1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
4Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
5Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
6Division of Hematology and Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
7Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Copyright © 2023 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
This study was reviewed and approved by the Institutional Review Board (IRB approval number: 2019-1476) of the Asan Medical Center (Seoul, South Korea) and Samsung Medical Center (Seoul, South Korea). The requirement of informed consent was waived by the IRBs because of the study’s retrospective nature.
Author Contributions
Conceived and designed the analysis: Suh C.
Collected the data: Kang S, Lee K, Kang EH, Park JS, Lee YS, Park CS, Go H, Huh J, Ryu JS, Lee SW, Kim SJ, Kim WS, Yoon SE, Ko YH, Suh C.
Contributed data or analysis tools: Kang S, Cho H, Lee K, Kang EH, Park JS, Lee YS, Park CS, Go H, Huh J, Ryu JS, Lee SW, Kim SJ, Kim WS, Yoon SE, Ko YH, Suh C.
Performed the analysis: Kang S, Cho H, Suh C.
Wrote the paper: Kang S, Cho H, Suh C.
Review the manuscript: Lee K, Kang EH, Park JS, Lee YS, Park CS, Go H, Ryu JS, Lee SW, Kim SJ, Kim WS, Yoon SE, Ko YH.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Total (n=138) | Low β2M (< 4.1) (n=112) | High β2M (≥ 4.1) (n=26) | p-value | |
---|---|---|---|---|
Age (yr) | ||||
≤ 60 | 94 (68.1) | 77 (68.8) | 17 (65.4) | 0.740 |
> 60 | 44 (31.9) | 35 (31.2) | 9 (34.6) | |
Median (range) | 53.5 (19–80) | 53.5 (19–80) | 54 (25–79) | 0.682 |
Sex | ||||
Male | 86 (62.3) | 71 (63.4) | 15 (57.7) | 0.589 |
Female | 52 (37.7) | 41 (36.6) | 11 (42.3) | |
ECOG PS | ||||
0 or 1 | 129 (93.5) | 109 (97.3) | 20 (76.9) | 0.001 |
≥ 2 | 9 (6.5) | 3 (2.7) | 6 (23.1) | |
Ann Arbor stage | ||||
I or II | 93 (67.4) | 83 (74.1) | 10 (38.5) | 0.001 |
III or IV | 45 (32.6) | 29 (25.9) | 16 (61.5) | |
Lymph node involvement | ||||
None/Regional | 99 (71.7) | 90 (80.4) | 9 (34.6) | < 0.001 |
Distant | 39 (28.3) | 22 (19.6) | 17 (65.4) | |
Non-nasal type | ||||
No | 114 (82.6) | 96 (85.7) | 18 (69.2) | 0.080 |
Yes | 24 (17.4) | 16 (14.3) | 8 (30.8) | |
Bone marrow involvement | ||||
No | 123 (89.8) | 104 (93.7) | 19 (73.1) | 0.006 |
Yes | 14 (10.2) | 7 (6.3) | 7 (26.9) | |
Serum LDH | ||||
Normal | 78 (56.9) | 76 (68.5) | 2 (7.7) | < 0.001 |
Elevated | 59 (43.1) | 35 (31.5) | 24 (92.3) | |
Serum creatinine | ||||
Normal (< 1.5 mg/dL) | 137 (99.2) | 112 (100) | 25 (96.1) | 0.188 |
Elevated (≥ 1.5 mg/dL) | 1 (0.7) | 0 | 1 (3.8) | |
Epstein-Barr virus DNA in blood | ||||
Detectable | 71 (51.4) | 49 (43.7) | 22 (84.6) | < 0.001 |
Non-detectable | 61 (44.2) | 58 (51.7) | 3 (11.5) | |
Unknown | 6 (4.3) | 5 (4.5) | 1 (3.8) | |
Primary treatment | ||||
Chemotherapy alone | 56 (40.6) | 37 (33.0) | 19 (73.1) | < 0.001 |
CCRT alone | 11 (7.97) | 10 (8.9) | 1 (3.8) | |
CCRT followed by chemotherapy | 71 (51.4) | 65 (58.0) | 6 (23.1) | |
PINK risk group | ||||
PINK low | 57 (41.3) | 52 (46.4) | 5 (19.2) | < 0.001 |
PINK intermediate | 37 (26.8) | 33 (29.5) | 4 (15.4) | |
PINK high | 44 (31.9) | 27 (24.1) | 17 (65.4) | |
Extranodal involvement | ||||
0 or 1 | 92 (66.6) | 82 (74.5) | 10 (35.7) | < 0.001 |
≥ 2 | 46 (33.3) | 28 (25.5) | 18 (64.3) | |
Chemotherapy regimen a) | ||||
SMILE | 35 (25.3) | 22 (19.6) | 13 (50.0) | 0.012 |
VIDL | 67 (48.5) | 59 (52.7) | 8 (30.8) | |
VIPD | 15 (10.8) | 13 (11.6) | 2 (7.7) | |
MIDLE | 4 (2.89) | 4 (3.6) | 0 | |
IMEP | 3 (2.1) | 3 (2.7) | 0 | |
DeVIC | 1 (0.72) | 1 (0.9) | 0 | |
DHAP | 1 (0.72) | 0 | 1 (3.8) | |
ESHAP | 1 (0.72) | 0 | 1 (3.8) |
Values ae presented as number (%) or median (range). β2M, serum β-2 microglobulin; CCRT, concurrent chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PINK, Prognostic Index for Natural Killer Lymphoma; PS, performance status.
a) Chemotherapy regimen abbreviations: SMILE, corticosteroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; VIDL, etoposide, ifosfamide, dexamethasone, and L-asparaginase; VIPD, etoposide, ifosfamide, cisplatin, and dexamethasone; MIDLE, methotrexate, ifosfamide, dexamethasone, L-asparaginase, and etoposide; IMEP, ifosfamide, methotrexate, etoposide, and prednisolone; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; DHAP, dexamethasone, cisplatin, and cytarabine; ESAHP, etoposide, corticosteroid, cytarabine, and cisplatin.
Baseline characteristics of the included patients
Total (n=138) | Low β2M (< 4.1) (n=112) | High β2M (≥ 4.1) (n=26) | p-value | |
---|---|---|---|---|
Age (yr) | ||||
≤ 60 | 94 (68.1) | 77 (68.8) | 17 (65.4) | 0.740 |
> 60 | 44 (31.9) | 35 (31.2) | 9 (34.6) | |
Median (range) | 53.5 (19–80) | 53.5 (19–80) | 54 (25–79) | 0.682 |
Sex | ||||
Male | 86 (62.3) | 71 (63.4) | 15 (57.7) | 0.589 |
Female | 52 (37.7) | 41 (36.6) | 11 (42.3) | |
ECOG PS | ||||
0 or 1 | 129 (93.5) | 109 (97.3) | 20 (76.9) | 0.001 |
≥ 2 | 9 (6.5) | 3 (2.7) | 6 (23.1) | |
Ann Arbor stage | ||||
I or II | 93 (67.4) | 83 (74.1) | 10 (38.5) | 0.001 |
III or IV | 45 (32.6) | 29 (25.9) | 16 (61.5) | |
Lymph node involvement | ||||
None/Regional | 99 (71.7) | 90 (80.4) | 9 (34.6) | < 0.001 |
Distant | 39 (28.3) | 22 (19.6) | 17 (65.4) | |
Non-nasal type | ||||
No | 114 (82.6) | 96 (85.7) | 18 (69.2) | 0.080 |
Yes | 24 (17.4) | 16 (14.3) | 8 (30.8) | |
Bone marrow involvement | ||||
No | 123 (89.8) | 104 (93.7) | 19 (73.1) | 0.006 |
Yes | 14 (10.2) | 7 (6.3) | 7 (26.9) | |
Serum LDH | ||||
Normal | 78 (56.9) | 76 (68.5) | 2 (7.7) | < 0.001 |
Elevated | 59 (43.1) | 35 (31.5) | 24 (92.3) | |
Serum creatinine | ||||
Normal (< 1.5 mg/dL) | 137 (99.2) | 112 (100) | 25 (96.1) | 0.188 |
Elevated (≥ 1.5 mg/dL) | 1 (0.7) | 0 | 1 (3.8) | |
Epstein-Barr virus DNA in blood | ||||
Detectable | 71 (51.4) | 49 (43.7) | 22 (84.6) | < 0.001 |
Non-detectable | 61 (44.2) | 58 (51.7) | 3 (11.5) | |
Unknown | 6 (4.3) | 5 (4.5) | 1 (3.8) | |
Primary treatment | ||||
Chemotherapy alone | 56 (40.6) | 37 (33.0) | 19 (73.1) | < 0.001 |
CCRT alone | 11 (7.97) | 10 (8.9) | 1 (3.8) | |
CCRT followed by chemotherapy | 71 (51.4) | 65 (58.0) | 6 (23.1) | |
PINK risk group | ||||
PINK low | 57 (41.3) | 52 (46.4) | 5 (19.2) | < 0.001 |
PINK intermediate | 37 (26.8) | 33 (29.5) | 4 (15.4) | |
PINK high | 44 (31.9) | 27 (24.1) | 17 (65.4) | |
Extranodal involvement | ||||
0 or 1 | 92 (66.6) | 82 (74.5) | 10 (35.7) | < 0.001 |
≥ 2 | 46 (33.3) | 28 (25.5) | 18 (64.3) | |
Chemotherapy regimen
|
||||
SMILE | 35 (25.3) | 22 (19.6) | 13 (50.0) | 0.012 |
VIDL | 67 (48.5) | 59 (52.7) | 8 (30.8) | |
VIPD | 15 (10.8) | 13 (11.6) | 2 (7.7) | |
MIDLE | 4 (2.89) | 4 (3.6) | 0 | |
IMEP | 3 (2.1) | 3 (2.7) | 0 | |
DeVIC | 1 (0.72) | 1 (0.9) | 0 | |
DHAP | 1 (0.72) | 0 | 1 (3.8) | |
ESHAP | 1 (0.72) | 0 | 1 (3.8) |
Values ae presented as number (%) or median (range). β2M, serum β-2 microglobulin; CCRT, concurrent chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PINK, Prognostic Index for Natural Killer Lymphoma; PS, performance status.
a)Chemotherapy regimen abbreviations: SMILE, corticosteroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; VIDL, etoposide, ifosfamide, dexamethasone, and L-asparaginase; VIPD, etoposide, ifosfamide, cisplatin, and dexamethasone; MIDLE, methotrexate, ifosfamide, dexamethasone, L-asparaginase, and etoposide; IMEP, ifosfamide, methotrexate, etoposide, and prednisolone; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; DHAP, dexamethasone, cisplatin, and cytarabine; ESAHP, etoposide, corticosteroid, cytarabine, and cisplatin.
Factors associated with overall survival and progression-free survival
Variable | Overall survival | Progression-free survival | ||||||||||
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Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||||||
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HR | 95% CI | p-value | HR | 95% CI | p-value | HR | 95% CI | p-value | HR | 95% CI | p-value | |
Female | 1.03 | 0.62–1.70 | 0.912 | - | - | - | 0.87 | 0.55–1.37 | 0.541 | - | - | - |
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B symptoms presence | 1.68 | 1.02–2.77 | 0.042 | - | - | - | 1.54 | 0.97–2.43 | 0.065 | - | - | - |
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ECOG PS 2–4 | 7.55 | 3.53–16.14 | < 0.001 | - | - | - | 5.71 | 2.71–12.03 | < 0.001 | - | - | - |
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Age ≥ 60 yr | 1.77 | 1.08–2.90 | 0.024 | 1.87 | 1.10–3.18 | 0.019 | 1.52 | 0.96–2.41 | 0.073 | 1.49 | 0.93–2.41 | 0.092 |
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Stage III–IV | 4.38 | 2.67–7.19 | < 0.001 | 5.69 | 2.88–11.22 | < 0.001 | 3.37 | 2.15–5.28 | < 0.001 | 2.93 | 1.83–4.70 | < 0.001 |
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Non-nasal type | 3.11 | 1.80–5.39 | < 0.001 | 3.13 | 1.56–6.28 | 0.001 | 2.69 | 1.61–4.49 | < 0.001 | 2.14 | 1.26–3.65 | 0.004 |
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Distant LN involvement | 3.22 | 1.96–5.28 | < 0.001 | - | - | - | 2.97 | 1.88–4.68 | < 0.001 | - | - | - |
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Serum LDH ≥ 250 U/L | 2.72 | 1.80–4.08 | < 0.001 | - | - | - | 2.35 | 1.74–4.81 | < 0.001 | - | - | - |
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Serum β2M ≥ 4.1 mg/L | 3.31 | 1.94–5.65 | < 0.001 | 2.87 | 1.58–5.21 | < 0.001 | 2.89 | 1.74–4.81 | < 0.001 | 2.16 | 1.28–3.66 | 0.003 |
B2M, β-2 microglobulin; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; LN, lymph node; PS, performance status.
Stratified models for overall survival and progression-free survival
3-Year overall survival | 3-Year progression-free survival | HR (95% CI) | AIC | C-index (95% CI) | |
---|---|---|---|---|---|
PINK risk group | |||||
Low | 84.1 (75.1–94.2) | 70.6 (59.4–83.8) | Reference | 562.6 | 0.80 (0.73–0.87) |
Intermediate | 54.0 (40.1–72.7) | 43.2 (29.9–62.5) | 3.12 (1.52–6.39) | ||
High | 29.5 (18.7–46.6) | 19.3 (10.5–35.8) | 6.85 (3.50–13.31) | ||
PINK-B risk group | |||||
Low | 84.1 (75.1–94.2) | 70.6 (59.4–83.8) | Reference | 556.9 | 0.82 (0.75–0.89) |
Intermediate | 46.8 (36.1–60.8) | 35.9 (25.9–49.8) | 3.72 (1.93–7.15) | ||
High | 17.6 (6.32–49.2) | 7.35 (1.16–46.7) | 12.6 (5.9–27.04) |
AIC, Akaike Information Criteria; CI, confidence interval; HR, hazard ratio; PINK, Prognostic Index for Natural Killer Lymphoma; PINK-B, Prognostic Index for Natural Killer Lymphoma serum β-2 microglobulin.
Values ae presented as number (%) or median (range). β2M, serum β-2 microglobulin; CCRT, concurrent chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PINK, Prognostic Index for Natural Killer Lymphoma; PS, performance status. Chemotherapy regimen abbreviations: SMILE, corticosteroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; VIDL, etoposide, ifosfamide, dexamethasone, and L-asparaginase; VIPD, etoposide, ifosfamide, cisplatin, and dexamethasone; MIDLE, methotrexate, ifosfamide, dexamethasone, L-asparaginase, and etoposide; IMEP, ifosfamide, methotrexate, etoposide, and prednisolone; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; DHAP, dexamethasone, cisplatin, and cytarabine; ESAHP, etoposide, corticosteroid, cytarabine, and cisplatin.
B2M, β-2 microglobulin; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; LN, lymph node; PS, performance status.
AIC, Akaike Information Criteria; CI, confidence interval; HR, hazard ratio; PINK, Prognostic Index for Natural Killer Lymphoma; PINK-B, Prognostic Index for Natural Killer Lymphoma serum β-2 microglobulin.