Clinical outcome of Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era Ai Sato,1 Naoya Nakamura,2 Minoru Kojima,1 Ken Ohmachi,1 Joaquim Carreras,2 Yara Yukie Kikuti,2 Hiroki Numata,3 Daisuke Ohgiya,4 Kei Tazume,5 Jun Amaki,1 Makiko Moriuchi,6 Mitsuki Miyamoto,1 Yasuyuki Aoyama,1 Hidetsugu Kawai,1 Akifumi Ichiki,1 Ryujiro Hara,1 Hiroshi Kawada,1 Yoshiaki Ogawa1 and Kiyoshi Ando1 Departments of 1Hematology–Oncology, 2Pathology,School of Medicine, Tokai University, Isehara; 3Department of Hematology, Ozawa Hospital, Odawara; 4 Department of Hematology, Ebina General Hospital, Ebina; 5Department of Hematology, Red Cross Hadano Hospital, Hadano; 6Department of Hematology, Atsugi Satoh Hospital, Atsugi, Japan
Key words Diffuse large B-cell lymphoma, Epstein–Barr virus (EBV), prognosis Correspondence Ai Sato, Department of Hematology–Oncology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Tel: +81-463-93-1121; Fax: +81-463-92-4511; E-mail:
[email protected] Funding Information Tokai University. Received February 10, 2014; Revised June 6, 2014; Accepted June 13, 2014 Cancer Sci 105 (2014) 1170–1175 doi: 10.1111/cas.12467
D
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)-positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV-positive DLBCL is controversial. To compare the clinical outcome of EBV-positive and EBV-negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBVencoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV-positive DLBCL patients. The median overall survival and progression-free survival times in patients with EBV-positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression-free survival could not be determined in EBV-negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV-positive DLBCL remains poor, even in the rituximab era.
iffuse large B-cell lymphoma is the most common subtype of malignant lymphoma and accounts for 33% of all cases of malignant lymphoma in Japan.(1) Diffuse large B-cell lymphoma usually arises de novo in lymph nodes, but can also be derived from extranodal organs. The WHO classification describes various special types of DLBCL, and DLBCLs harboring EBV in patients older than 50 years are termed EBV-positive DLBCL of the elderly (EBV-DLBCL of the elderly) as a new category.(2,3) The EBV-DLBCL of the elderly category accounts for 8–10% of all DLBCL in Asian countries,(4) but 1 site) IPI, High intermediate ⁄ High LDH, IU ⁄ L, median (range) LDH ≥ facility upper limit of normal IL2R, U ⁄ mL, median (range) IL2R ≥1000 U ⁄ mL IgG, mg ⁄ dL, median (range) IgA, mg ⁄ dL, median (range) IgM, mg ⁄ dL, median (range) Pathological subtype GCB type Activated B-cell (non-GCB) type NA†
11 6 9 6 12 9 339.5 11 2740 10 1501 226 78
170 38 ⁄ 214 114 ⁄ 216 57 ⁄ 208 121 ⁄ 204 96 ⁄ 202 262.0 135 1300 128 ⁄ 219 1275 251 72
1.0000† 0.0223† 0.5819† 0.1067† 0.0856† 0.2749† 0.1803‡ 0.2580† 0.1146‡ 0.2501† 0.3785‡ 0.8541‡ 0.9227‡
(78.6) (43.9) (64.3) (43.9) (85.7) (64.3) (154–1798) (78.6) (374–6780) (71.4) (561–2510) (128–1473) (20–176)
1 (8.3) 11 (91.7) 2
(75.6) (17.8) (52.8) (27.4) (59.3) (47.5) (132–5310) (60.0) (164–68 800) (58.4) (300–3644) (33–952) (8–1203)
54 (25.0) 162 (75.0) 9
0.3021†
†Fisher’s exact test. ‡Mann–Whitney U-test. ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B cell; IL2R, interleukin 2 receptor; IPI, international prognostic index; LDH, lactate dehydrogenase; NA, not available; PS, performance status. Cancer Sci | September 2014 | vol. 105 | no. 9 | 1171
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Original Article Clinical outcome of EBV(+) DLBCL, rituximab era.
www.wileyonlinelibrary.com/journal/cas
excluded from analysis in this study for the following reasons: 1 case with HIV infection (EBV-positive); 4 cases with a history of methotrexate (EBV-positive, 2 cases; EBV-negative, 2 cases); 4 cases with primary large B-cell lymphoma of the central nervous system (EBV-negative); and 12 cases in which the clinical records were unavailable (EBV-positive, 1 case; EBV-negative, 11 cases). Finally, we analyzed 239 patients that included 14 cases of EBV-positive DLBCL and 225 cases of EBV-negative DLBCL, resulting in an EBV-positive rate of 6.0% (Table 1). Because all EBV-positive DLBCL patients were older than 50 years, they satisfied the criteria of EBV-DLBCL of the elderly. Clinical data are summarized in Table 2. The median age was 71.5 years in EBV-positive patients and 68.0 years in EBV-negative patients (P = 0.3379). The percentages of patients aged over 60 years were 78.6% for EBV-positive and 75.6% for EBV-negative patients (P = 1.0000). The performance status was inferior in EBV-positive patients; the incidence of a performance status >2 in EBV-positive patients was higher than that in EBV-negative patients (43.9% vs 17.8%, respectively; P = 0.0223). Extranodal disease affecting more than two organs was found in 12 ⁄ 14 EBV-positive cases (85.7%) and 121 ⁄ 204 EBV-negative cases (59.3%) (P = 0.0856). Eleven out of 12 EBV-positive cases were non-GCB types (91.7%). In EBV-negative cases, GCB and non-GCB types were found in 54 patients (25.0%) and 162 patients (75.0%), respectively. In EBV-positive DLBCL, seven patients showed latency II and four showed latency III.
Table 3. Summary of therapy and treatment responses in patients with Epstein–Barr virus (EBV)-positive and EBV-negative diffuse large B-cell lymphoma (DLBCL) EBV-positive DLBCL Immunocompetent No treatment Treatment Chemotherapy, no rituximab Radiation Rituximab only R plus chemotherapy R-CHOP R-CHOP-like R-COP R-THP-COP R-CHO R-CHP R-CO No. of chemotherapy cycles, median (range) Response CR PR SD or PD NA
EBV-negative DLBCL
14 3 11 3
225 11 214 8
0 0 8 8 0 0 0 0 0 0 4.5 (1–8)
3 5 198 160 38 16 14 4 2 2 6 (1–8)
2 (25.0%) 2 (25.0%) 4 (50.0%) 0
147 (74.2%) 19 (9.6%) 29 (14.6%) 3
Fig. 1. Overall survival (OS) in immunocompetent Epstein–Barr virus (EBV)-positive versus EBV-negative patients with diffuse large B-cell lymphoma. The median OS in EBV-positive patients was 8.7 months; OS could not be determined in EBV-negative patients. Hazard ratio = 3.9; 95% confidence interval, 4.0–49.3; P < 0.0001.
(a)
(b)
P-value
0.0201†
0.0060‡
†Mann–Whitney U-test. ‡v2-test. C, cyclophospahmide; CR, complete remission; H, doxorubicin; NA, not available; O, vincristine; P, prednisolone; PD, progressive disease; PR, partial response; R, rituximab; SD, stable disease; THP, pirarubicin. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Fig. 2. Survival analysis in patients with diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy regimens similar to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone. (a) Overall survival (OS). The median OS in Epstein–Barr virus (EBV)-positive DLBCL patients was 8.7 months; OS could not be determined in EBV-negative patients. Hazard ratio = 4.3; 95% confidence interval, 3.6–121.6; P = 0.0002. (b) Progression-free survival (PFS). The median PFS in EBV-positive DLBCL patients was 6.8 months; median PFS could not be determined in EBV-negative patients. Hazard ratio = 5.6; 95% confidence interval, 13.0–384.6; P < 0.0001.
Treatment response. The various treatments are shown in Table 3. Both R-CHOP and R-CHOP-like regimens were used for chemotherapy. The R-CHOP and R-CHOP-like regimens were given to 8 ⁄ 14 EBV-positive and 198 ⁄ 225 EBV-negative patients. The median number of R-CHOP cycles was 4 (range, 1–8) in Cancer Sci | September 2014 | vol. 105 | no. 9 | 1172
Age,
Cancer Sci | September 2014 | vol. 105 | no. 9 | 1173
59 ⁄ M
84 ⁄ M
13
14
CS
IVA
IIIB
IIA
IIA
IIIB
IIIB
IIB
IA
IV*
IV*
IIA
IVB
IVA
IIIB
PS
3
1
0
0
1
2
4
0
NA
4
0
4
4
1
HI
H
HI
LI
H
H
LI
HI
LI
HI
LI
LI
HI
HI
IPI
None
intestine
Liver, small
Lung
tumor, rib
Left thoracic
Femur tumor
None
Intraoral ulcer
tissue)
tumor (soft
Abdominal
Liver
++
++
++
+++
+++
++
+++
tumor
+++
Retroperitoneal
+++
+++
++
CD20
Intraoral ulcer
Stomach
pleurae
Skin,
Lung
disease
Extranodal
+
+
NA
CD15
++ NA + NA NA
+ +++ +++ ++
NA +
+++
++
+++
+
+++ +++
++
+++
++
+++ ++
++ +++
+++
+
++
++
+++
+
+++
+
++
++
LMP1
++
ISH
EBER-
+
CD30
NA
NA
NA
+
+
+
+
EBNA2
NA
NA
II
NA
III
II
III
II
II
III
III
II
II
II
Latency
NA
GCB
NA
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
Non-GCB
GCB
GCB ⁄ non-
293
Plasma
Large
219 496
363 316 370 394
HRS cell None
None HRS cell None None Plasma
Poly Large
Large Poly Poly Poly Poly 768 220
None HRS cell
Large Poly
differentiation
249 1677
None None
Large Large
1798
209
None
Poly
differentiation
154
2740
12700
3530
952
NA
9710
1390
4520
6780
3570
374
688
1990
1250
IL2R (U ⁄ mL)
LDH (IU ⁄ L)
Necrosis
Others
Poly
subtype
Morphological
IgG
2418
605
1505
2424
NA
2001
561
634
1573
1421
1279
2510
1501
1069
(mg ⁄ dL)
IgA
454
162
495
305
NA
189
128
174
1473
149
238
396
226
190
(mg ⁄ dL)
IgM
129
42
30
91
NA
113
20
71
67
52
119
78
88
176
(mg ⁄ dL)
COP
COP
No treatment
COP
No treatment
No treatment
R-CHOP
R-CHOP
R-CHOP
R-CHOP
OP
R-CH (THP)
R-CHO
R-CHOP
R-CHOP
Therapy
6
1
0
8
0
0
1
8
3
2
6
6
4
5
cycles
No. of
CR
PD
NA.
PD
NA.
NA.
PD
PR
PD
PD
PD
CR
PR
CR
Response
OS
18.6
0.9
0.0
13.6
0.4
0.0
1.3
7.2
3.0
6.0
10.2
43.7
26.6
44.6
(months)
PFS
15.0
0.9
0.0
10.7
0.4
0.0
1.3
7.2
3.0
2.4
6.7
43.7
6.9
8.6
(months)
Relapse, chose the best supportive care, died
Progressive disease, died
Pneumonia by tumor invasion, died
radiation, died
Relapse, chose the best supportive care after
Chose the best supportive care, died
DIC, cerebral hemorrhage, died
Pneumonia, alveolar hemorrhage, died
Pneumonia, progressive disease, died
Sepsis, progressive disease, died
Refractory to EPOCH ⁄ R-DeVIC, died
MCNU-VP16-Dex, died
Refractory to R-CPA-VP16 ⁄ VP16 ⁄ R-MIT-
Alive, CR
rituximab, alive, 2nd CR
Progressive, treated with CEPP ⁄ VP16 ⁄
2nd CR
Relapsed, treated with Bendamustine, alive,
Outcome
survival; Poly, polymorphous type; PR, partial response; PS, performance status; R, rituximab; THP, pirarubicin; VP16, etoposide.
mediate; IL2R, interleukin 2 receptor; IPI, international prognostic index; Large, large-cell type; LDH, lactate dehydrogenase; LI, low intermediate; LMP, latent membrane protein; M, male; MCNU, ranimustine; MIT, mitoxantrone; NA, not available; OS, overall survival; PD, progressive disease; PFS, progression-free
cyte-colony stimulating factor; Dex, dexamethasone; EBER-ISH, Epstein–Barr virus-encoded RNA in situ hybridization; EBNA, Epstein–Barr virus nuclear antigen antibody; EPOCH, rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone; F, female; GCB, germinal center B cell; H, high; HI, high inter-
CEPP, cyclophosphamide, etoposide, procarbazine, prednisolone; CHO, cyclophosphamide, doxorubicin, vincristine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CPA, cyclophosphamide; CR, complete remission; CS, clinical stage; DeVIC, carboplatin, etoposide, interferon, dexamethasone, granulo-
74 ⁄ M
69 ⁄ F
8
12
55 ⁄ F
7
79 ⁄ M
69 ⁄ M
6
11
77 ⁄ F
5
76 ⁄ M
78 ⁄ F
4
63 ⁄ M
64 ⁄ M
3
9
80 ⁄ F
2
10
59 ⁄ F
gender
years ⁄
1
No.
Table 4. Details of clinical data for patients with Epstein–Barr virus-positive diffuse large B-cell lymphoma (n = 14)
www.wileyonlinelibrary.com/journal/cas Original Article Sato et al.
EBV-positive patients and 6 (range, 1–8) in EBV-negative patients. Treatment was discontinued for various reasons in 5 ⁄ 8 EBV-positive patients and 30 ⁄ 198 EBV-negative patients (P = 0.0201). Among EBV-positive patients, two patients died of infection in the nadir phase during chemotherapy, one patient discontinued treatment due to PD, and one patient refused to continue chemotherapy due to an adverse drug reaction. Two EBV-positive patients showed CR (25%), two showed partial response (25%), and four showed stable disease ⁄ PD (50%). In contrast, 147 EBV-negative patients showed CR (74.2%), 19 patients showed partial response (9.6%), and 29 patients showed stable disease ⁄ PD (14.6%). The overall response rate was better in EBV-negative than EBV-positive patients (P = 0.0060). Survival. The median follow-up time of surviving patients was 25.2 months (range, 0.8–71.3 months). Median OS was 8.7 months in EBV-positive patients and was not reached in EBV-negative patients (P < 0.0001; Fig. 1). Three EBV-positive patients could not receive chemotherapy because their general condition was poor and disease progression was rapid. Median OS and PFS were 8.7 and 6.8 months, respectively, in EBV-positive patients treated with R-CHOP ⁄ R-CHOP-like regimens. Both OS and PFS were worse in EBV-positive patients than in EBV-negative patients (P = 0.0002, P < 0.0001, respectively; Fig. 2). Among eight patients who received R-CHOP ⁄ R-CHOP-like regimens, four died without achieving CR. All three patients with latency III died
