00
 Transplant in CR1 (n=15) 79% (57100) 0.57 (0.22–1.48) 0.22 87% (69104) 0.55 (0.16–1.86) 0.30
BMT status (Early-Stage Disease)
Patients achieved complete remission
 No Transplant in CR1 (n=43) 57% (41–73) 1.00 81% (68–94) 1.00
 Transplant in CR1 (n=8) 86% (60112) 0.66 (0.19–2.21) 0.47 100%(100–100) 0.42(0.05–3.19) 0.34
BMT status (Advanced-Stage Disease)
 Patients achieved complete remission
 No Transplant in CR1 (n=10) 25% (0–51) 1.00 44% (12–77) 1.00
 Transplant in CR1 (n=7) 71% (38105) 0.37 (0.08–1.82) 0.19 71% (38105) 0.47 (0.10–2.29) 0.32
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PFS, progression free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio; not applicable, NA; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; BMT, bone marrow transplantation; CR1, first complete remission.

Stage III and IV disease

Of patients with stage III/IV disease, 61% (n=23) received CT alone, 8% (n=3) had RT and 32% (n=12) had chemotherapy along with consolidative (10/12) or palliative radiation therapy (2/12) (Supplemental Table 1). The median PFS and OS rates were 6 months (95% CI: 4–10) and 10 months (95% CI: 6–21), respectively. The estimated 2-year PFS and OS rates were 19% (95% CI: 6–32) and 29% (95% CI: 14–44), respectively. In the univariate Cox regression model, patients with stage III/IV disease had significantly worse outcomes than those with stage I/II disease with HR for PFS 1.65 (95% CI: 1.06–2.57; p= 0.03) and HR for OS: 2.08 (95% CI: 1.29–3.36; p = 0.004) (Figures 2A and 2B).

Figure 2.

Figure 2

Figure 2

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A: 5-year progression free survival stratified by stage

B: 5-year overall survival stratified by stage

Outcomes according to chemotherapy type

When all subjects, regardless of stage were included, there was no difference in PFS and OS in patients who received anthracycline (n=72) vs non-anthracycline-containing chemotherapy regimens (n=30) with an estimated 2-year PFS of 33% vs 39% (HR: 1.13; 95% CI: 0.65–1.97; p=0.66) and estimated 2-year OS of 47% vs 39%, respectively (HR: 0.84; 95% CI: 0.48–1.49; p=0.57) (Table 2). Estimates of 5-year PFS and OS stratified by chemotherapy regimen (anthracycline-based vs non-anthracycline) for all stages of patients with ENKTL are shown in Figure 3A and 3B. We further analyzed the data based on disease stage. Among the patients with stage I/II disease treated with chemotherapy, 51 patients received an anthracycline and 16 received non-anthracycline-containing chemotherapy regimens with a non-significant difference in 2-year PFS (p= 0.28) and 2-year OS (p=0.97). For patients with stage III/IV disease, 21 patients received anthracycline-containing regimen and 14 patients had non-anthracycline-containing chemotherapy with 2-year PFS of 17% vs 18% (HR: 1.16; 95% CI: 0.54–2.48; p=0.70) and 2-year OS of 21% vs 25% (HR: 1.13; 95% CI: 0.52–2.44; p=0.76). The limited sample size precluded analysis to compare outcomes by specific regimens, particularly those treated with an L-asparginase containing regimen (N=15).

Figure 3.

Figure 3

Figure 3

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A: 5-year progression free survival by chemotherapy regimen (anthracycline-based vs non-anthracycline) for all stages

B: 5-year overall survival by chemotherapy regimen (anthracycline-based vs non-anthracycline) for all stages

Race/ethnicity

When patients who historically have been considered low-risk for the development of ENKTL (black and white race, n=74; 61%) were compared to other ethnic groups3,17,18 (Asian, Hispanic, or Native American/First Nations, n = 45; 38%), there was no significant difference observed in PFS (HR: 1.47; 95% CI: 0.93 – 2.33; p=0.09) or OS (HR: 1.52; 95% CI: 0.91 – 2.55; p=0.10). Similarly, there was no difference in PFS or OS noted when Asian patients were compared to non-Asian patients residing in North America (HR for PFS: 0.83; 95% CI: 0.48–1.43; p=0.49 and HR for OS: 0.72; 95% CI: 0.39–1.35; p=0.30). Figures 4A and 4B display Kaplan-Meier curves stratified by Asian versus non-Asian race. While there were no differences in stage and B symptoms, other potentially relevant variables such as LDH, tumor size, and nasal vs extranasal sites were not available.

Figure 4.

Figure 4

Figure 4

Figure 4

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A. 5-year progression free survival of the overall study population stratified by Asian and non-Asian race

B. 5-year overall survival of the overall study population stratified by Asian and non-Asian race.

C. 5-year progression free survival of the overall study population stratified by treatment era.

Univariate and multivariate analysis

Univariate analyses demonstrated that stage I/II disease was significantly associated with better PFS and OS compared with advanced-stage disease (Table 2). In patients with stage I/II disease, the use of CT alone was associated with a decreased PFS (HR = 3.61; 95% CI: 1.88 – 6.90; p=0.0001) and OS (HR = 2.58; 95% CI: 1.22 – 5.47; p=0.01) compared with CMT for age, sex, and era of diagnosis (Table 3). By multivariate analysis adjusted for age, sex, and era of diagnosis, the use of chemotherapy alone and stage III/IV disease status were both highly associated with a higher risk of mortality, whereas race/ethnicity, type of chemotherapy regimen, and use of consolidative HSCT in first complete remission did not impact survival.

Table 3.

PFS and OS analyses adjusted for age, sex, and treatment type

Characteristic HR for PFS (95% CI) p-value HR for OS (95% CI) p-value
Race
 Asian (vs Non-Asian) 0.78 (0.44–1.37) 0.38 0.64 (0.34–1.21) 0.15
Race
 White/Black (vs Other races) 1.49 (0.93–2.38) 0.09 1.55 (0.92–2.60) 0.09
Stage
 Early (vs Advanced) 0.59 (0.37–0.92) 0.02 0.45 (0.28–0.73) 0.002
Chemo Regimen
 CHOP/Anthracycline (vs Non-Anthracycline) 1.06 (0.53–2.12) 0.87 0.79 (0.39–1.61) 0.52
Treatment Category
Stage 1 and 2 Patients
 Chemotherapy alone 1.00 1.00
 Radiation alone 0.21 (0.07–0.65) 0.01 0.30 (0.08–0.43) 0.06
 Combined modality Therapy 0.24 (0.12–0.51) 0.0001 0.33 (0.14–0.78) 0.01
BMT status
Only CR patients
 Transplant in CR1 (vs No Transplant) 0.59 (0.22–1.58) 0.27 0.67 (0.19–2.42) 0.53
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Abbreviations: HR, hazard ratio; CI, confidence interval; PFS, progression free survival; OS, overall survival; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; BMT, bone marrow transplantation; CR1, first complete remission.

Treatment by era

Chemotherapy regimens given to patients diagnosed before 2007 were primarily anthracycline-based: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), n=50 (85%); proMACE-cytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate), n=2 (3%); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine), n=3 (5%); and other regimens that did not include an anthracycline, n=4 (7%). In contrast, in those patients diagnosed during and after 2007, CHOP-based regimens were given to fewer patients, n=15 (35%), while L-asparaginase-based, n=15 (35%), and other (mainly represented by platinum- or gemcitabine-based regimens) n=11 (26%) were more commonly used. (Supplemental Table 2).

A total of 5 patients received radiation monotherapy before 2007 (stage I, n=3; stage II, n=1, and advanced stage, n=1). Radiation monotherapy was given to 14 patients who were diagnosed during and after 2007 (Supplemental Table 3). In our cohort, the majority of patients (83%, n=69) with stage I/II disease received curative radiation therapy as monotherapy or combined with chemotherapy. The data on dose was available in 81% (n=56) of patients with a median radiation dose of 50 Gy (range 30–66 Gy). Figure 4C demonstrates the PFS for patients treated before 2007 and those treated during and after 2007.

Role of HSCT

Fifty-seven percent (68/121) of patients achieved complete remission with frontline therapy. Twenty-two percent (15/68) underwent consolidation with HSCT in the first complete remission (CR1); among those, 8 patients underwent autologous HSCT, 3 patients proceed with allogeneic HSCT, and the exact type of HSCT was unknown for 4 patients. The estimated 2-year PFS for transplanted group was 79% vs 50% for patients in non-transplanted group, but the difference did not meet statistical significance (HR: 0.57; 95% CI: 0.22– 1.48; p=0.22). Similarly, the estimated 2-year OS rates for transplanted vs non-transplanted patients in CR1 were 87% vs 73% (HR: 0.55; 95% CI: 0.16–1.86; p=0.30). The outcomes were also not statistically significant when analyses were done separately for early versus advanced stage disease (Table 2), as well as based on multivariate analysis adjusted for age, sex, and era of diagnosis (Table 3). Note that 17 patients in our cohort underwent HSCT in the second CR.

Discussion

This case series represents one of the largest reported experience of ENKTL diagnosed and treated in North America.19–21 Similar to observations outside of North America, most patients presented with stage I/II at diagnosis.22 We also confirm that the poor outcomes historically seen in other regions are also observed in North America. Across the entire cohort, 5-year PFS and OS were only 28% and 33%, respectively. Consistent with the literature, for stage I/II disease treatment with CMT was superior to chemotherapy alone.11,23,24 Interestingly, in our series, patients with stage I/II disease treated with radiation therapy alone also had outcomes comparable to that of combined modality therapy. However, given the low number of patients, no meaningful treatment comparisons can be made. For advanced stage disease, outcomes in our cohort were poor, again likely due to most patients being treated before and during 2007 with anthracycline-based regimen such as CHOP chemotherapy.

Our results also show no statistical difference in outcomes in patients treated with an anthracycline before or after 2007, again with the caveats of a limited cohort size and heterogeneity of disease factors including stage. Our results are however consistent with multiple other studies which also report inferior outcomes with anthracycline-based chemotherapy.25 Suboptimal responses to anthracycline therapy are thought to be due to ENKTL expression of p-glycoprotein, which can confer resistance to doxorubicin.26,27 This has led to the development of regimens like DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) and VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone) which are platinum-based regimens given concurrently with radiotherapy for early stage disease. These combined modality regimens have resulted in better outcomes than those historically achieved with CHOP. Both regimens result in response rates of approximately 80% with a 5 year OS > 70% in non-randomized studies.28,29

For advanced stage disease, L-asparaginase/methotrexate-based chemotherapy regimens demonstrate better response rates than anthracycline-based chemotherapy and appear to have improved outcomes.30,31 Several regimens with various degree of intensity incorporating peg-asparginase have been studied, including P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin), P-GEMOX combined with programmed death 1 (PD-1) blocking monoclonal antibody, and DDGP (dexamethasone, cisplatin, gemcitabine, and peg-asparaginase).32–35 These regimen appear promising in advanced stage disease, albeit small numbers and limited follow up for some. As stated previously, due to our limited sample size, we were unable to rigorously assess differences in outcome between those who did and did not receive L-asparaginase as part of their treatment regimen.

HSCT in ENKTL has been reported to be associated with better survival outcomes, but also in need of further exploration as more studies are relatively small.36,37 The optimal timing, conditioning regimen, source of stem cells (autologous or allogeneic) is unknown. In our study, 15 patients in CR 1 received HSCT. However, due to a limited sample size in our cohort, no definitive conclusions can be made regarding the role of HSCT.

Registry studies in North America are limited and suggest that US ENKTL represents ~ 1–2% of all T/NK cell lymphomas and ~ 0.2 % of non-Hodgkin lymphoma with significantly higher incidence in Hispanics and Asia-pacific islanders.21,38 The frequency of ENKTL however varies widely depending on study population, e.g. based on data from the international T-cell lymphoma project, ENKTL can be seen up to 8% of T cell lymphomas in Europe and the USA.19 Reports from the U.S. suggest that outcomes may be worse in non-whites.39,40 In an effort to understand if there may be race-based differences in the ENKTL disease process, we evaluated the association between race and outcome, and found no significant differences. According to the 2020 United States Census Bureau statistics, 76.5% of the United States population is white, 13.4% black, 5.9% Asian, 1.3% American Indian or Alaska Native, and 18.3% of Hispanic or Latino ethnicity.41 The race breakdown of the ENKTL patients observed in our study suggest a disproportionately high number of Asian patients were diagnosed with this disease in North America. The latter finding may be attributable in-part to differences in population demographics in areas served by referral centers that participated in this study (e.g. BC Cancer and Stanford University). The absence of race-based survival disparity does suggest a similar disease biology and response to therapy in North American and Asian patients.

The strengths and weaknesses of this study should be highlighted. Given the rarity of this condition this is among one of the largest cohorts of patients with ENKTL diagnosed and treated within North America reported to date.19–21. As a retrospective study, there are significant limitations related to selection biases which led to treatment decisions and the lack of data on potential prognostic factors such IPI, LDH and disease bulk. While diagnoses were made by expert hematopathologists at academic institutions, due to the lack of a central pathology review, we could not confirm the presence of EBV by EBER in all cases. While EBV was even reported as negative in some patients, methods historically used to assess EBV status such as testing for latent membrane protein 1 expression, have been associated with lower sensitivity than EBER in ENKTL tissue samples.42 Thus it is plausible that there may have been some false negative EBV tests within this study timeframe. Detailed characterization of the anatomic extent of the disease was also not available, therefore nasal vs extranasal subtyping could not be discernedl.11 Despite this being a large north American cohort, the sample sizes were inadequate for any meaningful comparison between chemotherapy regimens used or the role of transplant. Finally, the ENKTL patients served by academic centers (a majority of the patients in our cohort) may be different in terms of baseline health, performance status, socioeconomic status, and other variables, resulting in different outcomes compared to the entire population of ENKTL patients. However, the poor overall outcomes observed within the cohort suggest that any differences in baseline variables did not lead to significantly better outcomes for ENKTL patients included in this cohort.

Overall, this study demonstrates that outcomes of ENKTL patients residing in North America are poor and appear to be similar to what is seen in Asia, where this disease is more common. Increased cooperation to improve treatments for this disease through global collaborations are required to better understand the biology and conducting large trials to optimize outcomes.

Supplementary Material

1

Short clinical practice points.

  • Outcomes of ENKTL remain poor in patients with early as well as advanced-stage disease.

  • Race/ethnicity has no effect on outcome for ENKTL patients in North America.

  • Combined modality therapy leads to favorable clinical outcomes in ENKTL patients with early stage disease.

  • International collaboration is crucial for further advances and to improve outcomes of patients with this rare disease.

Acknowledgement

The authors would like to acknowledge the staff of the CCaTS statistical consultation service at Mayo Clinic, for their assistance with statistical methods. This publication was supported by Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Footnotes

The authors declare that they have no competing financial interests in relation to the work described.

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